Zinc: another miracle

micronutrient


Dr N. P. Singh
Senior Consultant Pediatrician, Rockland Hospital


Until 1961 it was believed that zinc deficiency
in humans could never occur.
In 1958, a 21 year old male patient in the Iranian city
of Shiraz presented with dwarfism, hypo-gonadism,
hepato-splenomegaly, rough and dry skin, mental
lethargy, geo-phagia, and iron deficiency anaemia.
In the following three months 10 more patients with
a similar illness were seen in the same hospital.

Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency anemia,
hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961;
31: 532-546
Zinc and its effect
When pregnant mice were fed a diet
moderately deficient in zinc, their offspring
exhibited a malfunctioning immune system
for the first 6 months of life. More alarming,
the second & third generations also showed
signs of poor immunity - even though they
were fed a zinc-plentiful diet.
Jean Carper, writing in Jean Carper's Total Nutrition Guide, in ref to zinc studies done at U.C. Davis
Problem
Large sections of populations in Africa and Asia
are at risk of dietary zinc deficiency and resulting
high rates of stunting.
International Zinc Nutrition Consultative Group (IZiNCG). Assessment of the risk
of zinc deficiency in populations. Food Nutr Bull 2004;25:S130-62

30- 50% of children residing in low income setting have
low serum or plasma zinc
Overall poor dietary intake
Low intake of animal source of food
High consumption of phytates
Increased fecal losses during diarrheal illnesses
Zinc : Its role in human body
2
nd
most abundant trace element in body
There are no zinc stores in the body to mobilize
from, and in 16 hours an animal can be deficient
with rapid effects.
Functions:
Metabolism (functions in over 200 enzymatic reactions)
Antioxidant function
Immunity and Wound healing
Fetal Growth and Development
Production of brain neurotransmitters
Needed for protein & enzyme function, DNA synthesis
and genetic expression.

Stabilization of cell membranes.

Immunity & wound healing.

Vitamin A transport.

Taste and smell.

Fetal development.

Food sources
- Oysters, red meat, poultry.

- Sea food

- Beans, nuts, whole grains.

- Fortified breakfast cereals.

- Dairy products
Requirements
0-6 months : 2mg/day.
7 months-3 years : 3mg/day.
4-8 years : 5 mg/day.
Pre-adolescent children :10 mg/day.
Adolescents :12-15 mg/day.
Pregnancy :15 mg/day.
Lactation :20 mg/day.
Symptoms & Signs of Zinc
Deficiency

Growth retardation
Dwarfism
Alopecia
Delayed puberty in
adolescents
Rough skin
Poor appetite
Mental lethargy
Delayed wound healing
Delayed skeletal maturation
and defective mineralization
of bone (monkeys).

Weight loss

Intercurrent infections

Hypogonadism in males

Lack of sexual development
in females
Symptoms & Signs of Zinc
Deficiency

White spots on fingernails
Reduction in collagen
turnover and synthesis
(in chicks)
Reduction in collagen
(in humans)
Poor Immune system
Acne
Cross-linking of collagen
Short stature
Diarrhea
Pneumonia
Stretch marks (striae)
Hyaluronic acid
abnormalities (in swine)
Defective connective
tissue
Macular degeneration
Cataracts (in salmon)

Zinc Deficiency
Severe Deficiency
- Acrodermatitis enteropathica
- Syndrome of hypogonadism, stunting,
anemia, anorexia and hepatosplenomegaly.

Mild/Subclinical Deficiency
- susceptibility to infection/
- wound-healing time.
- Growth retardation
- Pregnancy related complications and LBW




Safe Upper Limit of Zinc Intake
0.5 -1 yr 13mg/d

1 - 6 yr 23mg/d

10 - 12 yr 32mg/d Girls
34mg/d Boys

Normal reference range: 60 -130 mcg/dl
To convert to international unit in micromol/L,
multiply by conventional units by 0.1530.
Trace elements in human nutrition and health. Geneva. WHO 1996.
Theme of Discussion
Zinc in Diarrheal Disease

