Zinc in Health and Disease

Introduction

• Zinc is the second most abundant trace element, after iron

• It participates in various steps of intermediary metabolism, regulation of immune

and inflammatory response, transmission of genetic information, hormonal actions
and maintenance of structural components like biomembranes and chromatin

Prasad AS Zinc: its role in human health. Frontiers in nutrition 2014 Sep
History
• Zinc oxide or calamine was applied topically to facilitate wound healing more
than 3000 years ago

• 1869- zinc required in growth of organism ‘aspergillus’ demonstrated

• Until mid 20th century, importance of zinc in human growth and development not
recognized

• 1973 association between zinc deficiency and acrodermatitis enteropathica

discovered

Nooshin et al An overview of zinc and its importance in dermatology Review article, ISSN 567863
• In 1961, a syndrome of anemia, hypogonadism and dwarfism was noted in
Iranians subsisting on flat bread, potatoes and milk

• Similar syndrome observed in Egyptian adolescents who mainly consumed bread

and beans

• Administration of supplemental zinc or diets with adequate animal protein

improved growth and corrected hypogonadism

• Subsequent studies showed the syndrome was due to dietary zinc deficiency

Nazanin et al. Zinc and its importance in human health. J Res Med Sci 2017 Feb
Metabolism of zinc
• Dietary intake averages 150 µmol/day

Absorption
• 33% average absorption mainly in duodenum and jejunum
• 60-70% from aqueous solutions. Less from solid diets

Distribution (total body zinc: 2-4 grams)

• Tissues- muscle 60%, bone 30%, other tissues 10%
• Plasma- 1µg/g, 80% bound to albumin, 20 % to α2macroglobulin

Cousins et al. Physiological reviews 2009

Homeostasis

• The gastrointestinal system maintain a constant level of zinc even if intake varies by
ten-fold range

• Intracellular homeostasis achieved by 24 zinc transporting proteins ( ZIP which

increase cytoplasmic zinc and ZnT which decrease it) and 4 metallothioneins

Excretion

• Gastrointestinal tract- 2.5-5.5 mg/day

• Renal, constant at 300-700 µg/day
• Other- skin and body fluids
Nazanin et al. Zinc and its importance in human health. J Res Med Sci 2017 Feb
RDA
Infants: 2-3 mg/day
Children
• 1-3 years: 3mg/day
• 4-8 years: 5mg/day
• 9-13 years: 8mg/day
Adolescents
• Male- 11mg/day
• Female- 9mg/day

Dietary reference intakes for micronutrients (2001), Institute of Medicine (US)

Dietary sources
• Oysters, meat, nuts, shell fish, poultry, eggs and milk products, whole grains are
rich sources of zinc
Sources Zinc (mg/100grams)
Oysters 40
Meat (beef) 6
Chicken liver 4
Nuts 3.5
Shell fish 2.7
Poultry 1.5
Eggs 1.3
Milk products 1.2

Nutrient database for standard reference, USDA 2015

Bioavailability

• Dietary inhibitors- phytates (depends on molar ratios of phytate to zinc within

diet), fibres, lignin and some minerals

• Promoters- human milk and animal protein

• Calcium and copper decrease absorption

• Iron- high iron content (more than 25mg) inhibit zinc absorption

Sanfstead HH Understanding zinc: recent observations J Lab ClinMed 2001

• Oral zinc supplements- zinc linked to aspartate, histidine and cysteine has highest
absorption followed by zinc chloride and acetate .

• Zinc oxide has least bioavailability

• Percentage of elemental zinc varies. Eg zinc sulfate has 23% elemental zinc.
220mg zinc sulfate has 50mg elemental zinc

Sanfstead HH Understanding zinc: recent observations J Lab ClinMed 2001

Functions of zinc
Biochemical function
• Catalytic role- cofactor for hundreds of metalloenzymes
• Structural role- activity of zinc finger proteins
• Regulatory role- maintain homeostasis

Cellular functions
• Growth and cell development
• Cell membrane integrity
• Tissue repair and wound healing

Christos et al,Zinc and human health: an update, review article,Arch toxicol 2012
Endocrine
• Reproduction- spermatogenesis
• Growth- IGF-1, GH action
• Thyroxine synthesis and action
• Insulin storage and release
• Prolactin secretion

• Skeletal - bone mineralization

• Hematology - coagulation factors production

Christos et al,Zinc and human health: an update, review article,Arch toxicol 2012
Neurological functions- cognition, memory, taste and visual acuity

Immunological functions-
• maintain adaptive and innate immunity
• Regulate inflammatory response to stress and pathogens
• Regulate apoptosis mediated by caspases
• Increases expression of antioxidants

Christos et al,Zinc and human health: an update, review article,Arch toxicol 2012
Zinc deficiency
Epidemiology

• Global estimates of zinc deficiency in pediatric population are lacking.

