Transcript Zinc: another miracle micronutrient

Zinc: another miracle
micronutrient
Dr. Pushpa Raj Sharma
Professor of Child Health
Institute of Medicine
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, hypogonadism,
hepatosplenomegaly, rough and dry skin, mental
lethargy, geophagia, 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 : Its role in human body



3rd 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
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 six months of life. More
alarming, the second and 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 reference 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
Symptoms of Zinc Deficiency
Delayed skeletal maturation  Delayed puberty in
adolescents
and
defective mineralization of
 Rough skin
bone (monkeys)
 Poor appetite
Weight loss
 Mental lethargy
Intercurrent infections
 Delayed wound
Hypogonadism in males
healing
Lack of sexual development
 Short stature
in females
Growth retardation
 Diarrhea
Dwarfism
 Pneumonia
 Stretch marks (striae)
Symptoms 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




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
 1 -6 yr
 10 -12 yr


13mg/d
23mg/d
32mg/d
34mg/d
Girls
Boys
Normal reference range: 60-130 mcg/dl

To convert to international unit in micromol/L multiply by
conventional units by 0.1530
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 cutoffs and possible effect of
coexisting nutritional deficiency on
plasma zinc level

Our study: Bhaktapur
Published in 2002 (Pediatrics; Vol 109; No 5; May 2002)







6-35 months
Diarrhoea > 96 hours
Passage of 3 or more loose or watery stools in
the 24 hour period before enrollment.
Daily during diarrhoea until 7 days after
recovery.
2.5 mg of Zinc/ml
Infants: 6ml (15mg)
Older children: 12 ml (30 mg)
Our 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
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
Pediatrics 2002;109:898-903
Enrollment Characteristics of 4 Groups:
(Duration of supplementation 9.9-10.6 days)
Variable
Placebo
Zinc
Vitamin Azinc
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
diarrhoea 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
concentration
(micro mol/dl)
8.6
8.7
8.8
8.7
Our 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 three days (81% v 68%, P=0.03).
Zinc supplemented patients had 12% shorter duration
of diarrhoea 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
Zinc in diarrheal diseases
Effect on persistent diarrhoea
40% reduction in treatment failures and 40%
reductions in deaths
In all studies effect of zinc did not vary significantly with1. 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 diarrhoeal diseases:
Evidence based:

Pooled analysis of RCTs:
1. Zn supplementation in preschool well nourished &
malnourished children:
 18% lesser incidence of acute diarrhoea
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 ORS:
Efficacy of 40mg 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 diarrhoea
Zinc syrup separately- most efficacious
Zinc with ORS
- next efficacious
ORS alone
- least efficacious
Combination of zinc with
iron/folic acid

One study in children in Peru with persistent diarrhoea found
higher rates of diarrhoea, 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 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 foetal life and may thus determine later
neurodevelopment and intellect
 Evidence from animal models, psychiatric
patients & early studies from infants suggests:
Zn def.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 wt gain & length with Zn
supplementation in prepubertal children
 Trial of Zn suppl + iron and 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
recognised to be associated with many
diseases for example, malabsorption
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 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: 12021210[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 whereas
serum iron was about 20% lower than in the controls


A randomized trial in preschool children in Papua New
Guinea demonstrated 38% reduction in plasmodium
falciparum health centre based episodes and episodes


Singhi S, Ravishanker R, Singhi P, Nath R. Low plasma zinc and iron in pica. Indian J
Pediatr 2003;70:139-43.
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

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, and 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 diarrhoea have zinc for one week.

THANK YOU
This presentation is available on