complementary and  

alternative medicine

Zinc: An Essential Micronutrient

ROBERT B. SAPER, MD, MPH, and REBECCA RASH, MA, Boston University School of Medicine, Boston, Massachusetts

Zinc is an essential micronutrient for human metabolism that catalyzes more than 100 enzymes, facilitates protein
folding, and helps regulate gene expression. Patients with malnutrition, alcoholism, inflammatory bowel disease, and
malabsorption syndromes are at an increased risk of zinc deficiency. Symptoms of zinc deficiency are nonspecific,
including growth retardation, diarrhea, alopecia, glossitis, nail dystrophy, decreased immunity, and hypogonadism
in males. In developing countries, zinc supplementation may be effective for the prevention of upper respiratory infec-
tion and diarrhea, and as an adjunct treatment for diarrhea in malnourished children. Zinc in combination with
antioxidants may be modestly effective in slowing the progression of intermediate and advanced age-related macular
degeneration. Zinc is an effective treatment for Wilson disease. Current data do not support zinc supplementation as
effective for upper respiratory infection, wound healing, or human immunodeficiency virus. Zinc is well tolerated at
recommended dosages. Adverse effects of long-term high-dose zinc use include suppressed immunity, decreased high-
density lipoprotein cholesterol levels, anemia, copper deficiency, and possible genitourinary complications. (Am Fam
Physician. 2009;79(9):768-772. Copyright © 2009 American Academy of Family Physicians.)

Z
inc is the second most abun- properties and may protect against macular
dantly distributed trace element degeneration from oxidative stress.9
in the body after iron.1 Zinc cata-
lyzes enzyme activity, contributes Uses and Effectiveness
to protein structure, and regulates gene ZINC DEFICIENCY
expression.2 It is found in a variety of foods, Zinc deficiency caused by malnutrition is the
such as beef, poultry, seafood, and grains.2,3 11th major risk factor in the global distribu-
Commercial zinc supplements contain tion of disease burden and is associated with
7 to 80 mg of elemental zinc, and are com- 1.8 million deaths annually.10 Serum zinc
monly formulated as zinc oxide or salts with levels are not a reliable measure of zinc stores
acetate, gluconate, and sulfate. In the 2002 and, therefore, are not recommended for
National Health Interview Survey, 2.5 per- routine screening. A presumptive diagnosis
cent of adults reported using zinc supple- of zinc deficiency can be made in the context
ments in the previous year.4 Multivitamins of zinc-deficiency symptoms, signs of mal-
were used by 62 percent of adults and con- nutrition (e.g., underweight, hypoalbumin-
tain 7.5 to 15 mg of elemental zinc.4 Zinc emia), or conditions commonly associated
supplements are commonly used to allevi- with zinc deficiency (Table 1).1,2 A meta-
ate a number of conditions, including zinc- analysis of 33 randomized controlled trials
deficient states, diarrhea, age-related macu- (RCTs) enrolling prepubertal children from
lar degeneration, upper respiratory infec- North and South America, Europe, Africa,
tion (URI), wound healing, and human and Asia who were at risk of zinc deficiency
immunodeficiency virus (HIV). showed that zinc supplementation modestly
enhanced linear growth and weight gain
Pharmacology (effect sizes of 0.35 and 0.31, respectively)
Zinc is absorbed in the small intestine. Pro- compared with the control group.11
longed, severe decreases or increases in zinc
DIARRHEA
intake are necessary to substantially affect
zinc stores.5 Zinc is a cofactor for polymer- A meta-analysis of 22 RCTs of zinc supple-
ases and proteases involved in many cellular ments versus placebo for the treatment of
functions (e.g., wound repair,6 intestinal epi- diarrhea in children from developing coun-
thelial cell regeneration).7 Zinc is also a cofac- tries found an 18 percent reduction of diar-
tor for thymulin, a thymic hormone essential rhea symptoms compared with placebo.12
for T-cell maturation.8 Zinc has antioxidant A meta-analysis of 15 prevention studies

