uauy

Linear Growth Retardation (Stunting) and Nutrition

Ricardo Uauy INTA University of Chile and

London School of Hygiene and Tropical Medicine

Stunting prevalence and number affected in developing countries

1990 2000 2010

010

2030

4050

Stun

ting

(%)

40.3

48.6

23.7

39.337.7

18.1

38.2

27.6

13.5

1990 2000 20100

5010

015

020

0

Num

ber o

f stu

nted

(milli

ons)

45

190

13

51

138

10

60

100

7

AFRICA ASIA LATIN AMERICASource: Department of Nutrition, World Health Organization

171 million children under 5 are stunted

Source: WHO Global Database on Child Growth and Malnutrition, May 2009

125 cms

4 yrs old7 yrs old7 yrs old

100 cms

Stunting Stunting

Most common form of undernutrition (PE/micronutrients)

Affects infants before and early after birth

Linked to maternal size, nutrition during pregnancy & fetal growth

Length that is lost early on is rarely recovered

Stunted have less lean body mass (lower RMR per kg bw)

105 cms

Methods• Data from WHO Global Database on Child Growth and Malnutrition – standardized data

• National surveys from 54 countries (52 DHS and 2 MICS) – all but 7 surveys conducted since 2000

• 32 low income, 17 lower middle income, 5 upper middle income

• Re-analyzed raw datasets with WHO standards – calculated mean WAZ, HAZ, WLZ by month

• Countries aggregated by WHO regions - only 2 countries in WPRO, grouped with EURO (Mongolia) and SEARO (Cambodia)

Source: Victora CG, de Onis M, Hallal PC, Blössner M, Shrimpton R. Worldwide timing of growth faltering: revisiting implications for interventions using the World Health Organization growth standards. Pediatrics, 2010 (Feb 15Epub print)

Mean z-scores for age all 54 studies, relative to the WHO standard

Source: Victora CG, de Onis M, Hallal PC, Blössner M, Shrimpton R. Worldwide timing of growth faltering: revisiting implications for interventions using the World Health Organization growth standards. Pediatrics, 2010 (Feb 15Epub print)

1930s UK: Boyd Orr: feeding trials of surplus milk disposal to school children: significant increase in height, improvement in “general appearance”. India: Aykroyd and Krishnan (1937) skimmed milk supplemented school children grew faster in heightNew Guinea: Malcolm (1971) & Lampl et al (1978): skimmed milk supplement increased height of stunted, low protein fed childrenUS: Fomon et al. (1977): skimmed milk (low energy, high protein)-fed infants showed same length growth but less weight gain than high energy formula. Bangladesh: Kabir et al (1992/3): ASF protein at 15% energy increases IGF-1 and linear growth cf 7.5% protein in children recovering from shigellosis

Milk/Animal source foods interventions improve linear growth

DJ Gunnell J Epidemiol Community Health 1998;52:142–152

Overall and cause specific mortality hazard ratios (95% CI) for men and women in relation to 1 SD increase in overall height and leg length adjusted for childhood socioeconomic

deprivation, calorie consumption, birth order, and adult Townsend score

Presenter

Presentation Notes

Key findings from the cohort study include: Diet, cardiovascular disease and cancer risk: First evidence in humans that that high levels of energy intake are associated with increased cancer risk in later life and that children whose family diets were rich in fruits had a reduced cancer risk. Leg length: Leg length has been found to be a sensitive indicator of pre-pubertal growth patterns and the measurement that best proves the beneficial effects of breast feeding and diet supplements on childhood growth. Breastfeeding: A series of studies examining the relationship between infant nutrition, growth, and health in adulthood is underway. Breastfeeding was associated with being taller in childhood and adulthood; the component of height associated with breastfeeding was leg length but not trunk length. These findings suggest that breastfeeding may be a factor underlying previous findings that taller people (in particular those with longer legs) have less heart disease.

