The role of nutrition in children growth & health

The Role of Nutrition
in Children’s Growth & Health
Abdulmoein Al-Agha, FRCPCH (UK)
Professor & Head of Pediatric Endocrinology,
King Abdulaziz University Hospital,
www.aagha.kau.edu.sa
Saturday, January 9, 2021

Agenda
• Introduction.
• Factors affecting post natal growth.
• Nutrition during infancy & its importance for growth.
• Nutrition & growth faltering.
• Malnutrition has a negative effects on the growth.
• Effective intervention to restore growth.
• Importance of macronutrients & micronutrients for children’s growth.
• The rationale for novel ingredients in ONS: Arginine & Vitamin K2.

Introduction
• Growth is a fundamental physiologic process that characterizes childhood.
• It should be closely monitored by paediatricians & families as an index of
child’s health.
• Nutrition plays fundamental role in determining the growth of children.
• An appropriate growth progression is considered as indicator of adequate
nutrient intake & good health.
• On the other hand, growth deceleration with / without short stature may
indicate inadequate nutrition.
• Nutritional growth retardation is most prevalent in populations at risk of
poverty.

• Protein-energy malnutrition, in early life led to compromised growth &
cognitive functions in young children.
• Important nutrients for children’s growth include:
• Calcium strengthens bones.
• Proteins (amino acids e.g., Arginine)
• Carbohydrates provide energy.
• Iron is essential for tissue oxygenation & growth.
• Essential fatty acids help the body to absorb other vitamins.
• Vitamins e.g., vitamin D, K & folic acid…..etc.)
• Trace elements include zinc, copper, iodine & selenium.

• The first 3 years of life are most crucial & vulnerable to the hazards of
undernutrition.
• All efforts should be made so that preschool children are given a
balanced nutritious home-based diet.
• It has been shown that it is not possible to meet 100% requirements of
recommended dietary allowances (RDA's) of micronutrients from
dietary sources alone.
• Most preschool children need administration of oral nutritional
supplements (ONS) to optimize their genetic potential for physical
growth & mental development.

Linear Growth in Children &
Role of Nutrition

Factors affecting children’s growth
Intra
uterine
Growth
factors
IGF2
Insulin
Nutrition
&Thyroid hormone Nutrition ,Thyroid &
Growth Hormone
Nutrition
,Thyroid
Growth & Sex
Hormones
Birth 1-2
years
Childhood Puberty

Postnatal linear growth can be described in three distinct phases:
1. Nutrition-dependent infancy phase.
2. Growth-hormone-dependent childhood phase.
3. Pubertal growth spurt during adolescence driven by sex steroids.

Linear Growth is regulated by GH in childhood
• GH is very essential for linear growth:
✓ Directly by binding to its receptors in
the growth plate (20%).
✓Indirectly (80%) via insulin-like growth
factor (IGF-1).
• GH & IGF-1 concentration and
subsequently an increased growth
velocity help determine the growth
curve of each child.
References: Lindsey et al. Mol Cell Endocrinol. 2016 September 5; 432: 44–55.

Linear Growth at the Epiphyseal growth plate
• Linear growth is determined by
the cell proliferation at the
growth plates of long bones.
• The growth hormone/insulin-
like growth factor (GH/IGF) axis
is critically important for the
regulation of bone formation
& longitudinal bone growth.
SCIENTIFIC OVERVIEW
ogenesis
in, isdeterminedbythegrowthplate, theareaof
r theendof thelongbonesinchildrenandadolescents. 1
growthplates, whichdeterminethefuturelengthandshape
ocesscalledchondrogenesis. 1
hondrogenesis(GPC)isregulatedbymanyfactorsincluding
intracellular andextracellular GPCmatrixfactors.1,2
ausedbyaprimar ydefect inthegrowthplate, or a
owthplateisadverselyaffectedbyadisorder elsewherein
n Growth Trajectories
ed “buildingblocks” for optimal growth, including
s. Conversely, nutrient deficienciesareconsidereda
short stature(stunting)inchildren.3
Thebest exampleof
histhe“catch-upgrowth” (CU)phenomenon..
seof rapidlinear growththat allowsachildtoaccelerate
er pre-illnessgrowthcurve. 4
Undernutritioncanleadto
Effects of a Nutritional Supplement on Catch-Up
(CU) Growth
Figure 1
RESTINGZONE
PROLIFERATIVE
ZONE
PREHYPERTROPHIC
ZONE
HYPERTROPHIC
ZONE
TRABECULAR
BONE
CHONDROGENESIS

Nutrition & Growth during infancy
• Nutrition provides the required “building blocks” for optimal growth,
including energy, proteins & micronutrients.
• Conversely, nutrient deficiencies are considered a leading cause of
underweight & short stature (stunting) in children.
• Undernutrition can lead to reduced plasma levels of insulin, insulin-like
growth factor-1, thyroid hormone, leptin and sex hormones.
• Nutrition in the first year most important as growth & development
most rapid as:
• Birthweight doubles at 6 months of age & triples at 1yr.
• Height ↑from 50 cm at birth- 70-75 cm at 1 yr.

