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Zinc deficiency and supplementation in children

Zinc deficiency and supplementation in children
Author:
Steven A Abrams, MD
Section Editor:
B UK Li, MD
Deputy Editor:
Alison G Hoppin, MD
Literature review current through: Jan 2024.
This topic last updated: Nov 09, 2023.

INTRODUCTION — Zinc is an essential trace element that plays a role in growth, tissue repair and wound healing, intestinal mucosal integrity, synthesis of testicular hormones, and the immune response. Zinc intake is closely related to protein intake; as a result, zinc deficiency is an important component of nutritionally related morbidity worldwide. Symptoms attributable to severe zinc depletion include growth failure, diarrhea, primary hypogonadism, skin disease, impaired taste and smell, and impaired immunity and resistance to infection. Zinc supplementation or food fortification in populations at risk for zinc deficiency appears to have beneficial effects on the incidence and outcome of serious childhood infectious diseases.

Zinc participates in numerous catalytic functions as part of 300 metalloenzymes (alkaline phosphatase) and regulation of gene transcription as part of 3000 transcriptase factors. It plays an additional role in maintaining insulin-like growth factor 1 (IGF-1) levels, apart from adequate caloric intake. Zinc is vital to normal anabolic activity including growth, tissue integrity, and wound healing, and, as a result, a deficiency affects rapid turnover areas including skin, intestinal mucosa, gonads, and immune cells.

This topic review will discuss the causes, clinical manifestations, and treatment of zinc deficiency in children, followed by a review of clinical application of zinc supplementation and underlying evidence. Zinc metabolism, actions, and clinical aspects in adults are discussed separately. (See "Overview of dietary trace elements", section on 'Zinc'.)

The use of zinc for cold symptoms, including potential side effects, is discussed separately. (See "The common cold in children: Management and prevention", section on 'Unproven therapies'.)

RECOMMENDED INTAKE

Recommended dietary allowance — The recommended dietary allowance for zinc ranges from 2 mg/day in young infants to 9 mg/day in adolescent females and 11 mg/day in adolescent males (table 1) [1]. Requirements are slightly higher during pregnancy and lactation.

Upper tolerable limit — The upper tolerable limit (UL) describes the upper threshold for chronic intake of zinc that avoids adverse effects. We prefer the ULs set by the World Health Organization (WHO) [2,3], which range from 13 mg/day in older infants, 23 to 34 mg/day in school-aged children, 34 to 36 mg/day in female adolescents and adults, and 40 to 48 mg/day in male adolescents and adults.

These ULs set by the WHO are considerably higher than those established by the National Academy of Medicine (NAM) in the United States more than 20 years ago:

The ULs set by the NAM were based on the concern that zinc competes with copper for absorption in the intestine and chronic intake of high doses of zinc may be associated with copper deficiency. Of note, the NAM's ULs for toddlers are below the usual average zinc intake for this age group in many countries, including the United States.

The ULs recommended by the WHO were based on estimates of the threshold at which zinc intake alters laboratory measures of copper sufficiency. These ULs are well above the dietary zinc intake for most individuals but could be exceeded if high-dose zinc is taken as a supplement [4]. The International Zinc Nutrition Consultative Group also supports higher ULs than those set by the NAM [5].

Note that it may be appropriate to use doses higher than the UL for acute treatment of zinc deficiency or diarrhea. (See 'Treatment' below.)

DIETARY SOURCES — Primary dietary sources of zinc include animal products such as meat and shellfish and certain plant products including chickpeas, cashews, and pumpkin seeds (table 2). Among plant products, fortified ready-to-eat cereal is the most common source of zinc [6]. Sufficient dietary zinc sources are available in a typical mixed diet. Lacto-ovo-vegetarians need more fortified grains or whole grains, legumes, milk, eggs, nuts, and seeds to achieve adequate levels [1,7]. (See "Vegetarian diets for children".)

ZINC DEFICIENCY

Etiology

Dietary zinc deficiency — Inadequate dietary zinc intake is thought to be an important worldwide health problem affecting poor children in resource-limited countries. The true prevalence of mild zinc deficiency is not known, because of the nonspecificity of symptoms and imprecise diagnostic methods.