Zinc in Intercurrent Infections

Miscellaneous use

Clinical Standpoints
Study by P R Sharma : Bhaktapur
Published in 2002 (Pediatrics; Vol 109; No 5; May 2002)

6-35 months
Diarrhea > 96 hours
Passage of 3 or more loose or watery stools in
the 24 hour period before enrollment.
Daily during diarrhea until 7 days after recovery.
2.5 mg of Zinc/ml
Infants: 6ml (15mg)
Older children: 12 ml (30 mg)
Pediatrics 2002;109:898-903
Profile of a randomized, placebo-controlled trial evaluating 3 RDAs of
daily zinc administration as treatment for acute diarrhea in children 6 to
35 months of age.
Same study:
Randomized placebo controlled trial in
Bhaktatpur with 450 children in each of
four groups placebo, Zn, Zn with Vit A
given by field worker, and Zn by mother

Enrollment Characteristics of 4 Groups:
(Duration of supplementation 9.9-10.6 days)
Variable Placebo Zinc Vitamin A-zinc Caretaker zinc
Mean age month 15.9 15.3 15.5 15.4
Percentage breast fed 81.4 82.8 83.6 83.7
Mean number of diarrhea
days before enrollment
2.2 2.1 2.2 2.2
Percentage dehydrated 11.9 12.1 10.4 12.1
Percentage wasted 23.3 21.5 23.8 20.3
Percentage of mother
who can read
50.0 53.1 45.6 58.1
Average plasma zinc
conc
n
(micro mol/dl)
8.6 8.7 8.8 8.7
Findings: n = 2053
(Pediatrics: vol. 109; No 5; May 2002)
Recommended Daily Allowances of zinc given daily by
caretakers or by field workers substantially reduced the
duration of diarrhea. The effect of zinc was not dependent
on or enhanced by concomitant vitamin A administration.
Prolonged diarrhea of more than 7 days decreased by
43 - 47% in Zn groups.


Vomiting during diarrhea was also more common in
children receiving zinc.
The recent report 2008: Bangladesh
More patients in the zinc group than in the control group
recovered by two days (49% v 32%, P=0.032) and by 3
days (81% v 68%, P=0.03).

Zinc supplemented patients had 12% shorter duration of
diarrhea than control patients (64.1 v 72.8 h, P=0.028)
and 11% less stool output (1.6 v 1.8 kg/day, P=0.039).

S K Roy Zinc supplementation in children with cholera in Bangladesh:
randomised controlled trial BMJ 2008;336:266-268
Combination of zinc with iron/folic acid
One study in children in Peru with persistent diarrhoea
found higher rates of diarrhea, respiratory infections, and
febrile episodes in the children who received multiple
micronutrients and zinc compared with those given zinc
supplementation alone.
Penny ME, Marin RM, Duran A, Peerson JM, Lanata CF, Lonnerdal B, et al. Randomized controlled trial of the effect
of daily supplementation with zinc or multiple micronutrients on the morbidity, growth, and micronutrient status of
young Peruvian children. Am J Clin Nutr 2004;79:457-65.[


In Zangibar another study daily iron and folic acid with iron
and folic acid and additional zinc or placebo in infants, the
iron and folic acid supplementation arms were stopped
early because of a significantly higher rate of mortality.
Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic
supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria
transmission setting: community-based, randomised, placebo-controlled trial. Lancet 2006;367:133-43
Zinc supplementation in the
treatment of diarrhoeal disease
Paulo Froes, MD, MPH, PgD OH & S
UNICEF/TACRO, Health and
Nutrition/Immunization Plus
Incorporating new global recommendations into
country-level policy and action
Zinc supplementation: clinical
evidence
Randomised placebo-controlled clinical trials
evaluating the impact of zn. supplementation
during acute and persistent diarrhea.

WHO meeting in New Delhi, 2001 convened
to review the results of all studies available.

Zinc in acute diarrhea
Reduces duration of diarrhea episode by up to 25%

Decrease by about 25% the proportion of episodes
lasting more than seven days

It is associated with a 30% reduction in stool volume

Conclusion: significant beneficial impact on the clinical
course of acute diarrhea: reduces both severity and
duration.
Zinc in persistent diarrhoea
Zinc-supplemented children had:
24% lower probability of continuing diarrhoa
42% lower rate of treatment failure or death


Conclusion: zinc supplementation reduces
the duration & severity of persistent diarrhea.

