Zinc deficiency and its management in the pediatric

population: A literature review and proposed etiologic

classification
Michael D. Corbo, MD,a and Joseph Lam, MD, FRCPCb
Toronto, Ontario, and Vancouver, British Columbia, Canada

Zinc is a trace element essential to the gastrointestinal, immune, integumentary, reproductive, and central
nervous systems. Zinc deficiency is prevalent in many areas of the world and is a diagnostically challenging
condition. Cutaneous manifestations typically occur in moderate to severe zinc deficiency and present as
alopecia and dermatitis in the perioral, acral, and perineal regions. Zinc deficiency is a potentially fatal
disease process. The aim of this review is to focus on the cutaneous manifestations, diagnosis, and
treatment of zinc deficiency in children, and to propose an etiologic classification system. ( J Am Acad
Dermatol 2013;69:616-24.)

Key words: acrodermatitis enteropathica; micronutrients; pediatric; zinc absorption; zinc deficiency; zinc
metabolism.

Z inc is a mineral involved in many biologic

pathways and enzymatic processes. Its im-
portance for healthy immune function, pro-
tein and DNA synthesis, wound healing, and cell
Abbreviations used:
AE:
IL:
MMP:
acrodermatitis enteropathica
interleukin
matrix metalloproteinase
division is well documented.1-7 Zinc plays an essen- NF: nuclear factor
tial role in central nervous system development; ROS: reactive oxygen species
SLC: solute-linked carrier
growth and maturation during fetal life, childhood,
and adolescence; is required for normal taste and
smell; and forms a critical component of the catalytic
site of hundreds of different enzymes.6-10 zinc transporters, coded from solute-linked carrier
It is estimated that more than 20% of individuals (SLC) gene families, which possess competing roles
worldwide are zinc deficient, especially in develop- in zinc homeostasis.1,15-17 ZnT transporters (SLC30)
ing countries.1,11 The estimated prevalence of zinc function by reducing intracellular zinc concentra-
deficiency in the United States is 1% to 3%,1,12 which tions, whereas Zip transporters (SLC39) function to
may be a result of a higher consumption of meat and increase intracellular zinc.1,15-17 There are 9 known
fortified breakfast foods. Zinc deficiency can be ZnT and 15 Zip transporters in human beings iden-
found in premature infants, children with poor tified to date,1,17 with both transporter families being
nutritional intake, elderly patients, and in individuals up-regulated or down-regulated based on zinc levels
with sickle cell anemia, anorexia nervosa, cystic in vivo.1,17
fibrosis, liver and renal disease, diabetes, HIV infec- Zinc absorption occurs predominantly in the
tion, and chronic alcoholism.1,13,14 jejunum via the specific transporter Zip4.1,18,19 It
can be absorbed through passive diffusion or attach
ZINC METABOLISM to the apical membrane of enterocytes, where trans-
Zinc is tightly regulated within the body by port is aided by metallothionein and cysteine-rich
transporters that work primarily in the duodenum, proteins.20-22 It is then taken into the cell and either
jejunum, and nephron.1,15-17 There are 2 types of released into the blood or back into the intestine.20

From the Department of Dermatology, University of Toronto,a and M1-700, Toronto, Ontario M4N 3M5, Canada. E-mail: michael.
Departments of Pediatrics and Dermatology, University of [email protected].
British Columbia.b Published online May 20, 2013.
Funding sources: None. 0190-9622/$36.00
Conflicts of interest: None declared. Ó 2013 by the American Academy of Dermatology, Inc.
Reprints not available from the authors. http://dx.doi.org/10.1016/j.jaad.2013.04.028
Correspondence to: Michael D. Corbo, MD, Department of
Dermatology, University of Toronto, 2075 Bayview Ave, Suite

616
J AM ACAD DERMATOL Corbo and Lam 617
VOLUME 69, NUMBER 4

Absorption can be reduced through ingestion of as nicotinamide adenine dinucleotide phosphate