Risk factors for dietary zinc deficiency include:

Prolonged exclusive breastfeeding – Symptomatic zinc deficiency occasionally occurs in infants who are exclusively breastfed and with delayed introduction of complementary foods beyond six months of age. The risk is increased in populations in which dietary zinc deficiency is common (typically, resource-limited settings or those with minimal meat intake) and in premature infants receiving only unfortified breast milk [8,9]. Other risk factors include malabsorptive disease including intestinal failure. The clinical presentation is similar to that of acrodermatitis enteropathica [10-13]. (See 'Acrodermatitis enteropathica' below.)

Transient neonatal zinc deficiency – This condition is caused by a rare pathogenic variant in the zinc transporter ZnT-2 gene (SLC30A2) [14]. Lactating people with this variant have very low zinc concentration in their breast milk and subsequent zinc deficiency in their breastfed infant [15]. An increasing number of clinical cases and gene abnormalities of the zinc transporter gene have been identified, and this can be considered in the differential diagnosis of infants presenting with signs of zinc deficiency, including growth failure and diarrhea.

Complementary foods with low zinc content – Many complementary foods offered to infants and small children, such as natural grains, have low zinc levels. Increasingly, weaning foods are fortified, but this practice is not widespread, especially in resource-limited countries [16]. The health consequences of subclinical zinc deficiency in infants and young children and benefits of zinc supplementation in this population are discussed below (see 'Supplementation and food fortification in resource-limited settings' below). Use of meat and liver during the first two years of life may provide a practical solution to enhancing zinc as well as iron status for infants in resource-limited countries. (See 'Prevention' below.)

Co-ingestion with phytates and fiber – Dietary phytates, which are present in cereal grains and legumes, interfere with zinc absorption and can contribute to zinc deficiency. This mechanism is seen in populations with diets high in grains and low in meats, such as areas of Africa, the Middle East, and Southeast Asia [17]. As an example, zinc deficiency was first described in adolescent males in Iran and Egypt [18,19]. The depletion was caused by inadequate zinc intake and poor zinc absorption because of the binding of ingested zinc to fiber and phytates in unleavened bread; in some cases, this was exacerbated by ingestion of clay (eating of earth, a form of pica). Affected patients suffered from severe growth retardation, anemia, hypogonadism, rough skin, and apathy or lethargy. The growth retardation and hypogonadism responded to zinc supplementation.

Acrodermatitis enteropathica — Acrodermatitis enteropathica (MIM #201100) is a recessively inherited partial defect in intestinal zinc absorption. It is the result of mutations in the SLC39A4 gene, which encodes a protein that appears to be involved in zinc transport [20,21].

Affected infants develop an erythematous and vesiculobullous dermatitis (picture 1), alopecia, diarrhea, ophthalmic disorders (including corneal scarring, cataract formation, retinal degeneration, and optic atrophy [22]), severe growth retardation, delayed sexual maturation, neuropsychiatric manifestations, and frequent infections (table 3). The syndrome is associated with severe zinc depletion and responds to oral supplementation with pharmacologic doses of zinc.

Underlying medical conditions — Reduced zinc levels, at times symptomatic, have been reported in several other conditions:

Crohn disease and ulcerative colitis – Low plasma zinc concentrations may occur in as many as two-thirds of patients with active Crohn disease [23]. The clinical significance of this observation is not known, although there are case reports of dermatitis resembling acrodermatitis enteropathica with alopecia and eczematous changes that responded to zinc administration [24-26]. Hypogonadism, growth retardation, and abnormalities in taste also have been reported [24]. In a registry study of almost 1000 patients with inflammatory bowel disease, 40 percent were found to have low serum zinc concentrations, defined in this case as a serum zinc <0.66 micrograms/mL [27]. This finding was associated with a range of complications including hospitalizations and surgeries, and normalization of serum zinc was associated with improvement in outcomes. However, these findings may not represent true zinc deficiency, since serum zinc concentrations are reduced in the setting of acute or chronic inflammation. (See 'Diagnosis' below.)

