Zinc another miracle micronutrient Dr Pushpa Raj Sharma

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. l 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 3 rd most abundant trace element in body l There are no zinc stores in the body to mobilize from, and in 16 hours an animal can be deficient with rapid effects. l Functions: v Metabolism (functions in over 200 enzymatic reactions) v Antioxidant function v Immunity and Wound healing v Fetal Growth and Development v Production of brain neurotransmitters l

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 l Large sections of populations in Africa and Asia are at risk of dietary zinc deficiency and resulting high rates of stunting. l l l International Zinc Nutrition Consultative Group (IZi. NCG). Assessment of the risk of zinc deficiency in populations. Food Nutr Bull 2004; 25: S 130 -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 and defective mineralization of bone (monkeys) Weight loss Intercurrent infections Hypogonadism in males Lack of sexual development in females Growth retardation Dwarfism l l l l l Delayed puberty in adolescents Rough skin Poor appetite Mental lethargy Delayed wound healing Short stature Diarrhea Pneumonia Stretch marks (striae)

Symptoms of Zinc Deficiency l l l 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) l Defective connective tissue l Macular degeneration l Cataracts (in salmon) l

Zinc Deficiency l Severe Deficiency l l Acrodermatitis enteropathica Syndrome of hypogonadism, stunting, anemia, anorexia and hepatosplenomegaly. l Mild/Subclinical Deficiency l l susceptibility to infection/ wound-healing time. Growth retardation Pregnancy related complications and LBW

Safe Upper Limit of Zinc Intake l 0. 5 -1 yr 13 mg/d l 1 -6 yr 23 mg/d l 10 -12 yr 32 mg/d 34 mg/d l Girls Boys Normal reference range: 60 -130 mcg/dl l To convert to international unit in micromol/L multiply by conventional units by 0. 1530

Role of zinc in childhood infections l Case reports & observational studies: Evidence of relation between low plasma zinc & increased susceptibility to infections l 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) l l l l 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: 6 ml (15 mg) Older children: 12 ml (30 mg)

Our study: l Randomized placebo controlled trial in Bhaktatpur with 450 children in each of four groups – placebo, 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 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) l 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. l l 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). l 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). l l 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 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 diarrhoeal diseases: Evidence based: Pooled analysis of RCTs: 1. Zn supplementation in preschool well nourished & malnourished children: l 18% lesser incidence of acute diarrhoea l 2. Zn supplementation in a dose of 10 -30 mg during acute diarrhoea in children (6 month – 3 years): l 15% faster recovery l 22% reduction in diarrhoea lasting for > 7 days l Stool output reduction by 30%

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

Combination of zinc with iron/folic acid l 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 l 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. [ l 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. l 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 l 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 l Maternal zinc supplementation during pregnancy resulted in a reduction of the health risks in Bangladeshi low-birth weight infants. l 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 (5 mg/d from day 30 -284). l 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%). l l Makonnen B et al. ; Journal of tropical pediatrics. 2003, vol. 49, no 6, 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 l Evidence from animal models, psychiatric patients & early studies from infants suggests: Zn def. affects cognition, neurodevelopment, responses to stress and emotion and motor activity l More trials needed to evaluate (critical period, risk group, reversibility) l

Other effects of Zinc l Large doses of Zn may decrease copper absorption of Zn from gut. Zn has been used in Wilson disease l Benefit in treatment of ADD l Zn lozenges in treatment of cold- at present, inconclusive.

Zinc and physical growth l A review of 33 different studies: small +ve impact on wt gain & length with Zn supplementation in prepubertal children l Trial of Zn suppl + iron and folates during pregnancy: increased fetal well being (heart rate & movement). l Other large subsequent trial in Burkina Faso- no effect

At risk diseases l 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 l 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 l Antioxidants and zinc supplements delayed progression of age related macular degeneration and reduced the risk of loss of vision. l 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 l 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 (Th 1) and Th 2 function develops, and lytic activity of natural killer cells and the percentage of precursors of cytolytic T cells is decreased. l 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: E 1002 -E 1007

No Limits l 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 l l A randomized trial in preschool children in Papua New Guinea demonstrated 38% reduction in plasmodium falciparum health centre based episodes and episodes l l 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 l 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 l Zn supplementation for 10 -14 days has preventive effect on childhood sicknesses l 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 l 8500 children < 5 years of age, supplemented in 17 trials: Vomiting is the only reported side effect l 5 of seven trials showed no difference between zinc and placebo l 2 trials showed slightly higher vomiting rates in zinc supplemented children, but IV use was not increased l

Zinc supplement and cost l Delivery mechanisms are syrups, dispersible tablets (easy to store) l Cost per course: NRs. 15 -20 l Will save cost of unnecessary antibiotics, other drugs and hospitalization l International studies have shown good cost effectiveness

The key message l No other treatment has been proven as efficacious as zinc in reducing the duration of acute diarrhea in children of developing countries. l 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. l Let every child with diarrhoea have zinc for one week. l

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