Micronutrient: Diarrhoea and Malnutrition

Dr.S.K.Roy Senior Scientist ICDDR,B ASCODD XII: Yogyakrta May 25th 27th , 2009

Welcome to my presentation

Outlook of the presentation

Background Major micronutrients related with Diarrhoea Relationship among Malnutrition, Diarrhoea and Micronutrient Micronutrient metabolism in diarrhoea Therapeutic effect of Micronutrients in Diarrhoea Preventive effect of Micronutrients in Diarrhoeal Disease Risk Factors for micronutrients deficiency in diarrhoea and malnutrition Gaps to fill, Strategies for improvent

Background
Diarrhoea remains a leading cause of morbidity and mortality among children <5 years of around the world Diarrhoea can be more frequent and severe due to micronutrient malnutrition ICDDR,B treats 120,000 patients yearly, 40% adults and 60% children, with 0.002% CFR

Causes of death among children aged under five years

(WHO, 2004)

10 Leading causes of death in the world

10 Leading causes of death in Low-income Countries

Distribution of global child deaths by cause

Bars=uncertainty bounds. *Work in progress to establish the cause specific contribution of being underweight to neonatal deaths, Lancet 2003 (Child Survival-1, Black et al)

Risk of mortality by malnutrition after treatment of diarrhoea

Mortality 140 /1000 100

10 0 55 65 75 85 Nutritional state (% NCHS standard)

Roy et al. 1983

Major micronutrients related to Diarrhoea

Zinc Vitamin A Folic Acid Iron Copper Magnesium

Relationship among Malnutrition, Diarrhoea and Micronutrient Deficiency

Malnutrition

Micronutrient Deficiency

Diarrhoea

Micronutrients deficiency causes Diarrhoea malnutrition

Diarrhoea (loss of water & electrolytes) AD PD Loss ofVitamin A Zinc Folic Acid Iron Copper

Immunity Infection Loss of Micronutrients Malnutrition

Physiological Functions of Zinc

Brain development Synthesis and metabolism of protein and Immunity nucleic acid

Functioning of insulin

Zinc

Wound and burn healing

Epithelial cell lining

Membrane stabilization

Calcification and mineralization of bone

Zinc Deficiency

Zinc Supplementation
Mucosa Levels of the brush border enzymes Enhanced cellular immunity

First Line of Defense Cellular Immunity Humoral Immunity

Size of spleen and thymus

Level of secretary antibodies

Functioning and production of T-cells, B-cells and macrophages Production of immunoglobulins (IgA, IgM, IgG)

Mechanism of diarrhoea in animal model

Deficient
Zn+ + in diet Intestinal mucosa Clinical abnormalaities

Growth

Enterocyte population

Enterocyte size

Ultrastructural abnormality Membrane defect

Lateral space Desmosen defect Mitochondrial disruption Lysosomal activity

Reduced absorption Increased secretion

Endoplasmic reticulam defect Ribosomal defect Na+ K+ ATP ase

Increased net secretion of Water and electrolytes Diarrhoea

Roy et al 2006

Animal model study on net transport of water and electrolytes during inin -vivo Perfusion (Mean + SEM)
Absorption Per/cm/hr ZD (n=5) ZAL (n=5) ZDR (n=5)

Water (l) Sodium (mmol) Potassium (mmol)

**p<0.001

27.6+2.0** 48.5+5.8 3.5+1.1* 0.07+0.2 7.2+2.0 0.07+0.02

57.7+5.2 7.7+3.0 0.03+0.1

(Roy et al 1985)

*p<0.005

Zinc in Cholera toxin induced secretion

Net secretion of water, sodium and potassium in zinc deficient, acutely repleted and ad Libitum zinc fed rats in response to cholera toxin (mean SEM)
+10 0

Water

Sodium

Potassium

+2 0

Transport of water

-10 -20 -30 -40 -50 -60 -70 ZAL ZD -8 ZDR -10 -2

-4

-6

(Roy et al. 1985,2005)

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Function of vitamin A
Epithelial tissue Formation

Immunity increase

Vitamin A
Antioxidant Embryonic development Develop structural protein

Mechanisms by which micronutrients deficiency may influence intestinal secretion and absorption

Host immunity

Hormonal control (e.g. aldosterone, thyroid)

Quality of cell membranes

Intestinal secretion/ absorption

Number of enterocytes

Integrity of Mucosal surface

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Micronutrient metabolism in diarrhoea

Zinc is excreted proportionately high with severity of diarrhoea Cu and Mg also excreted from diarrhoea Zinc absorption is substantially reduced during diarrhoea