Annual assessment of serum zinc has been recommended in pediatric patients with active inflammatory bowel disease, but specific benefits and the need for supplementation is uncertain, except in clinical circumstances associated with substantial mineral losses (eg, high-volume diarrhea or ostomy losses) or a markedly low serum alkaline phosphatase level [28].

Studies have suggested that zinc absorption is significantly reduced in children with Crohn disease, whereas endogenous fecal zinc excretion and urinary zinc excretion are unchanged [29]. This results in a negative or minimally positive zinc balance in children with Crohn disease. The long-term consequences of this and the optimum level of zinc intake for children with Crohn disease remain unclear. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Monitoring nutritional status' and "Vitamin and mineral deficiencies in inflammatory bowel disease", section on 'Zinc'.)

Cystic fibrosis – Dermatitis caused by zinc deficiency can be a presenting feature of cystic fibrosis in infants [30-32]. The dermatitis resembles acrodermatitis enteropathica but may be more widespread and may not respond to zinc supplementation alone [33]. Concomitant deficiencies in essential fatty acids or protein-energy malnutrition also may contribute to the dermatitis. An empiric trial of zinc supplementation has been suggested for cystic fibrosis patients with symptoms that may be attributable to zinc deficiency (growth retardation in young children, increased susceptibility to infections, delayed sexual maturation, anorexia), as outlined in consensus guidelines [34,35]. (See "Cystic fibrosis: Nutritional issues", section on 'Zinc'.)

Sickle cell disease – Low zinc levels can occur in children and adolescents with sickle cell disease, particularly in association with poor or delayed growth [36,37]. 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 [37,38]. Whether zinc deficiency promotes infection in children with sickle cell disease remains controversial [39]. A Cochrane review has found evidence of decreases in sickle cell crisis events with zinc supplementation [40]. An ongoing study is looking at the possible benefits of zinc supplementation in children <5 years of age (NCT03528434).

Liver disease – Low plasma zinc levels in children and adults with severe chronic liver disease may be related to hypoalbuminemia, reduced intake, and increased urinary excretion [41-43]. There is some evidence indicating that zinc supplementation in patients with hepatic encephalopathy improved cognitive function [44]. The low plasma concentration and the increased urinary excretion correct within seven days of liver transplantation [41,42].

Parenteral nutrition/intestinal failure – Children, including premature infants, receiving parenteral nutrition for intestinal failure are at risk for zinc deficiency if the parenteral nutrition has insufficient zinc concentrations (eg, due to a shortage of injectable zinc). They are also at risk for zinc deficiency after stopping the parenteral nutrition if they have ongoing zinc malabsorption due to the underlying intestinal disease [45]. A case series in children with intestinal failure weaned off of parenteral nutrition found 67 percent to be zinc deficient, indicating that intestinal failure alone can be the sole cause [46]. A case series described three premature infants with cholestasis who developed clinical zinc deficiency consisting of diaper dermatitis, perioral erosions, and bullae on the dorsal surface of the hands and feet due to insufficient parenteral zinc concentrations [47].

Kidney disease – Zinc deficiency caused by increased urinary excretion can complicate nephrotic syndrome in children [48]. 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 [49,50].

Clinical manifestations — Numerous signs and symptoms have been associated with zinc depletion (table 3). Mild zinc deficiency is associated with depressed immunity, impaired taste and smell, onset of night blindness, decreased spermatogenesis, and, sometimes, a mild psoriasiform dermatitis. Severe zinc deficiency is characterized by dermatitis (typically erythematous, scaly, vesiculobullous, or pustular lesions in the perioral and perianal areas or on extensor surfaces of the limbs), severely depressed immune function, frequent infections, diarrhea, and alopecia (picture 2) [51-53]. Experimental zinc deficiency has been produced in normal volunteers by restricting zinc intake [54]. They developed primary hypogonadism with decreased serum androgens, increased serum gonadotropins, and oligospermia. (See "Overview of dietary trace elements", section on 'Deficiency'.)

The importance of zinc in immune function is suggested by studies showing benefits of zinc for treatment or prevention of diarrhea or pneumonia in children in resource-limited settings, as discussed below. (See 'Supplementation and food fortification in resource-limited settings' below.)