zinc-binding substances such as cadmium, phytates, oxidases, that catalyze the formation of superoxide
and fiber.20-22 The resulting insoluble complexes from oxygen.27 Further, it is a key component in
remain in the gastrointestinal tract and are excreted superoxide dismutase, an enzyme capable of
in the stool.21 Consumption of high amounts of iron reducing hydroxide.27,30,31 Superoxide dismutase
and/or copper can potentially decrease zinc absorp- up-regulates metallothioneins, a family of low mo-
tion.20-22 In the absence of these substances, ingested leculareweight proteins that neutralize hydroxide as
zinc is released from food by a result of their high cysteine
pancreatic enzymes (eg, pro- content.27,30,31
teases, lipases) and forms CAPSULE SUMMARY Zinc also exerts a protec-
complexes with amino acids, tive effect against oxidative
d Zinc deficiency in infancy and childhood
phosphates, and organic stress through the zinc-
21 can result from a number of different
acids. These zinc-ligand finger-transactivating protein
causes.
complexes are absorbed A20. This protein inhibits in-
into the intestinal mucosa, d We propose a classification based on the terleukin (IL)-1b and tumor
where ZnT transporters pro- etiology of the zinc deficiency. necrosis factor-alfa activation
mote their release into the d
This revised classification may facilitate of nuclear factor (NF)-
circulation.17,19,21 The major- diagnosis and management of zinc kB.31,32 The NF-kB pathway
ity of zinc is then bound to deficiency in children. is known for its expression of
albumin and taken to the specific genes in response to
liver through the portal inflammatory cytokines and
circulation.1,17 oxidative stress. This pathway is also involved with
Approximately 80% to 85% of zinc is stored in the perpetuation of ROS.33 Zinc inhibits NF-kB
skeletal muscle and bone and has a slow turno- activation by preventing the induction of inflamma-
ver.1,17,23 The liver and skin account for 8% to 11% of tory cytokines IL-1b and tumor necrosis factor-alfa
total body stores.1,23 Most zinc is lost through pan- messenger RNA in mononuclear cells.31 With less
creatic secretions, feces, urine, sweat, menstrual inflammatory cytokines in circulation, perpetuation
fluid, semen, epithelial cells, and hair.1,24 Because of ROS by the NF-kB pathway is reduced.31
there is no specialized organ to regulate zinc in vivo,
daily dietary intake is required to maintain a steady Wound healing
state (Table I; available at http://www.jaad.org). Zinc plays an essential role in normal wound
healing. It is found in both the dermis and epidermis,
SOURCES OF ZINC where it aids in cell division, protection, and repair
Dietary zinc and maintainance.34,35 When applied to murine
A variety of food sources and their zinc content wounds, topical zinc oxide raises keratinocyte pro-
are listed in Table II (available at http://www.jaad. liferation by as much as 30%.36-38 This is accom-
org). plished through the ability of zinc to increase
intracellular signaling pathways that promote growth
Zinc preparations and tissue regeneration.39,40 Localized zinc levels in
Supplements containing elemental zinc are avail- rats increase by as much as 15% to 20% after
able for treatment of zinc deficiency. The most trauma.36,37 A decrease in zinc levels toward the
widely available products include zinc oxide, zinc later stages of the wound healing process is associ-
acetate, zinc sulfate, and zinc gluconate, which ated with normal scar maturation and reduced local
contain elemental zinc percentages of 80%, 30%, cell division.41,42 In rats with impaired zinc expres-
23%, and 14.3%, respectively. sion, wounds demonstrate slower healing rates and
decreased tensile strength of scar tissue.35,42
ZINC AND NORMAL SKIN PHYSIOLOGY In addition to contributing to an increased rate of
Anti-inflammatory and antioxidant properties re-epithelialization, zinc contributes to tissue granu-
Reactive oxygen species (ROS), such as superox- lation and cell migration for normal wound closure
ide, hydrogen peroxide, and hydroxide, are by- through the zinc-dependant matrix metalloprotei-
products of aerobic metabolism. These species nases (MMPs).35 MMPs are proteolytic peptidases
create oxidative damage to cells and have been involved in the degradation of the extracellular
shown to contribute to neurodegeneration, carcino- matrix.43 There are 23 unique human MMPs identi-
27-29
genesis, aging, and atherosclerosis. Zinc acts to fied to date.43 They are manufactured and released
prevent ROS formation by inhibiting enzymes, such by cells involved in repair of cutaneous trauma
618 Corbo and Lam J AM ACAD DERMATOL
OCTOBER 2013

including fibroblasts, macrophages, and keratino-

cytes.35,44 During the healing process, MMPs re-
leased in response to local growth factor signals
break down the components of the original extra-
cellular matrix.43 These components include colla-
gen, gelatin, elastin, laminin, vitronectin, and
fibronectin.35,43 MMPs have very specific roles in
the healing cascade such as degradation and remod-
eling of the extracellular matrix (MMP-2 and -9),45
epithelial cell migration and connective tissue re-
modeling (MMP-14),45,46 vascular remodeling
(MMP-9),45-47 wound contraction (MMP-3),48 and
re-epithelialization (MMP-1 and -10).48

CLINICAL PRESENTATION OF ZINC

DEFICIENCY
Symptoms of zinc deficiency are highly variable
and depend on severity. The cutaneous eruption
(Fig 1) represents the classic clinical presentation.
Both cutaneous and noncutaneous features of zinc
deficiency are outlined in Table III.

Etiology and classification of zinc deficiency

The following is an etiologic classification system
for zinc deficiency in children (Table IV).
Type I: inadequate intake. Inadequate intake
of zinc, as a result of absent zinc supplementation
during total parenteral nutrition, low breast milk zinc Fig 1. Zinc deficiency. Clinical photographs of female
levels, poor diet, or eating disorders such as anorexia infant with acrodermatitis enteropathica illustrating ero-
nervosa and bulimia nervosa, may cause zinc defi- sion, desquamation, and crusting in perioral region (A)
ciency in childhood.22,27,49-52 and diaper area and acral surfaces (B). Photographs
In the neonate and young infant, zinc deficiency courtesy of Dr Angela Hern
andez-Mart
ın, Madrid, Spain.
may arise as a result of inadequate supplementation
in total parenteral nutrition or low breast milk levels. Type II: excessive losses. Zinc deficiency re-
Low breast milk zinc results from zinc deficiency in sulting from excessive loss can be separated into 3
the mother or from an inherited mutation in the distinct subcategories: (1) digestive fluid losses (ie,
SLC30A2 gene.51 SLC30A2 encodes ZnT2, the trans- intestinal fistula, intractable diarrhea); (2) increased
porter responsible for secreting zinc into human urinary elimination (ie, liver cirrhosis, infection, renal
breast milk.51 This results in sequestration of zinc in disease, diabetes mellitus, diuretics, alcohol inges-
the lysosomes of mammary tissue, necessitating zinc tion); and (3) other (ie, blood loss from parasitic
supplementation or weaning from breast milk.53,54 infection, burns, excessive sweating, hemodialysis,
Once the infant is weaned, zinc supplements are no hemolysis).58 Normally, the body can maintain ade-
longer necessary.50 quate levels of zinc for several months during periods
Zinc deficiency in older infants, elementary of low intake through increased absorption and
school children, and adolescents may also result decreased excretion in the gastrointestinal tract, de-
from inadequate intake. Infants 7 to 12 months of age creased renal excretion, increased cellular redistribu-
who are exclusively breast-fed may not be getting tion, and possible retention in skeletal muscle, bones,
the required amount of zinc from breast milk.23,55,56 hair, liver, brain, and the skin.59-63 However, zinc stores
Malnourishment or a diet low in zinc-containing can be rapidly exhausted in the above disease states.
foods (ie, vegetarian) should be considered.23 A Type III: malabsorption. Acrodermatitis enter-
detailed intake diary may help analyze the types of opathica (AE) is a rare autosomal recessive disorder
food being ingested on a regular basis.57 The pres- affecting the Zip family of proteins required for
ence of other nutritional deficiencies can also be normal zinc absorption.1,50,64 The mutated gene is
indicative of a poor diet. believed to be SLC39A4 on chromosome 8q24.3,
J AM ACAD DERMATOL Corbo and Lam 619
VOLUME 69, NUMBER 4

