DR. M. S. PRASAD 1

ZincZincZincZinc

Dr. M. S. PrasadDr. M. S. PrasadConsultant & HeadDept. of PaediatricsSafdarjung Hospital & Vardhaman Mahavir Medical College New Delhi

Dr. M. S. PrasadDr. M. S. PrasadConsultant & HeadDept. of PaediatricsSafdarjung Hospital & Vardhaman Mahavir Medical College New Delhi

DR. M. S. PRASAD 2

ZincZinc Atomic No. 30 Atomic Weight: 65.409 Melting point: 7870 F [4200 C] Since 2500 yrs: in the production of

Brass. Romans used brass to make coins,

kettles and decorative items.

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Zinc in Zinc in naturenature

Zinc constitutes approximately 0.02% of the earth’s crust.

Zinc is a poor conductor of electricity and heat.

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ZincZinc

Metallic zinc first produced in India Metallic zinc first produced in India sometime in 1400s.sometime in 1400s.

Initial methodInitial method:: By heating mineral By heating mineral Calamine (ZnCOCalamine (ZnCO33) with wool.) with wool.

Later methodLater method:: By heating calamine By heating calamine with charcoal [Andreas Sigismund with charcoal [Andreas Sigismund Marggraf 1746]Marggraf 1746]

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Industrial Uses

Galvanization. Dry Cell Batteries. Roof Cladding. Die Casting. Making alloys: Brass, Prestal, German Silver,

Typewriter Metal, Nickel Silver, Spring Brass.

Red Oxide: protects from rusting.

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Industrial Uses Paints. Rubber Products. Cosmetics Pharmaceuticals Plastic Printing Ink. Soap.

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Industrial Uses

ZnS: Glows when exposed to UV light. Used in Luminous watch dials. Television Screen. Florescent light bulbs.

ZnCl2: Protects wood from decay and insects.

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1979 A 3 yr old girl suffering from ALL

developed “common cold”.

She took unsweetened zinc gluconate lozenges.

This cured her common cold.

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19841984

Numerous Numerous manufacturer placed on manufacturer placed on the market “the market “improved” improved” zinc lozenges that were zinc lozenges that were sweetened.sweetened.

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1985 - 1995 Many patents. Many trials by manufacturers. Zinc Gluconate forms very

bitter complexes with all carbohydrates (except fructose).

At least two formulations made the cold worse.

Trials dropped and discovery discredited.

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Areas of Zinc concentrationAreas of Zinc concentration

Pancreas, Prostate, Kidney, Liver, Muscles, and Retina.

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Co-factors of many enzymes

As many as 300 enzymes require zinc for optimum function.

Carbonic Anhydrase.

Alkaline Phosphatase.

CofactorsCofactors (continued)

LDH

Pancreatic Carboxypeptidase.

Superoxide Dismutase.

And many others.

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Nucleic Acid Metabolism and

Protein synthesis Zinc Finger Motif. Receptor for Steroid-

Thyroid, 1, 25 (OH)2 – D3

TF III-A Protein. A single amino acid

mutation results in resistance to this hormone and may lead to Rickets.

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FUNCTIONS OF ZINCFUNCTIONS OF ZINC Zinc is an Zinc is an antioxidantantioxidant nutrient. nutrient. Necessary for:Necessary for:

– Protein SynthesisProtein Synthesis– Wound HealingWound Healing

Vital for:Vital for:– Development of Reproductive OrgansDevelopment of Reproductive Organs– Prostate FunctionProstate Function– Male Hormone Activity Male Hormone Activity

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FunctionsFunctions [Continued][Continued]

Governs the Governs the contractility of musclescontractility of muscles Important for Important for blood stabilityblood stability Maintains body’s alkaline balanceMaintains body’s alkaline balance Helps in normal tissue functionHelps in normal tissue function Helps in digestion and metabolism Helps in digestion and metabolism

of phosphate.of phosphate.

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Functions Functions (Contd)(Contd)

Involved in cell-membrane structure.

Anti-oxidant metallo-thionine synthesis.

Part of several transcription factors: nucleophile.

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Functions (Continued)

A A component of many enzymes.component of many enzymes.

Multiple role in:Multiple role in: Nucleic Acid MetabolismNucleic Acid Metabolism Protein SynthesisProtein Synthesis

Important for membrane Important for membrane structure and functionstructure and function.