Diagnosis — Measurement of plasma zinc concentration is the most useful clinical test for zinc deficiency, despite limited sensitivity and specificity. However, this test often requires venipuncture and is not readily analyzed in many clinical laboratories, because sample contamination may occur. This makes it unsuitable for a routine screening test for healthy children without a clear medical indication. Because zinc is a cofactor for alkaline phosphatase activity, depressed serum alkaline phosphatase levels for age provide supportive evidence for zinc deficiency [55]. In specific clinical cases in which the zinc level is normal, a clinical response to zinc supplementation may confirm a diagnosis of zinc deficiency. In other situations, the diagnosis of zinc depletion is inferred by the response to zinc supplementation in placebo-controlled intervention (see 'Supplementation and food fortification in resource-limited settings' below). Additionally, lower zinc levels in acute and chronic infections may occur as part of the inflammatory response as acute phase reactants redistribute zinc from plasma to intracellular spaces. If this is a concern (eg, in patients with inflammatory bowel disease), it may be helpful to interpret serum zinc concentrations in combination with a marker of inflammation such as C-reactive protein, although adjustments for C-reactive protein are not commonly used clinically [56].

Low plasma zinc has been defined as <60 micrograms/dL (<9.2 micromol/L) [57]. However, subsequent analyses have suggested a higher threshold of 65 or 70 micrograms/dL (9.9 or 10.7 micromol/L) from morning samples [58,59]. Although plasma zinc concentration is moderately correlated with habitual intake, the test also has limited specificity because zinc levels are depressed during inflammatory disease states or pregnancy and increase with acute catabolic states [60]. Moreover, the test has limited sensitivity since patients with mild zinc deficiency may have normal plasma levels [61]. In general, its use should be limited to clear clinical indications and results interpreted based on the underlying reason for the evaluation. If it is performed, precautions are taken to avoid contamination of the sample by using a zinc-free collection tube.

In patients with hypoalbuminemia, measured zinc levels are typically decreased because most plasma zinc is bound to albumin. However, it is not clinically helpful to correct measured zinc levels for hypoalbuminemia, provided that patients with low plasma zinc levels are treated empirically with zinc supplements regardless of albumin levels.

Zinc levels may also be measured in neutrophils, lymphocytes, or erythrocytes, but these assays generally have poor sensitivity [1,62]. When measured in neutrophils, zinc deficiency is defined as <42 mcg/1010 cells [63]. When measured in lymphocytes, zinc deficiency is defined as <50 mcg/1010 cells [63].

Treatment

Inadequate intake or underlying conditions – For zinc deficiency due to inadequate oral intake, a typical oral replacement dose is 1 to 2 mg/kg/day of elemental zinc [64,65]. Resolution usually requires at least four to six weeks of therapy, depending on the etiology and severity. In some cases, it is necessary to co-administer copper to ensure that copper deficiency does not occur due to high zinc intake. These replacement doses are also appropriate for patients with underlying diseases that predispose to zinc deficiency, such as Crohn disease, cystic fibrosis, liver disease, or sickle cell disease. Note that it is acceptable if these short-term replacement doses exceed the upper tolerable limit (UL) for zinc, which refer to chronic intake of zinc. (See 'Zinc toxicity' below.)

Infants receiving long-term parenteral nutrition or those with intestinal failure may need additional zinc added to their parenteral nutrition or given orally, with close monitoring of serum zinc levels [46].

Acrodermatitis enteropathica – For acrodermatitis enteropathica, higher replacement doses are recommended: approximately 3 mg/kg/day of elemental zinc (13.2 mg/kg/day of zinc sulfate or 10.1 mg/kg/day of zinc acetate) [66,67]. We suggest measuring zinc levels every three to six months and adjusting the dose up or down as needed. Patients with acrodermatitis enteropathica require these high doses to overcome the defect in intestinal zinc absorption. (See 'Acrodermatitis enteropathica' above.)

Toxicity from zinc supplementation is rare, although long-term administration of high doses may lead to deficiencies of other minerals including iron and copper. Ingestion of up to 10 times the recommended daily intake produces no symptoms. (See 'Zinc toxicity' below.)