Infection and other

Environmental Factors

Brain Development

Growth muscle/bone Weight & HEIGHTBody composition

Metabolic ProgrammingCHO, Lipids, Proteinshormone,receptor,gene

Fetal & Infant

nutrition

Short term

Immunity

Work Capacity

DiabetesObesityCardiovascularDisease,Stroke Hyper-tension CancerAging

Cognitive capacity & Education

Long term NutritionDiet

• Any essential nutrient can condition abnormal embryonic & organ growth and development (Folate, I, Vit A, E, Fe, Zn, EFA, EAA Pr/Energy)

• Timing of nutrient deficit or excess is crucial ineffect: cell replication/migration/apoptosis/maturation

• Genetic polymorphism affecting nutrient metabolismtransport or tissue levels can modulate effects.

• Nutrients & toxicants (retinoic acid, Pb, Zn, folate)interact in defining normal or abnormal growth.

Nutrient Effects on Growth

Nutrient/Hormones Effects on Growth

Adipose tissue/ weight Hypertrophy

Hyperplasia Brain Bone / lengthaminoacids

I, Fe, Cu, Zn,

Na, K, P,

Energy

n-6 & n-3 EFA

Insulin, IGF1/BP3 Cortisol Leptin, GH T3/T4

Mechanisms by which nutrition conditions linear growth

Gene Expression (transcription factors, single or multiple genes)

Hormones receptors, binding proteins and signal transduction

Cell growth and turnover during critical periods

Nutrition : protein & zinc

IGF-1, IGF-BPs, T3

Oestrogens main regulator of pubertal growth spurt & GP fusion

Infection: Inhibits chondrogenesisCortisol,IL1,TNF,IL6, increase bone destruction

Linear Growth

Presenter

Presentation Notes

Figure 7.4 The growth of long bones. Long bones expand through activity within the epiphyseal growth plate, which lies at the interface of the bone shaft (diaphysis) and end (epiphysis). New cartilage cells (chondrocytes) are formed at the epiphyseal end of the growth plate, while mature cells on the diaphyseal end die and become calcified. The bone extends by virtue of this zone pushing the epiphysis away from the diaphysis.

Nutrition and Infection influence bone length growth

chondrocytes

T3

Nutrition Type 2 nutrients:protein & zinc Chondrogenesis & chondrocyte maturation:

IGF-1, IGF-1BPs, T3TGFβs (transforming growth factor) BMPs, (bone morphogenetic proteins)Oestrogens main regulator of pubertal growth spurt and GP fusion

Infection: Inhibition of chondrogenesisCortisol,IL1,TNF,IL6 , increase bone destruction

Osteoclasts

Kofoed et al. describe a novel mechanism for impaired growth in the form of a mutation in the gene for intra-cytoplasmic protein signal transducer and activation of transcription 5b (STAT5b).

The mutation disrupts the intracellular signalling that promulgates the physiologic effects of growth hormone. This finding illuminates an important arena of molecular genetic abnormalities involving the growth hormone–insulin-like growth factor I (IGF-I) axis.

GH activated signalling. Phosphorylation of the GH receptor leads to activation of metabolic, proliferative and transcriptional pathways. STAT 5b modulates transcription of IGF-1, IGF-BP3, and acid labile subunit, all critical for normal growth.

NEJM 349;12 1139-47 september 18, 2003

Length of the newborn at birth and maternalprotein synthesis in mid pregnancy for 26 women

Sarah L. DUGGLEBY* and Alan A. JACKSONClinical Science (2001) 101, 65–72

Maternal protein flux and neonatal Length

Linear growth (cm/week)Kashyap 1988 and Svenningsen 1982 found no significant difference in linear growth between groups. These findings differed from Kashyap 1986’s study that noted a significant increase in linear growth in infants receiving higher protein intakes.

The inclusion of the Kashyap 1988 study in the meta-analysis revealed a significant difference (WMD 0.16 cm/week, 95% 0.03, 0.30), with greater linear growth with high protein intakes compared to low protein intakes.