Acts as antibacterial in semen

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Daily Reference Intake

0 – 6 mo:0 – 6 mo: 2 mg/day2 mg/day 7 mo – 3 yr:7 mo – 3 yr: 3 mg/day3 mg/day 4 – 8 yr:4 – 8 yr: 5 mg/day5 mg/day 9 – 13 yr:9 – 13 yr: 8 mg/day8 mg/day 14 – 18 yr:14 – 18 yr:

– Male:Male: 11 mg/day11 mg/day– Female:Female: 9 mg/day9 mg/day

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RDA [Elemental Zinc]

0 – 6 mo: 3 mg 6 – 12 mo: 5 mg 1 – 10 yrs: 10 mg Adults: 15 mg

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Dietary SourcesDietary Sources Oysters. Liver, Meat. Grains, Wheat Bran, Whole meal wheat

flour and Bread, Oatmeal. Sardines, Crab. Nuts, Legumes. Cheese. Milk.

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Causes of Zinc Deficiency

Protein Energy Malnutrition.Protein Energy Malnutrition. DietaryDietary

– During periods of rapid growth– High phytate intake in diet

TPN without ZincTPN without Zinc Impaired AbsorptionImpaired Absorption

– Regional Enteritis– Cystic Fibrosis

Excessive LossesExcessive Losses [e.g. Chronic Diarrhoea] Inborn Error of Zinc MetabolismInborn Error of Zinc Metabolism

[Acrodermatitis enteropathica]

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Effects of Deficiencies

Acrodermatitis Enteropathica. Hypogonadism. Growth Failure. Impaired Wound Healing. Decreased Taste and Smell

acuity. Skin Ulcers. Decreased Immune Response. Iron Deficiency Anaemia. Altered Mood. Jitteriness.

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Effects of Effects of DeficiencyDeficiency

PEM + Zn Deficiency = Atrophy of Thymus.

Zinc supplementation accelerates healing of skin lesions.

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Effects of Zinc DeficiencyEffects of Zinc Deficiency Impaired growth. Poor wound healing Bullous Dermatitis. Immunity Defects

– Particularly T-Cell function with increased susceptibility to infection.

Alopacia Night Blindness. GIT Disturbances. Nervous System Disorders. Impaired Carbohydrate Metabolism.

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Biochemical Methods used in diagnosis of Zn deficiency

Plasma Zinc. WBC Zinc. Hair Zinc. Urine Zinc.

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Plasma Zinc Levels[Before Breakfast][Before Breakfast]

NormalNormal:: 60 – 100 μg60 – 100 μg//dldl

Moderate DeficiencyModerate Deficiency:: 40 – 60 µg40 – 60 µg//dLdL

Severe DeficiencySevere Deficiency:: < 40 µg/dL< 40 µg/dLIn patients with mild deficiency, plasma concentration may be within the normal range

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Acrodermatitis Enteropathica

Zinc malabsorption Zinc malabsorption Deficiency Deficiency RashesRashes [around mucocutaneous jn and extremities]

AlopaciaAlopacia Chronic DiarrhoeaChronic Diarrhoea [sometimes Steatorrhoea]

FTTFTT Low Serum ZincLow Serum Zinc Low Serum Alkaline PhosphataseLow Serum Alkaline Phosphatase Paneth Cell InclusionPaneth Cell Inclusion in intestinal mucosal biopsy. .

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Acquired acrodermatitis Acquired acrodermatitis with erythematous scaly with erythematous scaly

lesions and candida lesions and candida albicans superinfection albicans superinfection

occurs in premature occurs in premature neonates on parenteral neonates on parenteral

nutrition with insufficient nutrition with insufficient zinc supplements.zinc supplements.

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Treatment

Zinc Sulfate:Zinc Sulfate:

1 – 2 mg/kg/day orally1 – 2 mg/kg/day orally [Elemental Zinc]

Separately from meals and from Iron supplementationsDuration: 3 months

Acrodermatitis Enteropathica

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Wilson Disease

Zinc has unique ability to impair the Zinc has unique ability to impair the gastrointestinal absorption of copper.gastrointestinal absorption of copper.

Zinc acetate is given in adults at a dose of Zinc acetate is given in adults at a dose of 25 to 50 mg three times a day.25 to 50 mg three times a day.

Pediatric dosing guidelines have not been Pediatric dosing guidelines have not been established. established.

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Common Cold

3C Protease is an essential enzyme 3C Protease is an essential enzyme for replication offor replication of rhinovirusrhinovirus..

Zinc inhibits function of this Zinc inhibits function of this enzyme.enzyme.

Further studies requiredFurther studies required..

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HyperbilirubinemiaHyperbilirubinemia

Zinc protoporphyrinZinc protoporphyrin or or mesophyrinmesophyrin [ZnPP or ZnMP][ZnPP or ZnMP] are inhibitors of are inhibitors of haem haem oxygenaseoxygenase, the enzyme that begins , the enzyme that begins the break- down of haem. the break- down of haem.

Studies are under way involving a Studies are under way involving a single injection of these substances single injection of these substances shortly after birth to prevent the shortly after birth to prevent the formation of bilirubinformation of bilirubin..