Table III. Clinical manifestations of zinc deficiency Table IV. Etiologic classification system for zinc
Organ system Complication
deficiency in pediatric population
Integumentary system Delayed wound healing and Zinc deficiency category Examples
decreased tensile strength Type I: inadequate Total parenteral nutrition
of scar tissue intake without zinc
Scalp dermatitis supplementation
Alopecia Low maternal serum zinc
Dry skin levels in breast-feeding
Poor nail growth mothers
Bullous pustular dermatitis Low breast milk levels
Stomatitis Pregnancy in teenagers
Paronychia Inadequate or low-calorie diet
Blepharitis Anorexia nervosa or bulimia
Cheilitis nervosa
Immune system Increased allergic sensitivity Type II: excessive loss Fluid losseseintestinal fistula,
Increased inflammatory activity intractable diarrhea
Recurrent infections as result Increased urinary
of cell-mediated immune eliminationeliver cirrhosis,
dysfunction infection, renal disease,
Possible increased risk of diabetes mellitus, diuretics,
pneumonia alcohol
Gastrointestinal system Diarrhea Othereblood loss caused by
Anorexia parasitic infection, burns,
Hypogeusia (reduced excessive sweating,
ability to taste) hemodialysis, hemolysis
Abdominal pain Type III: malabsorption Acrodermatitis enteropathica
Glossitis High intake of copper/iron
Endocrine system Growth retardation Celiac disease
Hypogonadism Crohn’s disease
Central nervous system Neurosensory changes Ulcerative colitis
Psychological impairment Cystic fibrosis
Intention tremor Liver dysfunction
Impaired concentration Pancreatic dysfunction
Nystagmus Short bowel syndrome
Depression Irritable bowel disease
Night blindness High ingestion of phytates
Anosmia Ethylenediaminetetraacetic
Dementia acid
Dysarthria Penicillamine
Genitourinary system Hypogonadism Diuretics
Musculoskeletal system Decreased lean body mass Valproate
Bone fractures Type IV: increased Pregnancy
Pregnant state Delayed fetal growth demand Breast-feeding mothers
Low birth weight Preterm infants
Preterm labor Type V: other Down syndrome
Reduced fetal cognition Congenital thymus defect
and motor function
Spontaneous abortion

milk.50,66 It is postulated that this phenomenon

50,64
which encodes the Zip4 transporter. It is esti- occurs as a result of low moleculareweight binding
mated that the worldwide incidence of AE is ap- agents in human milk, which increase the bioavail-
proximately 1 in 500,000 children.65 There is no ability of zinc and delay the onset of clinical
predilection to sex or race. symptoms.50,66,67 Symptoms can be seen in
AE has the same cutaneous and noncutaneous nonbreast-fed infants in weeks 4 to 10 of life, as
findings as dietary zinc deficiency, but is unique in existing zinc stores become depleted.49 Serum zinc
the timing of its presentation. Symptoms typically levels are usually low in AE, although normal and
manifest when the child is weaned from breast high levels have been reported in the literature.68,69
620 Corbo and Lam J AM ACAD DERMATOL
OCTOBER 2013