• Study participants were less than 2.5 kilograms at birth• Study participants were not receiving parenteral nutrition attime of randomization• Study participants were exclusively formula-fed• Energy, Na, K, P, Zn or essential fatty acid intakes did notdiffer significantly (no more than 10% relative concentration)

LBW protein intake and length growth

Presenter

Presentation Notes

Test for overall effect: Z = 4.42 (P < 0.00001) 2 Linear growth (cm/week) Kashyap 1986 9 1.21 (0.32) 9 0.94 (0.19) 53.6 % 0.27 [ 0.03, 0.51 ] Svenningsen 1982 16 1.02 (0.38) 14 0.99 (0.35) 46.4 % 0.03 [ -0.23, 0.29 ] Subtotal (95% CI) 25 23 100.0 % 0.16 [ -0.02, 0.34 ] Heterogeneity: Chi2 = 1.74, df = 1 (P = 0.19); I2 =42% Test for overall effect: Z = 1.75 (P = 0.081) 3 Head growth (cm/week) Kashyap 1986 9 1.22 (0.28) 9 0.85 (0.15) 100.0 % 0.37 [ 0.16, 0.58 ] Subtotal (95% CI) 9 9 100.0 % 0.37 [ 0.16, 0.58 ] Heterogeneity: not applicable Test for overall effect: Z = 3.49 (P = 0.00048) Test for subgroup differences: Chi2 = 17.70, df = 2 (P = 0.00), I2 =89% -10 -5 0 5 10 Fa

Smith, W. J. et al. J Clin Endocrinol Metab 1997;82:3982-3988

VLBW Calorie and protein intake on IGF-1

Presenter

Presentation Notes

Relationships of IGF-I in serum of premature infants to intake of calories and protein, length of gestation, and day of life. A, IGF-I as a function of calories received per kg BW over the 3 days before blood sampling and as a function of the percentage of calories consumed over 3 days that consisted of protein (percentage of protein in diet). The figure shows the increase in IGF-I that results from increasing the protein content of the diet (a quadratic relationship) and the linear increase in IGF-I that results from supplying more calories. B, The linear increase in IGF-I that occurs with each week’s extension of gestation (mean ± SE, 4.03 ± 0.95 ng/mL·week). There is marked interaction on IGF-I between the length of gestation and the protein intake. As gestation is more prolonged, the magnitude of the rise in IGF-I at higher protein intakes is greater. C, The IGF-I value is not affected by age of the infant when the percentage of calories as protein in the diet is low (6%). However, as the protein content is improved, there is an interaction between age and dietary protein, such that IGF-I values in serum are markedly increased.

Smith, W. J. et al. J Clin Endocrinol Metab 1997;82:3982-3988

VLBW Calorie and protein intake on IGFBP-3

Presenter

Presentation Notes

Figure 3. Relationship of IGFBP-3 in the serum of premature infants to intake of calories and protein, length of gestation, and interval since birth. A, As the supply of calories increase, the IGFBP-3 level increases. The rise in IGFBP-3 observed with increasing percentage of calories as protein is not statistically significant, but there is a borderline interaction of calories and protein on IGFBP-3 (P = 0.059), with the lowest and highest IGFBP-3 values observed when both calories and protein are lowest or highest, respectively. B, A linear increase in IGFBP-3 occurs with each week’s extension of gestation (mean increase, 25.06 ± 11.83 µg/L·week gestation; P = 0.035). No interaction between protein in diet and length of gestation is observed. C, There is a linear increase in IGFBP-3 as the age of the infant increases (mean increase, 4.14 ± 1.33 µg/L·day of life; P = 0.003). No significant effect of dietary protein is seen, and no significant interaction between age and dietary protein is apparent.