• An analysis of data from Food and Agricultural Organization the prevalence might
be 40% worldwide

• Evidence from diet assessment studies in children indicate an overall prevalence

of zinc deficiency as 30-57% in children and adolescents from Asian and South
African countries
Groups at risk

Infants and children-

• exclusive BF provide adequate zinc for 1st 6 months
• delayed complementary feeding, use of cereal foods (low zinc content)

Adolescents, Pregnant and lactating women-

• Physiological requirement increase with pubertal spurt, pregnancy and lactation
Causes of zinc deficiency
Class of Causes Individual Causes

Inadequate intake GI disease: Crohn’s disease, jejunoileal bypass, small bowel resection,
acrodermatitis enteropathica
Pancreatic disease: cystic fibrosis

Reduced absorption Low dietary zinc, inadequately supplemented nutrition, diet rich in phytate,
sodium polyphosphate or EDTA

Increased losses GI: inflammatory bowel disease, diarrhea, steatorrhea, enterostomy, fistula.
Skin: burns
Urine: burns, trauma, sepsis, renal disease, drugs (eg, thiazides, penicillamine,
valproate, ACEI, ARB, cisplatin)
Dialysate: hemofiltration

Increased demand Systemic illness resulting in increased oxidative stress

Callum et al, zinc: physiology, deficiency, Nutrition in clinical practice Aspen 2012
 Consequences of zinc deficiency

System Signs and symptoms

Gastrointestinal system Loss of appetite, diarrhea, anorexia, taste and smell dysfunction

Hair and nails Early greying, alopecia, Blackening of nails, nail dystrophy

Skin Acne, delayed wound healing, dermatitis

Eye Impaired vitamin A metabolism, photophobia, conjunctivitis

Central nervous system Behavioral abnormalities, depressed mood, impaired cognition, intention tremor

Reproductive Impaired reproduction, hypogonadism in males, deficient mothers can have growth
retarded fetus
Growth and development Impaired immunity , thyroid dysfunction, growth failure, delayed sexual maturation,
decreased lean body mass, bone fractures
• Impairment of physical growth and development most significant during periods
of rapid growth- pregnancy, infancy and puberty

• Early infancy and preschool, diarrhea-prominent. Impaired cognition, behavioral

problems, learning disability.

• School going children - Skin problems, alopecia, growth retardation, recurrent

infections, impaired taste perception, poor cognitive performance.
Zinc and Infections

• Acute Diarrhea- by impairment of immune system and intestinal mucosal cell

transport.

• Various studies show children are benefitted by zinc supplements by reducing

duration and severity of diarrhea

• The World Health Organization and UNICEF recommend short term

supplementation (20mg/day or 10mg/day <6 months for 14 days) for acute
childhood diarrhea
• Pneumonia- a meta analysis of 7 RCT with 1066 children from developing
countries with severe acute lower respiratory tract infections compared
therapeutic role of zinc with placebo. No statistically significant differences
noted in the two groups in terms of duration of severe illness and hospitalization.

• A 2010 meta-analysis with 10 RCT with 50000 children <5years with ALTI who
received either zinc or placebo for more than 3 months. It was concluded that
prophylactic zinc significantly reduced incidence of ALTI by 35%.

Teeranai et al Zinc supplementation in pediatric pneumonia Can Fam Physician 2017

• Common cold: Researchers hypothesized that zinc inhibit rhinovirus binding and
replication in nasal mucosa.

• Studies show conflicting results, overall zinc appears to be beneficial. Recently, a

Cochrane review concluded “zinc (lozenges or syrup) is beneficial in reducing
the duration and severity of the common cold in healthy people, when taken
within 24 hours of onset of symptoms”

• However, more research is needed to determine the optimal dosage, zinc

formulation and duration of treatment before a general recommendation can be
made

Fact sheet for health professional, Zinc, NIH.gov

Disease Trials showing effects of zinc supplementation
Malaria One out of 7 trials showed significant reduction in prevalence of
malaria (Zeba et al, Nutr. J 2008) Most studies showed reduced
diarrhea morbidity in malaria

HIV No effect on viral load (Bobat et al, Lancet 2005)

Hepatitis C Improved response to interferon-α therapy (Murakami et al, J Nutr
Sci, 2005)

Shigellosis Faster recovery from acute illness (Roy et al, J Clin. Nutr, 2008)
Helicobacter Increased cure rate (Kashimura et al, 2001)
pylori
 Zinc and Sepsis
Pathogen