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Zinc Supplements

Infants & ChildrenInfants & Children:

0.5 – 1 mg/kg/24 hrs

in 1 – 3 doses. AdultsAdults:

25 – 50 mg/dose tid

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Advantages of Zinc Supplementation in Community

Improved immunocompetenceImproved immunocompetence

Reduction in incidence of Reduction in incidence of Acute and Persistent Acute and Persistent DiarrhoeaDiarrhoea in community in community

Increased activity levelsIncreased activity levels

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TPN Supplement

Preterm:Preterm: 400 400 μgμg/kg/24 hr/kg/24 hr Infants < 3 mo: Infants < 3 mo: 250 250 μgμg/kg/24 hr/kg/24 hr

Infants > 3 mo: Infants > 3 mo: 100 100 μμg/kg/24 hrg/kg/24 hr

Children: Children: 50 50 μμg/kg/24 hrg/kg/24 hr

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Other UsesOther Uses

Zinc is also used as ingredient in Zinc is also used as ingredient in shampoo and paste.shampoo and paste.

Zinc deficiency depresses appetite and Zinc deficiency depresses appetite and growth. It can be corrected with oral growth. It can be corrected with oral zinc supplements given over 1-2 mo. zinc supplements given over 1-2 mo.

20 mg Zinc daily for 14 days in Severe 20 mg Zinc daily for 14 days in Severe Malnutrition, Acute and Persistent Malnutrition, Acute and Persistent Diarrhoea and Measles.Diarrhoea and Measles.

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Excess of Zinc Excess of Zinc causes cirrhosiscauses cirrhosis

Excess of zinc has been associated with cirrhosis of liver in river Nile belt.

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Other features of Zinc Toxicity

G. I. Irritation.

Copper Deficiency.

Decreased HDL.

Zinc Pneumonia:– A form of Aspiration Pneumonia due to inhalation

of baby powder containing Zinc Stearate.

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Zinc ToxicityZinc Toxicity Acute Zinc Toxicity:

– GIT Disturbances

Chronic Zinc Toxicity:– Interferes with absorption of other essential

elements such as calcium.

Causes of acute toxicity:– Ingestion.– I. V. Infusion.– I. V. contamination during hemodialysis.

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Other Symptoms

Zinc Chloride has caustic action and can cause lacerations and dermatitis of the exposed skin.

Zinc pyrithione, found in shampoos, also is reported to cause dermatitis.

Zinc chloride and zinc sulfate can cause significant eye injuries.

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Symptoms (Contd)

Eye manifestations: Delayed Pulmonary vascular fibrosis. Drinking acidic beverages from galvanized

containers. Microscaopic haematuria. Acute Tubular Necrosis. Zinc Metal Fume Fever. [Page 303, Chapter 66, Pediatric and Adolescent Environmental Health 2004. Vol.2]

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Specific Treatment of Zinc Toxicity

Dimercaprol:2.5 – 5 mg/Kg deep I.M. every 4 hrs for 2 days, then 2.5 mg/kg x 2 for 7 – 14 days.

Penicillamine:250 mg – 2 g daily orally in divided doses.

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Zinc Zinc against against

DiarrhoeaDiarrhoea

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DiarrheaZn def

+

+

Zn & DiarrheaVicious Cycle

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Effect of zinc on time of recovery

4.7

6.2

0

1

2

3

4

5

6

7

Zinc Control

Day

s

Zinc ControlArch Dis Child. 1997 Sep;

77(3):196-200

25% reduction in time to recovery

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2002:2002: Zn deficiency included as a Zn deficiency included as a major risk factor in the global burden of major risk factor in the global burden of diseases.diseases.

2004:2004: WHO/UNICEF included Zn WHO/UNICEF included Zn supplements in the treatment ofsupplements in the treatment of acute diarrhoea.acute diarrhoea.

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Effects of zinc supplements on Diarrheal incidence in LBW children < 1 yr

1.36

1.96

0

0.5

1

1.5

2

2.5

Zinc Placebo

Pediatrics 2003 Dec;112(6 Pt 1):1327-32

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Zinc Zinc supplementatiosupplementatio

n has shown n has shown 18% reduction 18% reduction in incidence of in incidence of

diarrhoea.diarrhoea.

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Therapeutic EffectsTherapeutic EffectsZinc was found to have a

therapeutic benefit in seven trials of acute diarrhoea and five of

persistent diarrhoea.

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Mechanism of action of Zinc Direct GI effects:

– Intestinal water and electrolyte transport.– Brush Border Enzymatic Functions.– Intestinal Tissue Repair.– Improvement of Intestinal permeability.