Dexamethasone .25/mg x 2 x 7days affects Linear Growth and Neurodevelopment

122.8±7.4 cm

126.4±5.8 cm

Cerebral palsy 17/72 9/74Intelligence Q 78.2 84.4 ***Manual dexterity 6.6 4.8 ***Balance 6.9 3.2 ***Total impairment 19 11 ***Motor coordination 6.7 8.2 ***Visual perception 6.5 7.9 **Visual–motor int 7.1 7.9 **

Tsu F Yeh et al NEJMed 2004

Abstract. Growth and nutrition data from the feasibility phase of a clinical trial that was designed to evaluate the effect of diet protein modification in 24 infants with chronic renal insufficiency (CRI). GFRs less than 55 ml/min per 1.73 m 2 .

Twenty-four infants were randomly assigned at 8 mo of age to receive a low-protein (P : E ratio 5.6%) or control protein (P: E ratio 10.4%) formula, average intakes of 1.4 and 2.4 g/kg/d in low & control groups

Length/age Z at entry (low -2.2 + 1.4 vs. control -1.7 + 1.4). At 18 months the low protein group had a significantly lower length Z (-2.6+ 1.2 vs. while control remained unchanged -1.7+ 1.4).

The length velocity Z from 12 to 18 months were also different, with the low-protein group remaining strongly negative while the control group improved.

Presenter

Presentation Notes

Abstract. This report describes growth and nutrition data from the feasibility phase of a clinical trial that was designed to evaluate the effect of diet protein modification in infants with chronic renal insufficiency (CRI). The purpose of the proposed trial was to compare the safety (effect on growth in length) and efficacy [effect on glomerular filtration rate (GFR)] of a diet with a low protein: energy (P: E) ratio versus a control diet in such patients. Twenty-four infants with GFRs less than 55 ml/min per 1.73 m 2 were randomly assigned at 8 months of age to receive either a low-protein (P : E ratio 5.6%) or control protein (P: E ratio 10.4%) formula, which resulted in average protein intakes of 1.4 and 2.4 g/kg per day in the low and control groups, respectively. Overall energy intakes over a 10-month period of study averaged 92% + 12% recommended dietary allowance (RDA) for length in the low-protein group and 92+ 15% RDA in the control group. Weight for age standard deviation scores (SDS) were comparably low in both groups at the time of randomization (low-protein- 2.0+ 1,3, control -1.9+1.1) and at the end of the study (low-1.9 + 1.2, control-1.7 +_ 0.9). Length for age SDS at entry tended to be lower in the low-protein group but were not significantly different in the two groups (low -2.2 + 1.4 vs. control -1.7 + 1.4). However, at 18 months the lowprotein group had a significantly lower SDS for length (-2.6+ 1.2 vs. -1.7_+_ 1.4). The length velocity SDS from 12 to 18 months were also different, with the low-protein group remaining strongly negative (-1.0 +0.9) while the control group improved (-0.1+_ 1.1).

Koletzko B et al Am J Clin Nutr 2009;89:1836–45.

Energy and Protein intakes in the lower and higher protein groups

(n=540) low-protein 1.8-2.2 g/100Kcal(n=550) high-protein 2.9-4.4 g/100Kcal(n=588) breastfed children

Koletzko B et al AJCN 2009;89:1836–45.

HIGHER PROTEIN INTAKE INCREASES Weight for Length NOT Length for Age

(n=540) low-protein 1.8-2.2 g/100Kcal(n=550) high-protein 2.9-4.4 g/100Kcal(n=588) breastfed children

Mean z scores (95% CI)

*P < 0.05 **P < 0.01 ***P < 0.001 Significantly different from the Low Proteingroup (ANOVA adjusted for baseline value)