Prevention — Local foods that are naturally rich in zinc may prove to be an important solution to dietary zinc depletion and its health consequences (table 2). For infants, the use of meat and liver as a first food for infants may provide a practical solution in resource-limited countries [16]. This approach was explored in two studies of healthy breastfed infants in the United States, in which infants were randomized to be fed with either fortified cereal or beef as a first complementary food from age four to seven months [68,69]. Both diets provided estimated requirements of zinc and iron, and there were no differences in infant tolerance or acceptance or in serum zinc levels. These findings suggest that meat or liver may provide a practical solution to zinc and iron deficiency in resource-limited countries, if social, cultural, and economic barriers to this practice can be addressed by public health initiatives.

SUPPLEMENTATION AND FOOD FORTIFICATION IN RESOURCE-ABUNDANT SETTINGS

Supplementation – Routine zinc supplementation is not necessary or recommended for healthy infants and children in resource-abundant settings, where the risk of zinc deficiency is low. In these settings, zinc supplementation is generally limited to individuals with documented zinc deficiency or acrodermatitis enteropathica. Targeted testing for zinc deficiency or empiric supplementation may be appropriate for patients with an increased risk for zinc deficiency due to an underlying medical condition, as outlined above. (See 'Underlying medical conditions' above.)

Similarly, in these resource-abundant settings, empiric zinc supplementation does not appear to be beneficial for children with acute or persistent diarrhea, pneumonia, idiopathic growth failure, or other conditions [70]. This is in contrast with the case for children in resource-limited settings, as outlined in the next section.

Fortification – For most children, adequate zinc is supplied by widespread fortification of commonly used foods, such as breakfast cereals. As an example, among older infants enrolled in the Special Supplemental Nutrition Program in the United States, only 2 percent had inadequate zinc intake due to zinc fortification of foods provided by this program [71].

SUPPLEMENTATION AND FOOD FORTIFICATION IN RESOURCE-LIMITED SETTINGS — Zinc deficiency, associated with impaired immunity and propensity to infection, is thought to be common in children in resource-limited countries, where children also 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 [72].

Zinc is often provided via fortified foods including weaning foods. A meta-analysis showed that zinc fortification reduced the prevalence of zinc deficiency (odds ratio 0.76, 95% CI 0.60-0.96) and increased child weight (mean weight gain attributable to supplements 0.43 kg, 95% CI -0.11 to 0.75 kg) [73]. In many of the included studies, the fortification of foods was done with multiple micronutrients, so the findings may not reflect an independent effect of zinc supplementation.

Likely beneficial effects

Treatment of acute or persistent diarrhea — We agree with the World Health Organization (WHO) recommendation of zinc supplementation for children with acute diarrhea in resource-limited settings [74]. Dosing, supporting evidence, and other considerations are discussed separately. (See "Approach to the child with acute diarrhea in resource-limited settings", section on 'Vitamins and minerals'.)

Few data are available regarding the role of zinc in recovery from acute diarrhea in resource-abundant settings. Available data suggest that there is little or no benefit, but much larger and well-controlled trial data are needed [70].

Prevention of diarrhea — Numerous studies in resource-limited countries have shown that routine oral zinc supplementation reduces the incidence of diarrheal disease and diarrhea-related mortality in populations with high risk for zinc deficiency [72,75-82]. A meta-analysis found that supplementation modestly reduced the incidence of diarrhea in children 6 months to 12 years of age (risk ratio [RR] 0.91, 95% CI 0.90-0.93; 39 studies) [83]. A few trials in infants also suggest that zinc supplementation has a small protective effect on the risk for diarrhea [82,84,85]. One placebo-controlled study found that two weeks of zinc supplementation in infants aged 6 to 11 months in India reduced the frequency of diarrheal episodes by 39 percent and duration of the episodes by 36 percent [84].

Zinc supplementation given to pregnant women reduces the frequency of diarrhea in their offspring during infancy. In a placebo-controlled trial in Peru, infants whose mothers received prenatal zinc supplementation had a 34 percent lower risk of prolonged diarrheal episodes compared with controls [86]. In a similar trial in Bangladesh, prenatal zinc supplementation reduced the infant's risk for acute diarrhea by 16 percent and dysentery by 64 percent [87].