Zinc in bloody diarrhoea
Positive impact of the prevalence of dysentery in the month
following the supplementation


Improves sero-conversion to shigella-cidal antibody response
and increases the proportions of circulating B lymphocytes &
plasma cells and the IgA-specific immunoglobulin response.


Conclusion: zinc supplementation should be given as an
adjunct to antibiotic treatment of bloody diarrhea.
Cost-effectiveness studies
zinc supplementation significantly improved the
cost-effectiveness of standard management of
diarrhea for dysenteric as well as non-dysenteric
illness.


Sufficient evidence to recommend the inclusion of
zinc into standard case management of both
types of acute diarrhea.
The new WHO-UNICEF recommended policies
for health professionals on the Rx. of diarrhoea
Counsel mother to begin administering suitable home fluids immediately
upon onset of diarrhea in a child.
Treat dehydration with new low osmolarity ORS solution (or with
intravenous electrolyte solution in cases of severe dehydration)
Emphasize continued feeding or increased breastfeeding during, and
increases feeding after, the diarrhoeal episode
Use antibiotics only when appropriate, i.e., in the presence of bloody
diarrhoea or shigellosis, and abstain from administering anti-diarrhoeal
drugs
Advise mothers of the need to increase fluids and continue feeding
during future diarrheal episodes.

Provide children with 20 mg per day of zinc supplementation for
10-14 days (10 mg per day for infants under six months old).

Zinc in diarrheal diseases: -
Evidence based:
Pooled analysis of RCTs:
1. Zn supplementation in preschool well nourished &
malnourished children:
18% lesser incidence of acute diarrhea

2. Zn supplementation in a dose of 10 - 30mg during
acute diarrhoea in children (6month 3 years):
15% faster recovery
22% reduction in diarrhoea lasting for > 7
days
Stool output reduction by 30%

Zinc in diarrheal diseases
Effect on persistent diarrhea
40% reduction in treatment failures and 40%
reductions in deaths.

In all studies effect of zinc did not vary
significantly with -
1. age
2. nutritional status as assessed by anthropometry
3. type of zinc salts
4. little gain in efficacy with increased dose from
20 mg. to 30 or 40 mg.

Zinc in ORS:
Efficacy of 40 mg elemental zinc with a liter
of WHO ORS as compared with ORS without
zinc and zinc syrup separate from ORS in
reducing the duration of diarrhea.

Zinc syrup separately - most efficacious
Zinc with ORS - next efficacious
ORS alone - least efficacious


Zinc in Diarrhea: The key message
No other treatment has been proven as efficacious as
zinc in reducing the duration of acute diarrhea in children
of developing countries.

Antibiotics, antiparasitic, antimotility & antisecretory
drugs and enzymes are overused.

Decreasing the occurrence of prolonged and persistent
diarrhea by zinc administration may substantially reduce
the number of childhood diarrhea deaths.

Let every child with diarrhea have zinc for one week.
Role of zinc in childhood infections
Case reports & observational studies:
Evidence of relation between low plasma
zinc & increased susceptibility to infections

Limitations: Relative inadequacy of plasma
Zn as marker of def., lack of appropriate cut-
offs & possible effect of coexisting nutritional
deficiency on plasma zinc level.


Zinc as adjunct treatment in infants aged between 7
and 120 days with probable serious bacterial infection:
a randomised, double-blind, placebo-controlled trial
(AIIMS Study between 2005-2008)

Zinc reduced treatment failure in infants younger than 120
days with probable serious bacterial infection by 40%.

Use of zinc also reduced the number of deaths, although the
difference between the groups was not significant.

When analysis was restricted to infants 60 days or younger,
still recorded a beneficial effect. Time to recovery, weight gain,
or exclusive oral feeding was not affected by zinc supplements,
and weight at recovery did not differ significantly.
Zinc in respiratory infections
Three RCTs:
Bangladesh - 30% reduction in the duration of
illness in severe pneumonia.