241263months of age

Protein content for first yr of life

Presenter

Presentation Notes

FIGURE 3. Mean z scores (with 95% CIs) for length, weight, weight-for-length, and BMI in the lower-protein (n ¼ 540) and higher-protein (n ¼ 550) groups and in the breastfed (n ¼ 588) children at baseline (0–8 wk of age) and at 3, 6, 12, and 24 mo of age. *, **, ***Significantly different from the lowerprotein group (ANOVA adjusted for baseline value): *P , 0.05, **P , 0.01, ***P , 0.001. Background: Protein intake during infancy was associated with rapid early weight gain and later obesity in observational studies. Objective: The objective was to test the hypothesis that higher protein intake in infancy leads to more rapid length and weight gain in the first 2 y of life. Design: In a multicenter European study, 1138 healthy, formula-fed infants were randomly assigned to receive cow milk–based infant and follow-on formula with lower (1.77 and 2.2 g protein/100 kcal, respectively) or higher (2.9 and 4.4 g protein/100 kcal, respectively) protein contents for the first year. For comparison, 619 exclusively breastfed children were also followed. Weight, length, weight-for length, and BMI were determined at inclusion and at 3, 6, 12, and 24 mo of age. The primary endpoints were length and weight at 24 mo of age, expressed as length and weight-for-length z scores based on the 2006 World Health Organization growth standards. Results: Six hundred thirty-six children in the lower (n ¼ 313) and higher (n ¼ 323) protein formula groups and 298 children in the breastfed group were followed until 24 mo. Length was not different between randomized groups at any time. At 24 mo, the weight-for length z score of infants in the lower protein formula group was 0.20 (0.06, 0.34) lower than that of the higher protein group and did not differ from that of the breastfed reference group. Conclusions: A higher protein content of infant formula is associated with higher weight in the first 2 y of life but has no effect on length. Lower protein intake in infancy might diminish the later risk of overweight and obesity. This trial was registered at clinicaltrials.gov as NCT00338689. Am J Clin Nutr 2009;89:1836–45.

inta

Anthropometry During Recovery from PEM

-50

-40

-30

-20

-10

0

10

% o

f Sta

ndar

d

0 1 2 3 4 5

Weight for AgeLength for ageWeight for length

Months of treatment

Protein & energy needs for catch-up growth at varying rate of weight gain

Typical weight gain composition a High rate of fat depositionb

Net growth costs:kcal/gc 3.29 5.12

gross growth costs:kcal/gd 4.10 5.99

Dietary requirements Dietary requirementsRate of gain Proteine Energy f Protein/Energy Proteing Energyh Protein/Energyg/kg/d (g/kg/d) (kcal/kg/d) (%) (g/kg/d) (kcal/kg/d) (%)

1 1.02 89 4.6 1.0 91 4.22 1.22 93 5.2 1.1 97 4.55 1.82 105 6.9 1.5 115 5.210 2.82 126 8.9 2.2 145 6.020 4.82 167 11.5 3.6 205 6.9

a: 73-27% lean:fat equivalent to 14% protein and 27% fat b: 50:50% lean :fat equivalent to 9.6% protein and 50% fat c: based on 5.65kcals/g protein and 9.25kcals/g fatd: net costs adjusted for a 90% and 73% metabolic efficiency of fat and protein deposition respectively plus ME of additional

non-utilized protein e: 14% deposited tissue adjusted for a 70% efficiency of utilization plus the safe level of maintenance at 1.24*0.66 g/kg/d

=0.82(see text)f: maintenance energy at 85kcals/g, (which includes maintenance protein energy) + gross energy costs at 4.10kcal/g weight

gain.g: 9.7% deposited tissue adjusted for a 70% efficiency of utilization plus the safe level of maintenance at 1.24*0.66g/kg/d=0.82

g/kg/d 1.27*.58 g/kg/d =0.737 h: as in f except that gross energy costs are 5.99kcal/g weight gain. FAO/WHO 2008 TRS 935

4 6 8 10 12 14 16 18 20 22 24

0

-0.5

-1

-1.5

-2

-2.5

-3

Height for age Z score

USA 1810 Guatemala 1990

Age (years)

Early Growth of Children & Height as Adults

Lancet Malnutrition Series 2008

males females

WHICH NUTRIENTS CAN PROMOTE LINEAR GROWTH ?