Individuals with AE require lifelong zinc

supplementation.49,50
Medical conditions such as celiac disease, Crohn’s
disease, ulcerative colitis, cystic fibrosis, liver dys-
function, pancreatic dysfunction, short bowel syn-
drome, and irritable bowel disease can reduce
absorption of zinc in the small intestine.58
Chelating agents and medications such as phytates,
ethylenediaminetetraacetic acid, penicillamine, diu-
retics, and sodium valproate can interact with zinc in
the small intestine, decreasing absorption and de-
creasing serum levels below normal values with
prolonged use.20-22,57,64,70,71
Type IV: increased demand. Zinc deficiency
may be caused by increased demand in pregnant and
lactating women and in preterm infants. Zinc re-
quirements for pregnant women in the third trimes-
ter are nearly twice as high as nonpregnant women
as a result of fetal requirements.22,72,73 Lactation can
cause loss of up to 2 to 3 mg/d of zinc in the weeks
immediately after delivery and 1 mg/d for 1 to 2
months postpartum.22 Consequently, both pregnant
and lactating women have a higher recommended Fig 2. Zinc deficiency. Histopathologic findings on skin
daily zinc allowance (Table I). biopsy specimen from infant with acrodermatitis enter-
Preterm infants are born in a negative zinc balance opathica: confluent parakeratosis, focal spongiosis, and
as a result of decreased gut absorption, a higher epidermal acanthosis (A); and absence of granular layer in
metabolic rate needed for rapid growth, and inade- epidermis (B). (A and B, Hematoxylin-eosin stain; original
quate stores.50 Zinc stores are low because transfer of magnifications: A, 3200; B, 3100.) Images courtesy of Dr
zinc from mother to fetus occurs chiefly in the final Isabel Colmenero, Madrid, Spain.
trimester.49 Preterm infants also have higher urinary
and fecal losses than term infants.49 Normal breast response to zinc supplementation, and cutaneous
milk will correct the depleted state within a few histopathology can help to confirm the diagnosis.
weeks and no clinical symptoms usually present as a Up to 60% to 80% of serum zinc is bound to
result of prematurity.50 If the breast milk is zinc albumin; thus, the zinc value should be corrected for
deficient, however, either because of low maternal any concurrent decrease in the patient’s albumin
serum levels or a SLC30A2 mutation, zinc deficiency levels.1 Plasma zinc is considered to be deficient
develops more rapidly and with greater severity than below 70 g/dL (10.71 mol/L) for morning fasting
in a term infant.49,50 samples and below 65 g/dL (9.95 mol/L) for
Type V: other. Down syndrome and congenital nonfasting samples.22,81 Blood samples should be
thymus defects are associated with zinc deficiency for obtained before breakfast and the patient should not
reasons that remain unknown.58 Subjects with Down take multivitamins or supplements that contain zinc
syndrome or congenital thymus defects given zinc on the day of the test.
supplements were found to have increased neutrophil Inflammation, acute stress, pregnancy, and oral
chemotaxis, increased circulating thymic hormone, contraceptive use can lead to redistribution of zinc,
increased T lymphocytes, increased school atten- reducing plasma concentrations and leaving total
dance, decreased infections, and increased DNA body stores unaffected.1,9,17,22,82,83 In these situa-
repair in lymphocytes.74-80 Findings from subsequent tions, especially in pregnancy, the interpretation of a
studies have been discordant, however, and further low plasma zinc level may be uncertain. Conversely,
investigation is required. the body’s homeostatic mechanisms can maintain
normal plasma levels even when the body is in a
zinc-deficient state.84 A low level of serum alkaline
DIAGNOSIS OF ZINC DEFICIENCY phosphatase, a zinc-dependant metalloenzyme, sup-
Laboratory values ports a diagnosis of zinc deficiency, but it may be
Zinc deficiency may be diagnosed by clinical normal in mild cases.17 If plasma zinc levels and
history and examination. Laboratory testing, serum alkaline phosphatase are normal and clinical
J AM ACAD DERMATOL Corbo and Lam 621
VOLUME 69, NUMBER 4

Table V. Differential diagnosis of zinc deficiency

AELE unrelated to zinc Kwashiorkor
Condition deficiency AELE of cystic fibrosis Biotin deficiency (protein malnutrition)
Cutaneous Erythematous, scaly, Rare presenting sign Brittle hair/alopecia Flaky, peeling,
presentation crusted lesions in of cystic fibrosis Erythematous, fissured skin that
diaper region, Usually at age 3-7 mo perioral macules, changes from
extremities, trunk, with erythematous and dry skin/ erythematous to
and face papules and scaly dermatitis red-brown color
plaques in perineal, Hair brittle, dry, may
perioral, and acral straighten and turn
regions red to gray color
Key differentiating Caused by low- Associated with Sensorineural Thin, soft nail plates,
factors protein diet used failure to thrive, hearing loss change in hair color
for maintenance of respiratory and Myalgias Distended abdomen,
underlying abdominal failure to thrive,
metabolic disorder symptoms, edema, edema, loss of
and positive sweat muscle mass,
chloride test recurrent infections
Treatments Amino acid Multidisciplinary Oral administration Correction of fluid or
supplementation management of biotin electrolyte
(ie, isoleucine) Dietary modifications imbalances
and pancreatic Gradual
enzyme reintroduction of
supplements food and vitamins
Plasma zinc Can be low, usually Can be low, may be Normal Can be low, may be
and serum ALP normal normal normal

AELE, Acrodermatitis enteropathicaelike eruption; ALP, alkaline phosphatase.

suspicion remains high, a trial of zinc supplementation vacuolization in the cytoplasm of necrotic keratino-
can be conducted to assess clinical response.85 A cytes are commonly observed features.88
detailed dietary history, checking for other nutritional
deficiencies (ie, iron, vitamin D, and vitamin B12), and Differential diagnosis for zinc deficiency
analysis of maternal breast milk, if applicable, can also A number of disorders can present with signs and
be obtained.85 symptoms similar to zinc deficiency (Table V).

Histopathology TREATMENT
Histopathologic findings on light microscopy of Approximately 70% of patients with zinc defi-
skin biopsy specimens can be similar to those seen in ciency respond positively to zinc supplementation if
other deficiency states, such as vitamin B3 defi- initiated within 6 months of onset.58 The skin lesions
ciency.17 Confluent parakeratosis, a noticeably thin- heal without permanent sequelae, but extended
ner granular layer, focal spongiosis, and epidermal periods of deficiency may have permanent effects
acanthosis may be visualized in the early stages (Fig on growth and development in children.58,89 Studies
2). A collection of findings referred to as ‘‘necrolysis’’ of zinc deprivation on rats demonstrated reduced
can be appreciated in advanced disease. These motor activity, decreased brain mass, and short-term
include cytoplasmic pallor, ballooning and reticular memory loss persisting from early life to adult-
degeneration, and necrosis of keratinocytes in the hood.90 Similar experiments in mice showed stunted
stratum spinosum and granulosum.86 Nonspecific growth patterns, impaired learning and working
cytoplasmic pallor is the first of these findings to memory, and long-term immune dysfunction.91
appear and is often observed in isolation.17 Therapy is administered for up to 3 to 4 months in
Condensed chromatin in the nuclei of affected reversible deficiencies, but can be needed for more
keratinocytes and neutrophil crusts may be pre- than 6 months in patients showing only modest
sent.17 Chronic lesions typically exhibit psoriasiform gains.58 Children with acquired zinc deficiency should
hyperplasia with little to no cytoplasmic pallor.87 receive elemental zinc at 0.5 to 1 mg/kg/d to replenish
Under the electron microscope, swelling of the stores.49 Children with conditions leading to excessive
stratum spinosum, an intact basal lamina, and losses may require higher doses.49 Children with AE
622 Corbo and Lam J AM ACAD DERMATOL
OCTOBER 2013