India - 2.6 times increase in recovery rates from
severe ALRI (seen in boys only).

Nepal - More than 2600 children enrolled in a study
to find the impact of zinc as an adjunctive
therapy in pneumonia.


Efficacy of zinc as an adjuvant therapy for childhood
acute lower respiratory tract infections at Bhaktapur

Randomized double
Blinded
Case Controlled
Screening : 8823
2-12 months 4586
13-35: 4237

Total enrolled: 2683
2-12 months: 1107
13-35: 1576
Result:
yet to be published
Efficacy of zinc as an adjuvant therapy with
severe pneumonia admitted in KCH
Randomized
Double Blinded
Case Controlled

Total screened:
2271
Total enrolled: 641
2-12 months: 534
13-35: 107
Result:
Yet to be published
SFD infants and PEM
Maternal zinc supplementation during pregnancy resulted
in a reduction of the health risks in Bangladeshi low-birth
weight infants.
Osendarn SJ et al Zinc supplementation during pregnancy and effects
on growth and morbidity in low birthweight infants: a randomised placebo
controlled trial. Lancet. 2001 Apr 7; 357 (9262):1080-5

India: 68% reduction in mortality in term SFD infants with
zinc supplementation (5mg/d from day 30-284).

A study in Lesotho: in severe PEM cases mortality during
hospitalization was significantly lower in zinc group (4.7%)
compared to no zinc group (16.7%).
Makonnen B et al. ; Journal of tropical pediatrics. 2003, vol. 49, no6, pp. 353-360
Neurodevelopment & cognition
Zinc may act as neurotransmitter, and by influencing cell
division, maturation and growth in early fetal life and may
thus determine later neurodevelopment and intellect.

Evidence from animal models, psychiatric patients and
early studies from infants suggests: Zn deficiency affects
cognition, neurodevelopment, responses to stress and
emotion and motor activity.

More trials needed to evaluate (critical period, risk group,
reversibility).
Other effects of Zinc
Large doses of Zn may decrease copper
absorption of Zn from gut. Zn has been
used in Wilson disease.

Benefit in treatment of ADD.

Zn lozenges in treatment of cold - at
present, inconclusive.
Zinc and physical growth
A review of 33 different studies: small +ve impact on
weight gain and length with Zn supplementation in
pre-pubertal children.

Trial of Zn suppl + iron & folates during pregnancy:
increased fetal well being (heart rate & movement).

Other large subsequent trial in Burkina Faso - no
effect

At risk diseases
Zinc deficiency has now been recognized
to be associated with many diseases e.g.,
mal-absorption syndrome, chronic liver
disease, chronic renal disease, sickle cell
disease, diabetes, malignancy, and other
chronic illnesses.
Prasad AS. Clinical spectrum of human zinc deficiency.In:
Prasad AS, ed. Biochemistry of zinc. New York: 1993:219-258.
What is your diagnosis?
Eye problems
Antioxidants and zinc supplements delayed
progression of age related macular degeneration
and reduced the risk of loss of vision.
Age-Related Eye Disease Study Research Group (AREDS) Report No.
8. A randomized, placebo-controlled, clinical trial of high-dose
supplementation with vitamins C and E, beta-carotene, and zinc for
age-related macular degeneration and vision loss. Arch Ophthalmol
2001;
Immunological enhancement
It has now been shown that in people with zinc
deficiency, activity of serum thymulin (a thymus
specific hormone involved in T cell function) is
decreased, an imbalance between T helper cell
(Th1) and Th2 function develops, and lytic activity
of natural killer cells and the percentage of the
precursors of cytolytic T cells is decreased.
Prasad AS, Meftah S, Abdallah J, Kaplan J, Brewer GJ, Bach JF. Serum thymulin
in human zinc deficiency. J Clin Invest 1988; 82: 1202-1210[Medline]. 11. Beck
FWJ, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ. Changes in cytokines
production and T cell subpopulations in experimentally induced zinc-deficient
humans. Am J Physiol 1997; 272: E1002-E1007
No Limits
A study from Chandigarh, India found that plasma zinc levels
was about 45% lower in pica group than in controls where as
serum iron was about 20% lower than in the controls.
Singhi S, Ravishanker R, Singhi P, Nath R. Low plasma zinc and iron in pica. Indian J Pediatr
2003;70:139-43.
A randomized trial in preschool children in Papua New Guinea
demonstrated 38% reduction in plasmodium falciparum health
centre based episodes and episodes.
Shankeu AH, Genton B, Baisor M et al. The influence of zinc supplementation on
morbidity due to plasmodium falciparum: a randomized trial in preschool children in
Papua New Guinea. Am J Trop Med Hyg. 2000;62:663-9.
Zinc supplementation in patients with sickle cell anemia seems
to prolong red cell life span and reduces vascular obstruction
and also cause maturation of gonads.
Prasad AS, Abbasi AA, Rabbani P et al. Effect of zinc supplementation on serum
testosterone level in adult male sickle cell anemia subjects. Am J Hematol
1981;10:119-27.
Preventive aspects of Zn treatment
Zn supplementation for 10-14 days has
preventive effect on childhood sicknesses.