Prevention of pneumonia — A meta-analysis found that zinc supplementation given to children between two months and five years of age in resource-limited countries reduced the incidence of clinically confirmed pneumonia by approximately 20 percent (RR 0.79, 95% CI 0.71-0.88) [80,88]. The included studies were performed in Bangladesh, India, Peru, and South Africa. One study found a shorter course of pneumonia in children under five years of age in Mexico [89].

Unclear or marginal benefits

Enhancement of growth — Studies evaluating zinc supplementation in children at risk for zinc deficiency suggest that zinc supplementation probably enhances growth in young infants and has modest effects on growth in older children. A meta-analysis that focused on multinutrient supplementation also showed only modest growth benefits [90].

Young infants – A meta-analysis of studies conducted in infants less than six months of age in resource-limited countries found that oral zinc supplements improved growth, as measured by weight-for-age, weight-for-length, and weight-for-length Z-scores [91]. This meta-analysis was limited to a few studies, with substantial dropouts and other limitations noted. Further studies would be needed to assess this population before supplements could be recommended for this population.

Older infants – The above finding contrasts with a large randomized trial that studied infants up to 18 months of age in Tanzania, in which zinc supplementation alone (5 mg daily) had a slight negative effect on growth [92]. The combination of zinc with a multivitamin supplement (without iron) had a small positive effect on weight gain. The authors speculate that zinc supplements were not helpful in this age group because infants had adequate zinc intake through breast milk and the supplements may have interfered with absorption of other nutrients such as copper and iron. In this population, zinc or multivitamin supplementation had no effect on measures of cognition at 15 months of age [93]. Thus, the effect of zinc supplementation may depend on the age group and presence of other micronutrients such as iron. These data serve as cautionary evidence about the possible risks of single-nutrient interventions.

Young children – A meta-analysis focusing on children younger than five years of age from resource-limited countries found modest positive effects of zinc on linear growth, but this effect was attenuated in children given concurrent iron supplementation [94]. The doses of zinc used in these trials varied from 1 to 20 mg/day of elemental zinc, with a median of 10 mg/day. A subsequent meta-analysis also reported modest benefits of zinc supplementation on height and weight, with greater effects among children two to five years of age compared with those under two years of age [95].

School-aged children – A systematic review of more than 80 randomized trials from resource-limited countries found modest positive effects of zinc supplementation on height in children between 6 months and 12 years of age, although the benefits were greater for older children (>5 years) compared with younger children and infants [81]. Zinc supplementation had negative effects on copper status and increased risk for vomiting.

Zinc has no effect on growth in individuals without an underlying zinc deficiency (ie, it has no pharmacologic effect on growth) [96,97].

Adjunctive treatment for pneumonia or other bacterial infection — Studies conflict regarding the utility of adjunctive zinc for children with pneumonia. Several studies failed to show a benefit of adjunctive zinc supplementation on treatment failure or time to recovery [98,99].

By contrast, a study in 700 young infants (7 to 120 days old) in India with serious bacterial infections (pneumonia, sepsis, and diarrhea) suggests a beneficial effect of adjunctive zinc [100]. All subjects were treated with antibiotics according to a standardized protocol. Infants who were also treated with zinc (5 mg twice daily by mouth) had significantly less treatment failure as compared with those treated with placebo (10 versus 17 percent, respectively); treatment failure was defined as a need to change antibiotics within seven days of randomization or a need for intensive care, or death at any time within 21 days. The absolute risk reduction was 6.8 percent (95% CI 1.5-12.0). The population in this study had a high rate of underlying nutritional zinc deficiency, and whether adjunctive zinc treatment for bacterial infection is beneficial in other populations has not been established.

Prevention or treatment of malaria — A meta-analysis that included three randomized trials with more than 1700 children failed to show an effect of zinc supplementation on malarial parasitemia [101]. 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 [102]. However, the analysis raised the possibility that there may be benefit in subgroups of children.

Although zinc levels tend to decrease during the acute phase response in children with falciparum malaria [103], zinc supplementation does not appear to have a beneficial effect when used as an adjunct to treatment of the disease [104]. (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children" and "Treatment of severe malaria".)