should receive 3 mg/kg/d of elemental zinc for life or 10. Vallee BL, Falchuk KH. The biochemical basis of zinc physi-
have dosage guided by serum zinc measurements49; ology. Physiol Rev 1993;73:79-118.
11. Wuehler SE, Peerson JM, Brown KH. Use of national food
serum zinc measurements should be conducted every balance data to estimate the adequacy of zinc in national
3 to 6 months.17 Copper and iron levels should also be food supplies: methodology and regional estimates. Public
assessed regularly as a result of their interaction with Health Nutr 2005;8:812-9.
zinc. With adequate supplementation, symptoms be- 12. US Department of Agriculture, Agricultural Research Service.
gin to resolve after 1 or 2 days.49 For children with a USDA national nutrient database for standard reference, release
24. Nutrient data laboratory home page. Available from: URL:
dietary deficiency, a reduction in fiber, phytates, and http://www.ars.usda.gov/ba/bhnrc/ndl. Accessed March 4, 2012.
cadmium ingestion, if applicable, and introduction of 13. Prasad AS. Clinical spectrum of human zinc deficiency. In:
meat, liver, and other zinc-containing foods should Prasad AS, editor. Biochemistry of zinc. New York: Plenum
serve as adequate treatment.57,64 In most instances, Press; 1993. pp. 219-58.
treatment of the responsible underlying condition will 14. Leonard MB, Zemel BS, Kawchak DA, Ohene-Frempong K,
Stallings VA. Plasma zinc status, growth, and maturation in
result in resolution of symptoms. children with sickle cell disease. J Pediatr 1998;132:467-71.
Caution must be exercised so as not to exceed 15. Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. A novel
toxic limits of zinc supplementation. Acute zinc member of a zinc transporter family is defective in acroder-
overdose may cause diarrhea, light-headedness, matitis enteropathica. Am J Hum Genet 2002;71:66-73.
gait disturbances, lethargy, vomiting, epigastric 16. Wang X, Zhou B. Dietary zinc absorption: a play of Zips and
ZnTs in the gut. IUBMB Life 2010;62:176-82.
pain, and abdominal cramps.58,92 Chronic overdose 17. Maverakis E, Fung MA, Lynch PJ, Draznin M, Michael DJ,
may lead to neutropenia, leukopenia, copper and/or Ruben B, et al. Acrodermatitis enteropathica and an overview
iron deficiency, anemia, growth retardation, de- of zinc metabolism. J Am Acad Dermatol 2007;56:116-24.
creased high-density lipoprotein, and increased 18. Liuzzi JP, Cousins RJ. Mammalian zinc transporters. Annu Rev
low-density lipoprotein.58,92 Nutr 2004;24:151-72.
19. Liuzzi JP, Bobo JA, Lichten LA, Samuelson DA, Cousins RJ.
Responsive transporter genes within the murine
intestinal-pancreatic axis form a basis of zinc homeostasis.
CONCLUSION Proc Natl Acad Sci U S A 2004;101:14355-60.
Zinc deficiency can be a diagnostically challeng- 20. Lind T, Lonnerdal B, Stenlund H, Ismail D, Seswandhana R,
ing condition. We believe our proposed etiologic Ekstr€om EC, et al. A community-based randomized controlled
trial of iron and zinc supplementation in Indonesian infants:
classification system may help facilitate the diagnosis
interactions between iron and zinc. Am J Clin Nutr 2003;77:
and management of zinc deficiency in children. 883-90.
21. Lonnerdal B. Dietary factors influencing zinc absorption.
A special thanks to Dr Isabel Colmenero, Dr Angela
J Nutr 2000;130:1378S.
Hern
andez-Mart
ın, and Dr Antonio Torrelo for their assis-
22. Shrimpton R, Shankar AH. Zinc deficiency. In: Semba RD,
tance with obtaining the clinical and histopathological Bloem MW, editors. Nutrition and health in developing
images. A special thanks to Dr Faisal Al-Mohammedi for countries. 2nd ed. Totowa (NJ): Humana Press (Springer
interpreting the findings in the histopathology images. Science and Media LLC); 2008.
23. King JC, Shames DM, Woodhouse LR. Zinc homeostasis in
REFERENCES humans. J Nutr 2000;130:S1360-6.
1. Tuerk MJ, Fazel N. Zinc deficiency. Curr Opin Gastroenterol 24. Ganapathy S, Volpe SL. Zinc, exercise, and thyroid hormone
2009;25:136-43. function. Crit Rev Food Sci Nutr 1999;39:369-90.
2. Sandstead HH. Understanding zinc: recent observations and 25. National Institutes of Health: Office of Dietary Supplements.
interpretations. J Lab Clin Med 1994;124:322-7. Dietary supplement fact sheet: zinc. Available from: URL:
3. Solomons NW. Mild human zinc deficiency produces an http://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/.
imbalance between cell-mediated and humoral immunity. Accessed February 20, 2012.
Nutr Rev 1998;56:27-8. 26. Panel on Micronutrients, Subcommittees on Upper Reference
4. Prasad AS. Zinc: an overview. J Nutr 1995;11:93-9. Levels of Nutrients and of Interpretation and Use of Dietary
5. Heyneman CA. Zinc deficiency and taste disorders. Ann Reference Intakes, Standing Committee on the Scientific
Pharmacother 1996;30:186-7. Evaluation of Dietary Reference Intakes. 12 Zinc. Dietary
6. Fabris N, Mocchegiani E. Zinc, human diseases and aging. reference intakes for vitamin A, vitamin K, arsenic, boron,
Aging (Milano) 1995;7:77-93. chromium, copper, iodine, iron, manganese, molybdenum,
7. Maret W, Sandstead HH. Zinc requirements and the risks and nickel, silicon, vanadium, and zinc. Washington (DC): National
benefits of zinc supplementation. J Trace Elem Med Biol Academies Press; 2001. p. 442-501.
2006;20:3-18. 27. Prasad AS, Beck FW, Snell DC, Kucuk O. Zinc in cancer
8. Prasad AS, Beck FW, Grabowski SM, Kaplan J, Mathog RH. prevention. Nutr Cancer 2009;61:879-87.
Zinc deficiency: changes in cytokine production and T-cell 28. Lachance PA, Nakat Z, Jeong W. Antioxidants: an integrative
subpopulations in patients with head and neck cancer and in approach. J Nutr 2001;17:835-8.
noncancer subjects. Proc Assoc Am Physician 1997;109:68-77. 29. Uzzo RG, Leavis P, Hatch W, Gabai VL, Dulin N, Zvartau N,
9. Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME. et al. Zinc inhibits nuclear factor-k B activation and sensitizes
Zinc and human health: an update. Arch Toxicol 2012;86: prostate cancer cells to cytotoxic agents. Clin Can Res 2002;8:
521-34. 3579-83.
J AM ACAD DERMATOL Corbo and Lam 623
VOLUME 69, NUMBER 4