Type I and type II nutrients and the characteristics of their deficiencySee: Severe malnutrition: Hum Nutr. & Dietetics 10th Ed M. H. N. Golden B. E. Golden

CharacteristicsType l Type II

Tissue level variable Tissue level fixedUsed in specific pathways Ubiquitously usedCharacteristic physical signs No characteristic signsLate or no growth response Immediate growth responseStored in body No body storeBuffered response Responds to daily inputNot interdependent Control each others' balanceLittle excretory control Sensitive physiological controlUnlikely to influence length growth Likely to influence length growth(in most cases)

NutrientsIodine Ascorbic acid NitrogenIron Retinol Essential amino acidsCopper Tocopherol PotassiumCalcium Calciferol SodiumManganese Folic acid MagnesiumSelenium Cobalamine ZincThiamin Pyridoxine PhosphorusRiboflavin Water

Protein : strong experimental evidence in animals Good indirect data in humans

Zinc : Good experimental evidence in animalsGood meta analysis data in humans (weak effect)

Calcium & Length growth not thought to be limited by Phosphate: mineral supply in general

Other micronutrients:I, Fe, Mn, Ca, vitamin A, Vit D all potentially involved but specific deficiency signs & symptoms would be observed.

Nutrition and height growth: specific nutrients

Infection/stress: Good experimental and epidemiological evidence mediated by pro inflammatory cytokines & cortisol

Uganda: Rutishauser and Whitehead (1969): faster height growth of Karamoja children, (milk and meat), compared with Bugandan children (plantains). Peru: Graham et al. (1981): attained height of boys strongly associated with protein intake.Korea: Paik et al. (1992), height-for-age correlated with animal protein intake in Korean school children Denmark: 2004 IGF-I & height positively associated with milk intake not meat or vegetable protein at 2.5 years: milk increases IGF-1 in 8-year-old Danish boys

Epidemiology: Milk/Animal source foods improve height growth

6 mo Length Kenyanchildren R2 0.41 n=68

Regressioncoefficients p<

Birth weight 0.59 0.05Pregnancy fat gain 0.23 0.000Lactation weight gain 0.24 0.02Child supplementation -0.19 0.000

Neumann et al 1994

30 mo Length Kenyanchildren R2 0.84 n=118


Length at 18 mo 0.87 0.000Maternal fat intake 0.17 0.001Season 0.08 0.08Household size -0.08 0.072

Neumann et al 1994

Length velocity ofchildren (18-30mo) R2 0.27 n=118


Maternal fat intake 0.25 0.018Season 0.27 0.005Household size -0.14 0.12Child’s fat intake 0.38 0.025Iron intake 0.45 0.07Diarrhea (% days) -0.18 0.05

Neumann et al 1994

Meat diet boosts kids' growthBringing up children as vegans is unethical argues Lindsay Allen of the University of California, Davis, who carried out the research

22 February 2005

Annual meeting of the American Association for the Advancement of Science

2-year study of Kenyan 7y olds, given 60g minced beef/dChildren showed improved B12 status

up to an 80% greater increase in upper-arm muscleoutperformed their peers in intelligence, problem solving and arithmeticwere more active in the playground, more talkative and playful, and showed more leadership skills,"

Allen L. H. J. Nutrition (suppl.), 133. 3875S - 3878S (2003).

http://www.nature.com/news/�

USAID: Global Livestock CRSP Child Nutrition Program (Kenya study)2-yr study of Kenyan 7y olds Design: daily snacks 1000–1125 kJ at school (5 per wk)

1) Control: no snack2) Energy snack: Veg stew: maize, beans and vegetables + fat3) Milk snack: Veg stew plus 200 mL milk4) Meat snack: Veg stew + 60 g minced beef.