Excretion of trace elements in stool during persistent diarrhoea (median, range)

Micronutrients Zinc (mg/Day) Mg (g/kg) Cu (g/kg) Median (Range) 4. 5 (1.10-68.57) 4673 (736- 71214) 21.5 (1.53-138.2)
Roy et al 2004

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Loss of total zinc (mg) over 4 days in stool during Persistent diarrhoea and recovery phase
Diarrhoea Rice suji+Zn (15) Rice suji + Placebo (19) Chicken diet+ Zn (15) 35.511.1 9.86.2 28.110.5 Recovery p value* 5.03.3 <0.001 4.44.5 8.27.0 0.24 0.004

*t-test

Roy et al 2001

Lancet Series , 2003

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Therapeutic effect of Micronutrients in Diarrhoea

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Zinc supplementation in children during acute diarrhoea Total stool weight (g/kg body weight)(median range)

Placebo
All children 329 (32(32-1464) n=37

Zinc
238 (35 (35-2416) n=37 229 (33 (33-2496) n=37 279 (43 (43-2416) n=30

p value*
0.06 <0.04 <0.049

Ht/age <95% 326 (31(31-1460) n=33 Serum zinc (<14mol/L) 326 (99(99-1464) n=25

*Mann*Mann -whitney U test

Roy et al. 1997

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Probability of recovery from cholera by zinc supplementation

Roy et al,BMJ, 2008

Impact of zinc supplementation on period of recovery in days and weight gain in shigella dysentery
Zinc (n=28)
Time (days) to recovery, median (range) Time (days) to disappearance of mucous from stool median (range) Body weight (kg) On admission, mean SD At discharge, mean SD p value *Mann-whitney U test *Mannapaired tt-test Roy et al. 2007 2 (1(1-8) 2 (1(1-7)

control (n=28)
4 (1 (1-8 ) 4 (1 (1-7 )

p value*
0.03 * 0.04

8.75 1.2a 9.20 0.4

0.000

9.38 1.4a 9.60 1.8

0.12

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Impact of Zinc Supplementation on Weight Gain(in kg) in Stunted,Wasted and Zinc Deficient Children with Acute Diarrhoea
On admission H/A <95% of NCHS median Placebo (n=42 Zinc (n=50) Serum Zinc <14 mol/L Placebo (n=40) Zinc (n=43)
*Willcoxons

On discharge

p value*

6.28 (4.52-8.80) 6.08 (4.03-8.50)

6.27 (4.50-8.82) 6.20 (4.20-8.80)

0.7 0.006

6.31 (4.52-9.16) 6.04 (4.22-8.80)

6.23 (4.50-9.86) 6.20 (4.20-8.80)

0.49 0.05

Matched pair test

(Roy et al. 1997)

Impact of zinc supplementation on period of recovery in days in persistent diarrhoea patients (mean SD) Placebo
All Patients n=68 7.0 3.8

Zinc
n=73 6.4 3.6 n=34 6.1 3.2 n=49 6.0 3.5

p Value
0.30

Patients <70% W/A n=30 of NCHS median 8.1 3.7 Male children only n=42 7.6 4.1

0.03

0.05

(Roy et al. 1998)

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Pooled Analysis of the Therapeutic Effect of Zinc Supplementation on Acute and Persistent Diarrhoea Recovery Continuation for >7 d, failure, death Trial Recovered Censored Excluded RR n n n (95%CI) 1368 931 101 0 6 9 30 0 1 0.79(0.69,0.90) 0.85(0.57,1.28) 0.85(0.78,0.92) 0.85(0.76,0.95) 24 52 32 32 87 0 1 0 0.82(0.60,1.12) 0.85(0.61,1.19) 0.45(0.26,0.78) 0.98(0.57,1.67) 0.76(0.62,0.92) 0.75(0.62,0.91) 0.76(0.63,0.91) 11(7.9) 7(7.4) 164 138 55 55 9(20.5) 13(9.6) 17(17.9) 22(50.0) 0.81(0.35,1.88) 0.37(0.14,0.92) 0.25(0.10,0.64) 0.60(0.38,0.93) 0.58(0.37,0.90) 0.61(0.26,1.46) Zinc 47(6.4) Control 57(8.6) OR
(95% CI)

Acute Diarrhoea Indonesia 0.92(0.83,,1.02) India Bangladesh Pooled multifactorial Pooled random effect Persistent Diarrhoea Peru Bangladesh Bangladesh Pakistan Pooled Pooled multifactorial Pooled random effect

0.72(0.48,1.07) 0.77(0.33,1.79) 0.80(0.62,1.02) 0.78(0.56,1.09)