30. Ho E, Quan N, Tsai YH, Lai W, Bray TM. Dietary zinc 51. Murthy SC, Udagani MM, Badakali AV, Yelameli BC. Sympto-
supplementation inhibits NF-kappa B activation and protects matic zinc deficiency in a full-term breast-fed infant. Derma-
against chemically induced diabetes in CD1 mice. Exp Biol tol Online J 2010;16:3.
Med 2001;226:103-11. 52. Gehrig KA, Dinulos JG. Acrodermatitis due to nutritional
31. Prasad AS, Bao B, Beck FWJ, Kucuk O, Sarkar FH. Anti-oxidant deficiency. Curr Opin Pediatr 2010;22:107-12.
effect of zinc in humans. Free Radic Biol Med 2004;37: 53. Chowanadisai W, Lonnerdal B, Kelleher SL. Identification of a
1182-90. mutation in SLC30A2 (ZnT-2) in women with low milk zinc
32. Davis JN, Kucuk O, Djuric Z, Sarkar FH. Soy isoflavone concentration that results in transient neonatal zinc defi-
supplementation in healthy men prevents NF-k B activation ciency. J Biol Chem 2006;281:39699-707.
by TNF-a in blood lymphocytes. Free Radic Biol Med 2001;30: 54. Seo YA, Kelleher SL. Functional analysis of two single
1293-302. nucleotide polymorphisms in SLC30A2 (ZnT2): implications
33. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and for mammary gland function and breast disease in women.
NF-kB signaling. Cell Res 2011;21:103-15. Physiol Genom 2010;42A:219-27.
34. Van Den Oord JJ, De Ley M. Distribution of metallothionein in 55. Krebs NF, Westcott JE, Butler N, Robinson C, Bell M,
normal and pathological human skin. Arch Dermatol Res Hambidge KM. Meat as a first complementary food for
1994;286:62-8. breastfed infants: feasibility and impact on zinc intake and
35. Schwartz JR, Marsh RG, Draelos ZD. Zinc and skin health: status. J Pediatr Gastroenterol Nutr 2006;42:207-14.
overview of physiology and pharmacology. Dermatol Surg 56. Hambidge KM, Krebs NF. Zinc deficiency: a special challenge.
2005;31:837-47. J Nutr 2007;137:1101-5.
36. 
Agren MS. Zinc in wound repair. Arch Dermatol 1999;135: 57. Cole CR, Grant FK, Swaby-Ellis ED, Smith JL, Jacques A,
1273-4. Northrop-Clewes CA, et al. Zinc and iron deficiency and their
37. 
Agren MS, Chvapil M, Franz
en L. Enhancement of interrelations in low-income African American and Hispanic
re-epithelialization with topical zinc oxide in porcine children in Atlanta. Am J Clin Nutr 2010;91:1027-34.
partial-thickness wounds. J Surg Res 1991;50:101-5. 58. Yanagisawa H. Zinc deficiency and clinical practice. Japan
38. Jin L, Murakami TH, Janjua NA, Hori Y. The effects of zinc Medical Association Journal 2004;47:359-64.
oxide and diethyldithiocarbamate on the mitotic index of 59. Lukaski HC, Bolonchuk WW, Klevay LM, Milne DB, Sandstead
epidermal basal cells of mouse skin. Acta Med Okayama HH. Changes in plasma zinc content after exercise in men fed
1994;48:231-6. a low-zinc diet. Am J Physiol 1984;247:88-93.
39. Hansson A. Extracellular zinc ions induces mitogen-activated 60. Milne DB, Canfield WK, Gallagher SK, Hunt JR, Klevay LM.
protein kinase activity and protein tyrosine phosphorylation Ethanol metabolism in postmenopausal women fed a diet
in bombesin-sensitive Swiss 3T3 fibroblasts. Arch Biochem marginal in zinc. Am J Clin Nutr 1987;46:688-93.
Biophys 1996;328:233-8. 61. Baer MJ, King JC. Tissue zinc levels and zinc excretion during
40. Huang JS, Mukherjee JJ, Chung T, Crilly KS, Kiss Z. Extracel- experimental zinc depletion in young men. Am J Clin Nutr
lular calcium stimulates DNA synthesis in synergism with 1984;39:556-70.
zinc, insulin and insulin-like growth factor I in fibroblasts. Eur 62. Hess FM, King JC, Margen S. Zinc excretion in young women
J Biochem 1999;266:943-51. on low zinc intakes and oral contraceptive agents. J Nutr
41. Lansdown ABG, Sampson B, Rowe A. Sequential changes in 1977;107:1610-20.
trace metal, metallothionein and calmodulin concentrations 63. Milne DB, Canfield WK, Mahalko JR, Sandstead HH. Effect of
in healing skin wounds. J Anat 1999;195:375-86. dietary zinc on whole body surface loss of zinc: impact on
42. 
Agren MS, Franz
en L. Influence of zinc deficiency on breaking estimation of zinc retention by balance method. Am J Clin
strength of 3-week-old skin incisions in the rat. Acta Chir Nutr 1983;38:181-6.
Scand 1990;156:667-70. 64. Dufner-Beattie J, Wang F, Kuo Y-M, Gitschier J, Eide D,
43. Nagase H, Visse R, Murphy G. Structure and function of Andrews GK. The acrodermatitis enteropathica gene ZIP4
matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; encodes a tissue-specific, zinc-regulated zinc transporter in
69:562-73. mice. J Biol Chem 2003;278:33474-81.
44. Barron L, Wynn TA. Fibrosis is regulated by Th2 and Th17 65. Champion RH, Burton JL, Ebling FJG. Textbook of dermatol-
responses and by dynamic interactions between fibroblasts ogy. 5th ed. London, UK: Blackwell Scientific Publications;
and macrophages. Am J Physiol Gastrointest Liver Physiol 1992. p. 2373.
2011;300:G723-8. 66. Arnaud J, Favier A. Determination of ultrafiltrable zinc in
45. Mirastschijski U, Impola U, Jahkola T, Karlsmark T, Agren MS, human milk by electrothermal atomic absorption spectrom-
Saarialho-Kere U. Ectopic localization of matrix metallo- etry. Analyst 1992;117:1593-8.
proteinase-9 in chronic cutaneous wounds. Hum Pathol 67. Weymouth RD, Kelly R, Lansdell BJ. Symptomatic zinc defi-
2002;33:355-64. ciency in a premature infant. Aust Paediatr J 1982;18:208-10.
46. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases 68. Garretts M, Molokhia M. Acrodermatitis enteropathica with-
and the regulation of tissue remodeling. Nat Rev Mol Cell Biol out hypozincemia. J Pediatr 1977;91:492-4.
2007;8:221-33. 69. Mack D, Koletzko B, Cunnane S, Cutz E, Griffiths A. Acroder-
47. Mirastschijski U, Zhou Z, Rollman O, Tryggvason K, Agren MS. matitis enteropathica with normal serum zinc levels: diag-
Wound healing in membrane-type-1 matrix metalloproteinase- nostic value of small bowel biopsy and essential fatty acid
deficient mice. J Invest Dermatol 2004;123:600-2. determination. Gut 1989;30:1426-9.
48. Gill SE, Parks WC. Metalloproteinases and their inhibitors: regu- 70. Wester PO. Urinary zinc excretion during treatment with
lators of wound healing. Int J Biochem Cell Biol 2008;40:1334-47. different diuretics. Acta Med Scand 1980;208:209-12.
49. Jen M, Yan AC. Syndromes associated with nutritional 71. Keen CL, Taubeneck MW, Daston GP, Rogers JM, Gershwin
deficiency and excess. Clin Dermatol 2010;28:669-85. ME. Primary and secondary zinc deficiency as factors under-
50. Ackland ML, Michalczyk A. Zinc deficiency and its inherited lying abnormal CNS development. Ann. N Y Acad Sci 1993;
disordersea review. Genes Nutr 2006;1:41-50. 678:37-47.
624 Corbo and Lam J AM ACAD DERMATOL
OCTOBER 2013