Immunomodulatory effects: Antimicrobial effect: Antioxidant effect:

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Immunomodulatory effects

Enhances cellular immunity Higher levels of secretary antibodies. Facilitates functions of Neutrophils, NK Cells,

Monocytes and Macrophages. T-helper & cytotoxic T-Lymphocyte activity.

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Antimicrobial Effect

Zinc Sulphate has been shown to have an Zinc Sulphate has been shown to have an antimicrobial effect on the enteric pathogen.antimicrobial effect on the enteric pathogen.

The following enteric pathogens tested were inhibited:– S. typhi [20% inhibition at conc. 0.8 mg/ml]– S. paratyphi [1.2 mg/ml]– V. cholerae 01 and Shigella flexneri [1.4 mg/ml]– Shigella sonnei [1.6 mg/ml]

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Antioxidant EffectAntioxidant Effect

Scavenging effect against NOScavenging effect against NO– The excess production of NO triggers formation of cyclic

nucleotides, which causes secretion and malabsorption. Stabilizes thiol groups and Stabilizes thiol groups and

phospholipids in membrane. phospholipids in membrane. Occupies sites of redox active Occupies sites of redox active

metals such as iron.metals such as iron.

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WHO/UNICEF WHO/UNICEF Consensus StatementConsensus Statement

Zinc supplementation, given at a dose of about 2 RDA per day (10 to 20 mg/d)

for 14 days, is efficacious in significantly reducing severity of

diarrhoea as well as duration of the episode.

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Recommendations of Recommendations of IAP Task ForceIAP Task Force

A uniform dose of 20 mg of elemental Zinc should be given during the period of diarrhoea and for 7 days after cessation of diarrhoea to children older than 3 months.

Recommendations for below 3 months must await further research.

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Recommendations Recommendations of IAP Task Forceof IAP Task Force

Iron containing formulations should not be used with zinc as iron interferes with zinc absorption.

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Sazawal S, Black RE, Bhan MK: Zinc supplementation in young children with acute diarrhoea in India.

• This study evaluated the effects of daily supplementation with 20 mg of elemental zinc on the duration and severity of acute diarrhoea.

• There was 23% reduction (95% C. I.) in the risk of continued diarrhoea.

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Sazawal et al (Contd.)

• The reductions in the duration and severity of diarrhoea were greater in children with stunted growth than in those with normal growth.

• CONCLUSIONCONCLUSION:: For infants and young children with acute diarrhoea, zinc supplementation results in clinically important reductions in the duration and severity of diarrhoea.

N Engl J Med 1995 Sep 28; 333 (13): 839-44.

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Bhandari N, Bahl R, Taneja S.Bhandari N, Bahl R, Taneja S.:: Zinc Supplementation in Young North Indian ChildrenZinc Supplementation in Young North Indian Children

Door to Door Survey. 4 months daily zinc supplementation. 6 to 30 months of age residing in urban

slums of Dakshinpuri in south Delhi. Zinc supplementation reduced the incidence

of severe, persistent and recurrent diarrhoeaPEDIATRICS Vol. 109 No. 6 June 2002, p e86

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Bhatnagar S, Bahl R, Sharma PK: Zinc with oral rehydration therapy.

The authors evaluated the effect of zinc treatment as an adjunct to oral rehydration therapy.

Zinc treatment reduced total stool output and stool output per day.

The duration of diarrhoea was also low. The risk of persistent diarrhoea was low.

J Pediatr Gastroenterol Nutr. 2004 Jan; 38(1): 34-40

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Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat:

Therapeutic effects of Zinc.

The effects of supplemental Zinc given with Oral Rehydration Therapy.

The study concluded that Zinc supplementation reduces the duration and severity of acute and persistent diarrhoea.

Am J Clin Nutr 2000; 72: 15161522

DR. M. S. PRASAD 66

BMJ 2002; 325 (7372): 1059

Children with diarrhoea were treated with zinc 20 mg per day for 14 days.

Bangla Desh: 8070 children aged 3 – 59 months studied.

They had shorter duration and lower incidence of diarrhoea.

The incidence of ARI was also low. Hospital admission was low.

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Hospitalization due to diarrhoea

0.59

0.98

0

0.2

0.4

0.6

0.8

1

1.2

Zinc Placebo

Odds Ratio

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There is innumerable There is innumerable number of studies on number of studies on

the role of Zinc in the role of Zinc in Diarrhoea, ARI and Diarrhoea, ARI and

Malnutrition. All show Malnutrition. All show statistically significant statistically significant beneficial effect of zinc beneficial effect of zinc

supplementation.supplementation.

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ZincZinc is especially is especially

important in adolescence important in adolescence because of its role in because of its role in

growth and sexual growth and sexual maturation.maturation.

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