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 Zinc

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

Zinc reduces the severity and duration of acute and chronic diarrhea in children from developing countries. A 12, 13
Zinc acetate is an effective maintenance therapy for Wilson disease. B 35, 36
Clinical zinc deficiency in adults should be treated with zinc supplements at two to five times the C 40, 41
recommended dietary allowance.
Zinc in combination with vitamins C and E, and beta-carotene may slow the progression of B 14
intermediate and advanced age-related macular degeneration.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.
org/afpsort.xml.

demonstrated that zinc supplementation conferred a light-sensitive cells and support tissues with or without
14 percent reduced risk in the incidence of diarrheal epi- blood vessel fragility and edema [“wet” or “dry” age-
sodes compared with placebo.13 It is uncertain if zinc’s related macular degeneration, respectively]), the zinc plus
effect on diarrhea is because of an independent effect or antioxidant group had a modest reduced risk of worsen-
repletion of zinc deficiency. No data are available for zinc ing visual acuity compared with placebo (27 percent,
and childhood diarrhea in industrialized countries. P = .008). However, there were increased hospitalizations
because of urinary tract infections and nephrolithiasis
AGE-RELATED MACULAR DEGENERATION in the two zinc arms versus non-zinc arms (11.1 versus
The evidence supporting zinc and antioxidants for slow- 7.6 percent; P = .003).16 It would be prudent for smokers
ing the progression of age-related macular degeneration at risk of advanced age-related macular degeneration to
comes predominantly from the Age-Related Eye Disease refrain from taking the beta-carotene component because
Study (AREDS).14,15 AREDS randomized 3,640 mostly of the increased risk of lung cancer in smokers taking
well-nourished adults 55 to 80 years of age with age-related this supplement.17 The value of zinc plus antioxidants is
macular degeneration to oral zinc oxide, antioxidants unknown in persons younger than 55 years, those with a
(vitamin C, vitamin E, beta-carotene), zinc plus anti- family history of age-related macular degeneration, and
oxidants, or placebo. For participants with intermediate those with a different nutritional status.
age-related macular degeneration (i.e., many medium- There are no published RCTs addressing zinc for the
sized drusen or at least one large drusen) or advanced primary prevention of early age-related macular degen-
age-related macular degeneration (i.e., breakdown of eration.18 Results of prospective cohort studies are
mixed. A meta-analysis of four such studies found an
odds ratio of 0.91 (95% confidence interval [CI], 0.74
Table 1. Characteristics of Zinc Deficiency to 1.11) for the association between high zinc intake
and early age-related macular degeneration.19 A sub-
Symptoms sequent cohort study found the highest decile of zinc
Growth retardation, delayed puberty, erectile dysfunction, intake for Australian adults to be associated with a
diarrhea, alopecia, glossitis, nail dystrophy, hypogonadism 44 percent reduction in the risk of age-related macular
(in males), decreased immunity1,2 degeneration.20
Associated diseases
Crohn disease, celiac disease, chronic alcoholism, cirrhosis, URI
sickle cell disease, acrodermatitis enteropathica
A meta-analysis including 12 RCTs with a total of 5,512
Associated conditions
children in developing countries found a reduction in URI
Pregnancy, lactation, prolonged intravenous feeding, vegan
diet, short bowel syndrome, history of intestinal surgery
incidence in those using zinc supplements compared with
(e.g., gastric bypass) placebo (8 percent; 95% CI, 1 to 15 percent).13 Regarding
treatment, a meta-analysis of eight RCTs with 890 pre-
Information from references 1 and 2. dominantly adult participants with URI in industrialized
countries who were treated with zinc lozenges found no