In 2-3 months after treatment:
25% reduction in diarrhea (9 studies)
34% reduction in pneumonia (5 studies)

* Zinc supplementation is already added
in IMCI strategy by WHO
Safety of zinc supplementation
8500 children < 5 years of age, supplemented
in 17 trials:
Vomiting is the only reported side effect.

5 of seven trials showed no difference between zinc and
placebo.

2 trials showed slightly higher vomiting rates in zinc
supplemented children, but IV use was not increased.
Zinc supplement and cost
Delivery mechanisms are syrups, dispersible
tablets (easy to store).

Cost per course: NRs. 15-20

Will save cost of unnecessary antibiotics,
other drugs and hospitalization.

International studies have shown good cost
effectiveness.


Clinical Standpoints
Zinc Deficiency
Zinc nutritional status is difficult to measure adequately using lab
tests due to its distribution throughout the body as a component of
various proteins and nucleic acids.

Plasma or serum zn levels are the most commonly used indices for
evaluating zn deficiency, but these levels do not necessarily reflect
cellular zinc status due to tight homeostatic control mechanisms.

Clinical effects of zinc deficiency can be present in the absence of
abnormal laboratory indices so consider risk factors (inadequate
caloric intake, alcoholism & digestive diseases) and symptoms of
zinc deficiency (growth in infants and children) when determining
the need for zinc supplementation.

Groups at Risk of Zinc Inadequacy
People with gastrointestinal and other diseases.

Vegetarians

Pregnant and lactating women

People with sickle cell disease

Alcoholics
Zinc and Health
Immune function:


The common cold: Researchers have hypothesized that zinc could reduce
the severity and duration of cold symptoms by directly inhibiting rhinovirus
binding and replication in the nasal mucosa & suppressing inflammation
Several studies are described in which zn is administered as a lozenge or
zinc-containing syrup that temporarily "sticks" in the mouth and throat. This
allows zn to make contact with the rhinovirus in those areas.


Age-related macular degeneration


Wound healing:


Zinc and Health
Interactions with iron and copper: Fortification of foods with iron does not
significantly affect zinc absorption. However, large amounts of supplemental iron
(> 25 mg) might decrease zinc absorption. Taking iron supplements between
meals helps decrease its effect on zinc absorption. High zinc intakes can inhibit
copper absorption, sometimes producing cu. deficiency and associated anemia.


It is also used for asthma; diabetes; high blood pressure; acquired
immunodeficiency syndrome (AIDS); and skin conditions such as psoriasis,
eczema, and acne.


It is also used for malaria and other diseases caused by parasites.






Symptoms of Zinc Deficiency

Low zinc will produce an altered sense of taste leading to cravings of
saltier, sweeter food.


Deficiency can also be indicated by diarrhea, low energy, chronic
fatigue, infertility, poor immunity, bad memory, inability to focus, ADD
symptoms, slow wound healing, nerve dysfunction, ringing in the ears.