ZINC TOXICITY — Little toxicity occurs with zinc supplementation. Ingestion of up to 10 times the recommended daily intake produces no symptoms. Chronic intake of high doses of zinc may be associated with copper deficiency because zinc inhibits intestinal absorption of copper. (See 'Recommended intake' above.)

The acute ingestion of 1 to 2 g zinc sulfate produces nausea and vomiting associated with irritation and corrosion of the gastrointestinal tract [105]. Large doses of zinc compounds also can produce acute renal failure caused by tubular necrosis or interstitial nephritis [106]. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin deficiencies".)

SUMMARY

Dietary sources of zinc – Primary dietary sources of zinc include animal products such as meat, seafood, milk, and fortified foods such as breakfast cereal (table 2). Sufficient dietary zinc sources are available in a typical mixed diet. Adequate zinc can also be obtained from a balanced lacto-ovo-vegetarian diet that includes foods rich in zinc, including zinc-fortified cereals, legumes, nuts, seeds, eggs, and milk. (See 'Recommended intake' above.)

Clinical manifestations – Symptoms attributable to severe zinc depletion include growth failure, primary hypogonadism, impaired taste and smell, and impaired immunity (table 3). Severe zinc deficiency is characterized by severely depressed immune function, frequent infections, dermatitis (typically in the perioral and perianal areas), diarrhea, and alopecia (picture 2). (See 'Clinical manifestations' above.)

Causes of zinc deficiency

Dietary deficiency – Zinc depletion primarily occurs in resource-limited countries, where complementary foods typically provide inadequate amounts of bioavailable zinc. Symptomatic zinc deficiency occasionally occurs in infants who are exclusively breastfed with delayed introduction of complementary foods beyond six months of age, especially in premature infants and in populations with underlying zinc deficiency. (See 'Dietary zinc deficiency' above.)

Genetic – Acrodermatitis enteropathica is a recessively inherited partial defect in intestinal zinc absorption. Affected infants develop an erythematous and vesiculobullous dermatitis (picture 1), alopecia, ophthalmic disorders, diarrhea, and severe growth retardation. The syndrome responds to oral supplementation with pharmacologic doses of zinc. (See 'Acrodermatitis enteropathica' above and 'Treatment' above.)

Medical conditions – Reduced zinc levels, at times symptomatic, have been reported in malabsorptive conditions (Crohn disease, cystic fibrosis, intestinal failure), sickle cell disease, severe liver disease, kidney disease (nephrotic syndrome), and children maintained on parenteral nutrition without zinc supplementation. (See 'Underlying medical conditions' above.)

Diagnosis – Plasma zinc concentrations are the most useful clinical test for zinc deficiency, despite limited sensitivity and specificity. A low plasma zinc concentration usually is defined as a value less than 60 to 65 mcg/dL. Because much of plasma zinc is bound to albumin, zinc levels will be somewhat reduced in patients with hypoalbuminemia. (See 'Diagnosis' above.)

Treatment – For children with documented zinc deficiency, replacement doses of zinc are 1 to 2 mg/kg/day of elemental zinc for at least four to six weeks. (See 'Treatment' above.)

Approach in resource-limited settings

Routine supplementation – Zinc deficiency is common in children in resource-limited countries, and zinc deficiency appears to contribute to the risk of diarrhea and pneumonia in these populations. Routine oral zinc supplementation, often done via food fortification, reduces the incidence of these disorders. (See 'Supplementation and food fortification in resource-limited settings' above.)

Acute diarrhea – We suggest zinc administration to treat acute or persistent diarrhea in children from populations in which zinc deficiency is common (Grade 2B). Zinc administration slightly reduces the duration of diarrhea but also may cause vomiting. We use a dose of 10 mg daily for 10 to 14 days for children >6 months; this dose is as effective as the traditional 20 mg dose but is less likely to cause vomiting. There is less evidence that zinc supplementation is useful for enhancement of growth or prevention or treatment of malaria. (See 'Treatment of acute or persistent diarrhea' above and 'Unclear or marginal benefits' above.)

Zinc toxicity – Little toxicity occurs with zinc supplementation. Ingestion of up to 10 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/day may be associated with copper deficiency. (See 'Zinc toxicity' above.)

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Topic 5354 Version 34.0

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