May 1, 2009 ◆ Volume 79, Number 9 www.aafp.org/afp American Family Physician  769
Zinc

evidence of a statistically significant reduction in dura- OTHER USES

tion.21 Methodologic problems included poor blinding, Zinc deficiency is associated with the rapid progression
small sample size, high drop-out rates, and variability of HIV.32 However, most RCTs of zinc in persons who
in zinc dosage and formulation. Subsequent studies in are HIV positive have shown no increase in CD4 cell
adults22-25 and children26,27 showed similarly mixed results. counts or decrease in viral load.33,34 Wilson disease can
Overall, robust data are lacking for the effectiveness of be successfully treated with zinc because of its ability
zinc lozenges in reducing the duration or severity of URI. to compete with copper for binding sites.35 Zinc acetate
has been shown to be effective in the long-term treat-
WOUND HEALING ment of Wilson disease and is approved by the U.S. Food
Zinc deficiency is associated with impaired wound heal- and Drug Administration for maintenance therapy.36
ing.28 Although zinc is a common ingredient in topical Although oral zinc has been used for acne, minocycline
products used to treat skin conditions such as ulcers, (Dynacin) is twice as effective.37
diaper rash, and hemorrhoids, relatively few studies sup-
port its use for accelerating wound healing. An RCT of Contraindications, Adverse Effects,  
46 infants with diaper dermatitis found no significant and Interactions
difference in resolution between zinc oxide ointment Chronic ingestion of zinc supplements up to the toler-
and ointment base alone.29 A meta-analysis of 181 par- able upper intake level (40 mg elemental zinc per day in
ticipants from six RCTs of oral zinc sulfate versus pla- adults) is generally considered safe. Use of zinc supple-
cebo for venous or arterial leg ulcers found no significant ments above the tolerable upper intake level in well-
difference in time to ulcer resolution.30 An RCT compar- nourished pregnant and lactating women is contraindi-
ing surgical mesh impregnated with zinc oxide ointment cated.2 Common adverse effects of excessive zinc intake
versus mesh with ointment base alone found no statisti- include metallic taste, nausea, vomiting, abdominal
cally significant difference in time to secondary closure cramping, and diarrhea (Table 2).2 Prolonged exposure
of pilonidal surgery wounds.31 to amounts greater than the tolerable upper intake level

Table 2. Key Points About Zinc Supplements

Effectiveness Probably effective: zinc deficiency; Wilson disease

Possibly effective: slow progression of age-related macular degeneration; childhood diarrhea and URI in
developing countries
Probably ineffective: URI, wound healing, human immunodeficiency virus
Adverse effects Metallic taste, nausea, vomiting, abdominal cramping, diarrhea, suppressed immunity, reduced levels of
high-density lipoprotein cholesterol, decreased copper stores, urinary tract infection, nephrolithiasis
Interactions Penicillamine (Cuprimine), tetracyclines, quinolones; decreased copper absorption
Contraindications Use with caution in pregnant and lactating women
Dose* Zinc deficiency: two to five times the recommended dietary allowance† (depending on severity) for six months
Diarrhea: 5 to 20 mg
Age-related macular degeneration: 80 mg of elemental zinc with 2 mg of copper, 500 mg of vitamin C,
400 IU of vitamin E, 15 mg of beta-carotene
Dose should not exceed the tolerable upper intake level‡ for prolonged periods
Cost $4 to 15 for three-month supply
Bottom line Safe at doses less than or equal to the tolerable upper intake level‡; useful for zinc deficiency, Wilson disease,
and childhood diarrhea in malnourished populations; possibly useful in combination with antioxidant
supplements for slowing the progression of age-related macular degeneration

URI = upper respiratory infection.