72. Krebs NF. Zinc supplementation during lactation. Am J Clin 82. Liuzzi JP, Lichten LA, Rivera S, Blanchard RK, Aydemir TB,
Nutr 1998;68:S509-12. Knutson MD, et al. Interleukin-6 regulates the zinc trans-
73. Donangelo CM, Vargas-Zapata CL, Woodhouse LR, Shames porter Zip14 in liver and contributes to the hypozincemia of
DM, Mukherjea R, King JC. Zinc absorption and kinetics the acute-phase response. Proc Natl Acad Sci U S A 2005;102:
during pregnancy and lactation in Brazilian women. Am J 6843-8.
Clin Nutr 2005;82:118-24. 83. Pilch SM, Senti FR. Analysis of zinc data from the second
74. Bjorksten B, Back O, Gustavson KH, Hallmans G, H€aggl€ of B, national health and nutrition examination survey (NHANES
T€arnvik A. Zinc and immune function in Down’s syndrome. II). J Nutr 1985;115:1393-7.
Acta Paediatr Scand 1980;69:183-7. 84. Johnson PE, Hunt CD, Milne DB, Mullen LK. Homeostatic
75. Fabris N, Mocchegiani E, Muzzioli M, Provinciali M. Neuro- control of zinc metabolism in men: zinc excretion and
endocrine-thymus interactions: perspectives for intervention balance in men fed diets low in zinc. Am J Clin Nutr 1993;
in aging. Ann N Y Acad Sci 1988;521:72-87. 57:557-65.
76. Fabris N, Mocchegiani E, Muzzioli M, Provinciali M. The role of 85. Gibson RS, Hess SY, Hotz C, Brown KH. Indicators of zinc
zinc in neuroendocrine-immune interactions during aging. status at the population level: a review of the evidence. Br J
Ann N Y Acad Sci 1991;621:314-26. Nutr 2008;99:S14-23.
77. Franceschi C, Chiricolo M, Licastro F, Zannotti M, Masi M, 86. Mori H, Matsumoto Y, Tamada Y, Ohashi M. Apoptotic cell
Mocchegiani E, et al. Oral zinc supplementation in Down’s death in formation of vesicular skin lesions in patients
syndrome: restoration of thymic endocrine activity and of with acquired zinc deficiency. J Cutan Pathol 1996;23:
some immune defects. J Ment Defic Res 1988;32:169-81. 359-63.
78. Licastro F, Mocchegiani E, Masi M, Fabris N. Modulation of 87. Jensen SL, McCuaig C, Zembowicz A, Hurt MA. Bullous
the neuroendocrine system and immune functions by zinc lesions in acrodermatitis enteropathica delaying diagnosis
supplementation in children with Down’s syndrome. J Trace of zinc deficiency: a report of two cases and review of the
Elem Electrolytes Health Dis 1993;7:237-9. literature. J Cutan Pathol 2008;35:S1-13.
79. Licastro F, Chiricolo M, Mocchegiani E, Fabris N, Zannoti M, 88. Welsmann K, Kvist N, Kobayasi T. Bullous acrodermatitis due
Beltrandi E, et al. Oral zinc supplementation in Down’s to zinc deficiency during total parenteral nutrition: an ultra-
syndrome subjects decreased infections and normalized structural study of the epidermal changes. Acta Derm
some humoral and cellular immune parameters. J Intellect Venereol 1983;63:143-6.
Disabil Res 1994;38:149-62. 89. Kumar P, Lal NR, Mondal AK, Mondal A, Gharami RC, Maiti A.
80. Chiricolo M, Musa AR, Monti D, Zannotti M, Franceschi C. Zinc and skin: a brief summary. Dermatol Online J 2012;18:1.
Enhanced DNA repair in lymphocytes of Down syndrome 90. Frederickson C, Danscher G. Zinc-containing neurons in
patients: the influence of zinc nutritional supplementation. hippocampus and related CNS structures. Prog Brain Res
Mutat Res 1993;295:105-11. 1990;83:71-84.
81. Domell€ of M, Hernell O, Abrams SA, Chen Z, L€onnerdal B. Iron 91. Sandstead HH. Zinc: essentiality for brain development and
supplementation does not affect copper and zinc absorption function. Nutr Rev 1985;43:130-7.
in breastfed infants. Am J Clin Nutr 2009;89:185-90. 92. Fosmire GJ. Zinc toxicity. Am J Clin Nutr 1990;51:225-7.
J AM ACAD DERMATOL Corbo and Lam 624.e1
VOLUME 69, NUMBER 4