70(15.4) 85(17.7) 0.85(0.60,1.19) 14(24.6) 16(29.6)

16(37.2) 12(27.3) 1.58(0.64,3.91)

Comparison of cumulative stool output (mg kg-body wt) of children with persistent diarrhoea during hospitalization

Khatun et al, 2001

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Table :Zinc and copper supplementation in Diarrhoeal disease

Outcome variable Intervention Mean SD Difference (95% Cl)*
62.2 33.5 64.4 37.8 64.4 35

Adjusted Difference (95% Cl)**

Duration of diarrhea (hours)* from enrollment

Placebo Zn Zn+Cu

2.2 (-4.1,8.5) 2.2 (-3.8,8.2)

1.9 (-2.23,2.55) -0.9 (-2.37,2.2)

* The difference is as compared with the placebo group ** Adjusted for following covariates: age, gender,prior duration of diarrhea, weight-for-age Z-score at most 2, dehydration status, receipt of medication, water safety, wealth index, type of stool, baseline serum zinc and serum copper.

Preventive effect of Micronutrients in Diarrhoeal Disease

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40 Cumulative length gain (mm)

Impact of Zinc Supplementation on Length Gain in Acute Diarrhoea Patients (mean SD)
Zinc Placebo *p <0.03

30

* * *

20

* * *

10

week1

week2

week3

week4

week5

week6

week 7

week 8

Week of follow up

(Roy et al, 1997)

Morbidity among Stunted (<91% Ht/age) Patients of Acute Diarrhoea During 8 Weeks of Follow-up Period
2.5

Number of attacks

Placebo
2

Zinc

*p<0.05

1.5

* *

0.5

* *
0

All diarrhoea

Watery Diarrhoea URTI

LRTI

All RTI

Type of illness

(Roy et al, 1997)

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Effect of supplementation with zinc or vitamin A or both on Diarrhoea and dysentery

There was no overall effect of high-dose vitamin A supplements on the incidence of diarrheal disease. However, there was a significant interaction between supplementation and age: vitamin A increasedthe incidence of diarrhea in children <30 mo of age, but tended to reduce the incidence in older children.

The finding of a significant adverse effect of vitamin A supplements in adequately nourished children highlights the need to review the criteria for selecting populations of preschool-age children for vitamin A supplementation.

Summary of the use of vitamin A, zinc, and folic acid supplementation for the prevention and treatment of diarrhoeal disease in childhood.
Supplementation Current recommendation type Vitamin A Universal twice-yearly supplementation for children 6-59 months of age, for overall reduction in mortality Trials of prevention of diarrhoea associated morbidity, no.(finding) 9 (2 noted positive effects, 2 noted adverse effects, and 5 noted no effects) Trails of diarrhea treatment, no (finding) 5 (2 noted positive effects in the subgroup, but not overall; 3 noted no effects) 20 ( 16 noted positive effects, and 4 noted no effects)

Zinc

Supplementation for 10-14 days for the treatment of diarrhea Supplementation in conjunction with iron for children 6-24 months of age in areas where malaria is not endemic and where the prevalence of anemia is 40%

24 (18 noted positive effects, and 6 noted no effect)

Folic acid

None

1 (no effect was noted)

Micronutrients and Diarrheal Disease* CID 2007:45 (suppl 1* S75 )

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Risk Factors for micronutrients deficiency in diarrhoea and malnutrition

a. b. c. Inadequate dietary intake (cultural/geographical/economic/ignorance) Decreased bioavailability Loss of micronutrients in diarrhoea During acute and persistent diarrhoea, large amounts of zinc and other micronutrients are lost through stool (Roy et al 2004) Children with severe PD lost about 300 g/kg/day in stool. (Rothbaum et al. 1982) AD leads to Zn & Cu depletion. (Castillo-Duran et al. 1988) PD in children is associated with lower serum levels of Zn & Cu (Rodriguez et al. 1985) Children with PD appear to be at high risk for developing Vitamin A deficiency. (Natarajan et al. 1990)

Explore the potential: Research

1. ZINC suppl. In adults diarrhoea 2. Add zinc in ORS packets Clinical : zinc to AD, PD, Shigellosis, cholera

A.To improve the content and bioavailability of zinc

Increase intake of food with highly bioavailable zinc Reduce phytate and inhibitors for absorption Using germination, fermentation and soaking to reduce phytic acid, a potent inhibitor of zinc absorption. (Gibson et al.1998) .

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B. Adequacy of micronutrients in diets, through dietary diversification specially animal foods, coloured vegetables

C. Food fortification for improving the status of micronutrients

D. Genetically modified food grains for higher micronutrient content.

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