*—All doses are for milligrams of elemental zinc per day.
†— Recommended dietary allowance 2 (by age) = 0 to 6 months: 2 mg; 7 months to 3 years: 3 mg; 4 to 8 years: 5 mg; 9 to 13 years: 8 mg; 14 to
18 years: 11 mg (boys), 8 mg (girls); older than 19 years: 11 mg (men), 8 mg (women); pregnancy: 11 mg; lactation: 12 mg.
‡—Tolerable upper intake level per day 2 (by age) = 0 to 6 months: 4 mg; 7 to 12 months: 5 mg; 1 to 3 years: 7 mg; 4 to 8 years: 12 mg; 9 to 13 years:
23 mg; 14 to 18 years: 34 mg; older than 18 years: 40 mg.

770  American Family Physician www.aafp.org/afp Volume 79, Number 9 ◆ May 1, 2009
 Zinc

may suppress immunity, decrease high-density lipopro- effective preventive measure for diarrhea and URI, and
tein cholesterol levels, and cause hypochromic micro- an adjunct treatment for diarrhea. Zinc has been shown
cytic anemia and copper deficiency.38 Furthermore, the to be an effective treatment for Wilson disease. No con-
Health Professionals Follow-up Study of 46,974 adult sistent benefit of zinc has been found for treatment of
men found a 2.3 increased relative risk of advanced pros- URI, wound healing, or HIV. Ongoing zinc supplemen-
tate cancer in men using elemental zinc in amounts of tation up to the tolerable upper intake level is generally
100 mg per day or more.39 Zinc may inhibit absorption safe. Higher doses should be limited to short-term use
of penicillamine (Cuprimine), tetracyclines, and quino- because of an increased risk of gastrointestinal adverse
lones. Iron supplements and phytates, found in grains effects, copper deficiency, anemia, and genitourinary
and legumes, can inhibit zinc absorption and should be complications.
taken at least two hours apart from zinc supplements. Members of various family medicine departments develop articles for
“Complementary and Alternative Medicine.” This is one in a series coor-
Dosage dinated by Sumi Sexton, MD, and Benjamin Kligler, MD, MPH.
Mild zinc deficiency should be treated with zinc supple-
mentation at two to three times the recommended dietary The Authors
allowance (RDA), whereas moderate to severe deficiency
ROBERT B. SAPER, MD, MPH, is an assistant professor of family medi-
can be treated at four to five times the RDA.40,41 Treat- cine at Boston University School of Medicine, Boston, Mass., and director
ment should last for six months. For acute diarrhea in of integrative medicine in the Department of Family Medicine at Boston
malnourished children six to 36 months of age, 20 mg Medical Center. Dr. Saper received his medical degree from Harvard Medi-
per day of elemental zinc has been used.12 To slow the cal School, Boston, Mass., and completed a family medicine residency at
the University of California, San Francisco. He completed a research fel-
progression of age-related macular degeneration, 80 mg lowship in complementary and alternative medicine at Harvard Medical
of elemental zinc with 2 mg copper should be used daily School and Harvard School of Public Health.
in combination with 500 mg of vitamin C, 400 IU of REBECCA RASH, MA, earned her master of arts degree in medical nutri-
vitamin E, and 15 mg of beta-carotene.14 Table 3 lists tion sciences from the Department of Family Medicine at Boston Univer-
common oral zinc preparations. sity School of Medicine.
Address correspondence to Robert B. Saper, MD, MPH, Boston Medical
Bottom Line Center, Department of Family Medicine, One Boston Medical Center
Despite zinc’s many essential roles in human physi- Place, Dowling 5 South, Boston, MA 02118 (e-mail: robert.saper@bmc.
org). Reprints are not available from the authors.
ology, no robust data support zinc supplementation
alone for persons with a normal zinc status. However, Author disclosure: Dr. Saper received a Career Development Award (K07
AT002915-03) from the National Center for Complementary and Alterna-
zinc in combination with antioxidants may be mod-
tive Medicine, National Institutes of Health.
estly effective in slowing the progression of age-related
macular degeneration. In children living in develop-
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772  American Family Physician www.aafp.org/afp Volume 79, Number 9 ◆ May 1, 2009