Table I. Recommended daily dietary allowances for

zinc25,26
Age Male Female Pregnancy Lactation
0-6 mo 2 mg* 2 mg*
7-12 mo 3 mg 3 mg
1-3 y 3 mg 3 mg
4-8 y 5 mg 5 mg
9-13 y 8 mg 8 mg
14-18 y 11 mg 9 mg 12 mg 13 mg
$ 19 y 11 mg 8 mg 11 mg 12 mg

Used with permission of Office of Dietary Supplements, National

Institutes of Health.
*Adequate intake.

Table II. Food sources rich in zinc12,25

Food Milligrams per serving Percent DV
Oysters, 6 medium, breaded and fried 76.7 511
Beef shanks, cooked, 3 oz 8.9 59
Crab, Alaska king, cooked, 3 oz 6.5 43
Pork shoulder, cooked, 3 oz 4.2 28
Breakfast cereal fortified with 25% of DV for zinc, 3/4 -cup serving 3.8 25
Lobster, cooked, 3 oz 3.4 23
Chicken leg, roasted, 1 leg 2.7 18
Pork tenderloin, cooked, 3 oz 2.5 17
Baked beans, canned, ½ cup 1.7 11
Cashews, dry roasted, 1 oz 1.6 11
Yogurt, fruit, low fat, 1 cup 1.6 11
Raisin bran cereal, 3/4 cup 1.5-10.8 10-72
Chickpeas, ½ cup 1.3 9
Cheese, Swiss, 1 oz 1.2 8
Almonds, dry roasted, 1 oz 1.0 7
Milk, whole, 1 cup 1.0 7
Chicken breast, roasted, ½ breast with skin removed 0.9 6
Cheese, cheddar or mozzarella, 1 oz 0.9 6
Peas, boiled, ½ cup 0.9 6
Kidney beans, cooked, ½ cup 0.8 5
Oatmeal, instant, 1 packet 0.8 5
Flounder or sole, cooked, 3 oz 0.3 2

Used with permission of Office of Dietary Supplements, National Institutes of Health.

DV, Daily value.