Production of inflammatory cytokines

Upregulation of import proteins

Serum Redistribution of zinc from serum to liver Liver

Decrease serum zinc Increase in liver zinc

Nutritional immunity (limit zinc to Cytokine production

pathogens)

Reprogramming of immune system Acute phase reactants synthesis

Fig.1.Possible functions of zinc in sepsis

Weibke et al, Zinc and sepsis, Nutrients MDPI, 2018

• One of the characteristics of acute phase reaction is hypozincemia possibly due to
redistribution

• Several studies have shown a correlation between a patient’s serum zinc

concentration and the severity of the inflammatory response or sepsis

• In critically ill patients, those with high SOFA score had significantly lower serum
zinc level than patients with a low SOFA score, whereby high SOFA score was
associated with higher mortality.

Weibke et al, Zinc and sepsis, Nutrients MDPI, 2018

Zinc deficiency and impaired immunity
Innate immunity
Neutrophils Chemotaxis, oxidative burst and phagocytosis decreases
Monocytes Chemotaxis and adhesion decreases
Macrophages Cell maturation and functional activity impaired
Natural killer cells Cell proliferation and lytic function impaired
Dendritic cells Number and activity decreases

Adaptive immunity
Thymus Thymic atrophy, thymulin and thymocyte count decreases
T-cells Function decreases, CD4/CD8 ratio decreases, Th1/Th2 imbalance
B-cells Maturation and T-cell dependent antibody production decreases
Zinc and Chronic diseases

• Acrodermatitis enteropathica is a genetic disorder due the mutation of the gene

encoding ZIP-4 causing disturbance in zinc uptake. The low zinc levels results in
skin lesions, growth retardation and lymphopenia

Img. Malcolm Pinto et al, Acrodermatitis enteropathica in an infant, Indian journal of Dermatology, Venerology and Leprosy 2015
• Chronic inflammatory conditions reported to be associated with zinc deficiency
include bronchial asthma, atherosclerosis, rheumatoid arthritis, inflammatory
bowel diseases and systemic lupus erythematosis

• In hemolytic diseases such as sickle cell anemia and thalassemia, reports have
suggested low plasma zinc levels and have attributed this to high protein turnover
in hemolysis and hyperzincuria

Prasad AS J Clinical chemistry ,1995

• Chronic kidney disease – low zinc due to altered protein metabolism,
gastrointestinal malabsorption and altered renal excretion and tissue redistribution

• Chronic liver disease- induction of hepatic metallothionein and activation of

specific zinc transporters, decreased dietary intake, poor absorption and increased
urinary excretion. Moreover, hypoalbuminemia in cirrhosis alters the plasma zinc
levels.

Damianaki K, Renal handling on zinc in CKD, Neph Dia Tr, 2020

Fig.2. Zinc deficiency influencing various chronic diseases

Laura M. Int J Environ Res Public Health 2010

Biomarkers of zinc
• No specific marker of zinc status due to homeostatic mechanisms

• Zinc levels in RBCs, leukocyte and plasma or serum can be measured. Others
include urine and hair zinc concentration and activity of zinc dependent enzymes
such as carbonic anhydrase and ALP

Serum zinc concentration μg/dL (μmol/L)

<10 years >10 years >10 years (Males)
(Females)
AM
AM 65(9.9)
65(9.9) 66(10.1)
66(10.1) 70(10.7)
70(10.7)
PM
PM 57(8.7)
57(8.7) 59(9.0)
59(9.0) 61(9.3)
61(9.3)
Conversion factor μmol/L= μg/dL 6.54

Suggested lower cutoffs (2.5th percentile) of serum zinc. NHANES II data

Prevention and treatment
• Best prevent measure is by increasing intake of foods rich in absorbable zinc

• Demonstrated benefits for pneumonia, diarrhea and growth impairment

• Zinc supplementation shows height and weight increments in underweight and

stunted children

• In prepubertal children, zinc supplementation enhanced beneficial effect of

calcium, vitamin D, and growth hormone therapy for bone mass accrual.

Penny ME. Zinc supplementation in public health. Ann Nutr Metab. 2013
• Zinc
  deficiency in infants and children upto 5 years can be treated with zinc
sulfate salt 100g of elemental zinc/kg/day. Children may receive 8-10mg/day and
adolescents 15-mg/day

• Acrodermatitis enteropathica : zinc sulfate or gluconate, infants and toddlers 90-

130mg/day and older children 180-220mg thrice daily

• Wilsons disease- zinc sulfate, gluconate or acetate salts, 220mg thrice daily
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