Trial confounded by changes in food intake at home. Only meat snack group increased energy intake

Effects of meat↑ MUAC↑Cognitive Development ↑ Plasma B12No influence on height growth

Change in energy intakes:

-150-100

-500

50100150200250300350

Control Veg stew

Milk Meat

Kca

l/day

snack

Home

overall

New Guinea children grow taller with skim milk

Malcolm, LA Br J Nutr 1970 24: 297-305

children were stunted but otherwise OK on their low protein diets height growth increased with skim milk

Controltaro/

sweet potato- 0.5

0

0.5

1

1.5

2

2.5

supplementedmargarine taro milk

Height cmFat skinfoldmm

Protein intake g/kg 0.64 0.63 1.13 2.24Energy intake Kcal/kg 59.5 100 152 107

P:E % 4.3 2.5 3.2 8.4

Height (cms )gained After intervention

Meat/milk eating African children are taller/thinner than those eating mainly starchy foods

8080

8585

9090

9595

100100

105105

110110

115115

00--66 77--1212 1313--2424 2525--3535 00--66 77--1212 1313--2424 2525--3535

Age, MonthsAge, Months

KaramojaKaramoja (herdsman: milk/meat) (herdsman: milk/meat) Tall/normal Tall/normal height:thinheight:thinBuganda (farmers: plantains)Buganda (farmers: plantains) Short and fatShort and fat

Height for age (%)Height for age (%) Weight for height (%)Weight for height (%)

RutishauserRutishauser & & WhiteheadWhitehead (1969) Brit J Nutr 23: 1(1969) Brit J Nutr 23: 1--1313

Child growth is slightly impaired on vegan diets:

In preschool children who are vegan with slower growth, lack of meat and all other ASF, maintaining energy density can be problematic. After this stage of life, growth of vegan children in the USA and UK differs only very slightly from the reference populations (e.g. - 0.1 SD for height at 10 years).

O’Connell JM, Dibley MJ, Sierra J et al. (1989) Growth of vegetarian children: The Farm Study. Pediatrics 84, 475–481.

Sanders TAB & Manning J (1992) The growth and development of vegan children. J Hum Nutr Diet 5, 11–21.

(from Millward & Garnet Proc Nutr Soc (2010), 69, 103–118)

Human foetal growthRCT of prenatal zinc supplementation and foetal bone growth

Impoverished Peruvian women: daily supplements of 60mg Fe and 250µg folic acid, +/- 25 mg ZnFemur diaphysis length greater in foetuses of zinc supplemented mothers (P<0.05) Merialdi et al Am J Clin Nutr 2004;79:826 –30.

Zinc: Animal studiesZinc stimulates bone protein synthesis and bone formation

Zinc augments the anabolic effect of IGF-1 on osteoblasts and inhibits osteoclast activity (bone resorption)(Merialdi et al Am J Clin Nutr 2004;79:826 –30).

Effect size of Zn on Height mean 95% CI

Negative

Positive

Brown K et al AJCN 2002

probed by measurements of:

bone growth: tibial length and epiphyseal cartilage width

muscle growth: gastrocnemius muscle growth

protein synthesis: 14C-phe large dose

proteoglycan synthesis: 35S uptake

insulin, T3 and plasma and tissue IGF-1

Yahya et al (1990). J Endoc 127, 497-503.Yahya & Millward (1994). Clinical Science 87, 213-224.Yahya et al (1994). Clinical Science 87, 607-618.Tirapegui et al (1994)Clinical Science 87, 599-606.