Symptoms may be present, but because they are so diverse and a/w
other health conditions, its often hard to make the link to zn deficiency
without a test.

Health Risks from Excessive Zinc
Acute adverse effects of high zinc intake include nausea, vomiting,
loss of appetite, abdominal cramps, diarrhea, and headaches.

Chronic effects as low copper status, altered iron function,
reduced immune function, and reduced levels of HDL.
Reductions in a copper-containing enzyme, a marker of copper status, have
been reported with even moderately high zinc intakes of approx. 60 mg/day
for up to 10 weeks.

>80 mg per day of zinc for 6.3 years, have been a/w a significant
increase in hospitalizations for genitourinary causes, raising the
possibility that chronically high intakes of zinc adversely affect
some aspects of urinary physiology.
Interactions with Medications
Antibiotics: Both quinolone and tetracycline interact with zinc in the
gastrointestinal tract, inhibiting the absorption of both zinc & antibiotic.
Taking the antibiotic at least 2 hours before or 46 hours after taking a
zinc supplement minimizes this interaction.

Penicillamine: Zinc can reduce the absorption & action of penicillamine,
a drug used to treat rheumatoid arthritis. To minimize this interaction,
individuals should take zinc supplements at least 2 hours before or after
taking penicillamine.

Diuretics: Thiazide diuretics viz. chlorthalidone, hydrochlorothiazide
increase urinary zinc excretion by as much as 60%. Prolonged use of
thiazide diuretics could deplete zinc tissue levels, so clinicians should
monitor zinc status in patients taking these medications.
Forms of Zinc supplements
Here are the most common forms of zinc supplements :
Pills
Powder
Lozenges
Nasal sprays
Nasal gels


The most common way (and practical) to take zinc is by
the form of oral supplement pills.
What is the best chemical form of zinc
supplement?

Zinc supplements come in different chemical forms :
Zinc acetate
Zinc sulfate
Zinc picolinate
Zinc glycerate
Zinc monomethionine
Zinc gluconate
Zinc oxide


The reason for these chemical formulas is because zinc alone is not easily
absorbed by our bodies. To optimize absorption it is chelated to amino acids
like zinc picolinate or made in inorganic form such as zinc sulfate or zinc
oxide.


What is the best chemical form of zinc
supplement?

The best form of zinc is Picolinate

Why is zinc picolinate the best form?

Because it has the highest absorption rate of all.
Meaning that for every gram that you take you get the
maximum amount digested and absorbed straight to your
blood, cells and so on. Even better, picolinate is of THAT
much more expensive than other forms so its a win-win.

Prescribing tool
Proper Use
Zinc supplements are most effective if they are taken at least 1 hour before or
2 hours after meals. However, if zinc supplements cause stomach upset, they
may be taken with a meal. You should tell your health care professional if you
are taking your zinc supplement with meals.


Missed Dose
If you miss a dose of this medicine, take it as soon as possible. However, if it
is almost time for your next dose, skip the missed dose and go back to your
regular dosing schedule. Do not double doses.
If you miss taking zinc supplements for one or more days there is no cause for
concern, since it takes some time for your body to become seriously low in
zinc.
Precautions
When zinc combines with certain foods it may not be absorbed
into your body and it will do you no good. If you are taking zinc,
the following foods should be avoided or taken 2 hours after you
take zinc:
Bran
Fiber-containing foods
Phosphorus-containing foods such as milk or poultry
Whole-grain breads and cereals


Do not take zinc supplements and copper, iron, or phosphorus
supplements at the same time. It is best to space doses of these
products 2 hours apart, to get the full benefit from each dietary
supplement.

Side Effects
Check with your doctor as soon as possible if any of the following side
effects occur:
Rare
Chills
continuing ulcers or sores in mouth or throat
fever
heartburn & indigestion
nausea
sore throat
unusual tiredness or weakness
Symptoms of overdose
Chest pain
dizziness & fainting
shortness of breath
vomiting
yellow eyes or skin
Other side effects not listed may also occur in some patients. If you notice any other effects, check
with your healthcare professional.

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