RAT STUDIES:- PROTEIN AND ENERGYMechanisms and interrelationships of action on bone and

muscle growth in the rat

Protein specifically regulates bone length growth:

0 1 2 3 4 5 6 7

days of diet

-0.10

0.02

0.13

0.25

0.37

0.48

0.60

20%

7%

3.5%

0.5%

tibial length growth (mm/d)

dietaryprotein

0 2 4 6 8 10 12 14

days of refeeding

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

20% agecontrol

20%

12%

9%

6%

3%

dietaryprotein

tibial length growth (mm/d)

*corticosterone: to giveplasma levels observed after prolonged starvation

dietary proteinconcentration

dietary energyat iso N Intake

20%

7%

3.5%

0.5 %

100%

50%75%25%CS*

Protein deficiency is as powerful as energy deficiency if not more so, in inhibiting tibial length growth

Epiphyseal cartilage width, protein and proteoglycan synthesis inhibited within 3 days of protein deficiencyActual length growth inhibition observed after 3 days of protein deficiencyDietary protein can maintain bone growth in conditions of modest energy deficiency which reduces bodyweightInsulin, T3 and IGF-1 all fall with protein deficiency, but relationships with changes in proteoglycan synthesis and epiphyseal cartilage are not symetrical.Corticosteroids mediate main inhibitory influence of severe energy deficiency, possibly also in acute malnutrition

Long bone growth and protein and energy deficiency: summary of findings

Millward DJ. A protein-stat mechanism for the regulation of growth and maintenance of the lean-body mass. Nutr Res Revs 1995 8; 93-120.

Linear Growth and body composition are controlled mainly at the level of long bone growth and muscle growth

BONE GROWTH

Bone length growth primary driver of whole body linear growth:

Genetic determination of rate/time course (canalization)

●Dietary protein and other type II nutrients are key regulators:Protein more powerful than energy in the rat.

SKELETAL MUSCLE GROWTH

growth rate and target weight controlled by bone length growth

passive stretch physiological stimulus for growth

target weight requires adequate dietary protein

muscle activity required for maximum phenotypic Muscle mass

Body GROWTH

Growth driven by Functional demand and food intake. Protein Energy.

Lempl et al Science 1992

Lampl M, Veldhuis JD, Johnson MLSaltation and stasis: a model of human growth. Science 1992.

Serial length measurements of normal infants were assessed weekly, semiweekly or daily 19 females/12 males during their first 21 mo

Presenter

Presentation Notes

Science. 1992 Oct 30;258(5083):801-3. Saltation and stasis: a model of human growth. Lampl M, Veldhuis JD, Johnson ML. Department of Anthropology, University of Pennsylvania, Philadelphia 19104. Comment in: Science. 1995 Apr 21;268(5209):442-7. Human growth has been viewed as a continuous process characterized by changing velocity with age. Serial length measurements of normal infants were assessed weekly (n = 10), semiweekly (n = 18), and daily (n = 3) (19 females and 12 males) during their first 21 months. Data show that growth in length occurs by discontinuous, aperiodic saltatory spurts. These bursts were 0.5 to 2.5 centimeters in amplitude during intervals separated by no measurable growth (2 to 63 days duration). These data suggest that 90 to 95 percent of normal development during infancy is growth-free and length accretion is a distinctly saltatory process of incremental bursts punctuating background stasis.

What is Optimal Growth

• Paradigm of “bigger is better” has never been tested critically, are we really promoting “heavier is better” ?

• NCHS-WHO standards reflect feeding practices of USA community where reference data was obtained, population has significant burden of chronic disease

• New WHO standards for weight and length are based on NEW feeding recommendations,

• “Normal” standards should be validated relative to early and late measures of health. Optimal should be based on lowest morbidity and healthy lifespan.

leaner and taller

Probability of Obesity in Boys according to Height

0

0.05

0.1

0.15

0.2

0.25

< -2 -2 to -1 -1 to 0 0 to + 1 +1 to +2 > + 2

1987-90

1993-96

2000-02

Length Z Score age 6 yrs

PrePregnancy

BMI

MaternalGlucoseInsulin

PlacentalFetal blood

flow

Fetal growth

restriction

Fetal Macrosomia

feedingfast

Weight gain

EarlyAdiposityrebound

PubertalSexual

maturation

CentralObesity

Metabolic syn

High BMIObesity

Hormonal responses

Hormonal responses

uauy

Documents