Malnutrition & growth falttering
ENDOCRINE
Lowers IGF-1 (Liver)
Lowers thyroid hormone
Lowers androgens
Lowers estrogens
POOR
NUTRITION
Calories
Protein
Vitamins
Minerals
INFLAMMATION
raises cytokines
sustains epithelial injury
lowers appetite
stimulates glucocorticoids
Millward J. Nutr Res Rev (2017), 30, 50–72

Linear Growth at the Epiphyseal Growth Plate
• Undernutrition impairs the rate of
longitudinal bone growth and length
of the growth plate
o GH and IGF-1 can be impacted
• In states of growth restriction, the
growth plate conserve growth capacity
until conditions improve- enabling
catch up growth to help achieve full
growth potential.
References: Gat-Yablonski, G. Nutrients no. 7 (1):517-51.

Breast-feeding
Stimulates Optimal Initial Growth
WHO: Breastfeeding exclusively for 6 months = 820,000 lives saved per year
https://www.unicef.org/publications/files/UNICEF_Breastfeeding_A_Mothers_Gift_for_Every_Child.pdf

Nutrition plays key role for growth in early life
• The role of genetics on height growth from infancy to early childhood is relatively small.
• Nutrition is recognized as a key influential factor for height growth in early child growth.
48
58
68
78
88
98
108
0 1 2 3 4 5
LengthorHeight(cm) Age (Years)
Pelotas, Brazil
Accra, Ghana
South Delhi, India
Olso, Norway
Muscat, Oman
Infants & young children
with different ethnic
background grow in very
similar speed when
environment is affluent and
supportive
References: WHO Multicentre Growth Reference Study Group (2006). Acta Paediatr Suppl 450: 56-65

Rapid growth raises the risk of malnutrition
An infant / toddler’s rapid growth rate
coupled with very high metabolic rate
makes the risk of growth faltering
highest during the first 3 years.
Dietary energy is expended on:
1) basal metabolism.
2) functional activity.
3) requirements for growth, which varies
by life stage and circumstances.
The basal metabolic rate corresponds
to changes in growth velocity
Son’kin V, Tambovtseva R. Energy metabolism in children and adolescents. In,
Bioenergetics, 2012. Ed, Dr. Kevin Clark. Intech Press. Chapter 5: 121-142Saturday, January 9, 2021

Nutrition & Growth faltering
• Children at sub-optimal
growth may not born to
be small.
• Growth faltering usually
happens after breastfeeding
is discontinued.
• Poor quality of
complementary/solid
food.
References: Leroy et al., J. Nutr. 144: 1460–1466, 2014Saturday, January 9, 2021

Poor
Dietary Intake
Serious Complications
Family Concern
Physician ConcernWeight < 5th %
Height Slows
Height < 5th %
Energy/
Protein/
Vitamins/
Minerals
Deficient
At-Risk? FEEDING PROBLEMS
Murray RD. Pediatr Ann 2018;47:e465-e469Saturday, January 9, 2021

Identify “Risks groups of poor
growth
Medical & dietary history red flags:
• Infant/ toddler.
• Repeated infections.
• Food insecurity.
• Hospitalization.
• Chronic diseases.
• Neuro-physical disabilities.
• Prematurity/ IUGR.
• Stress /mental illness in the family.
• Poor diet quality/ picky eaters.

Feeding history of picky eaters
• Difficult to feed.
• Parenting style more rigid.
• Mothers often were picky eaters too.
• Breastfeeding was limited.
• Early solid food introduction.
• Suspicious of new tastes, textures, colors.
• A lower enjoyment of food.
• A slow, disengaged eater.
• Prefers liquids to solids.
✓Limited variety of foods consumed
✓Limited vitamins & minerals
✓Lower diet quality at a critical time
✓May or may not be underweight

Reference: Malnutrition: The Child At-Risk, Robert Murray MD, FAAP Professor of Pediatrics,
The Ohio State University, March 2016
When to Intervene ?
A family’s concern about their child’s nutrition
usually precedes a physician’s concern
LIMITED NUTRITION INTAKE
NUTRITION DEPLETION
WEIGHT FALTERING
NUTRIENT DEFIENCIES
HEIGHT FALTERING

Nutritional management
Objectives:
improve energy & nutrient intake.
promote weight/height gain and enable catch-up growth.
correct nutritional deficiencies.
support parents to make the dietary changes.
1
2
3
4

Important Nutrients for
Optimal Growth Potential
• Arginine
• Vitamin K2

Amino acids & Growth
• Based on growth & nitrogen balance, amino acids have been classified
as essential (indispensable) or nonessential (dispensable) types.
• Essential amino acids are those whose carbon skeletons are not
synthesized by human cells and, must be provided from the diet (e.g.,
arginine, glycine, proline, and taurine).
• Essential amino acids (e.g., glutamine, glutamate, and arginine) play an
important roles in multiple signalling pathways, thereby regulating gene
expression, intracellular protein turnover, nutrient metabolism, and
oxidative defence mechanisms.

Roles of amino acids in nutrition
& whole-body homeostasis.
Besides serving as building
blocks for proteins.
AA have multiple regulatory
functions in cells.
These nutrients are crucial for
growth, development, and
health of animals and humans
Adv Nutr. 2010 Nov; 1(1): 31–37.
Published online 2010 Nov 16. doi: 10.3945/an.110.1008

Arginine

Serum Arginine levels are lower in stunted children
References: Semba, R. D.,2016. EBioMedicine 6:246-252.
74
76
78
80
82
84
86
88
90
92
SerumArgconcentration
Serum arginine in children (12-59 months) with and without stunting
(N=313)
Stunted non-stunted
P=0.0003

• Data collected from the Copenhagen School Child Intervention (n=261, age 7-13 y)
• Arginine intake was estimated via a 7-d food diary at baseline(2002) and 3-year follow-up(2005)
• The association between arginine intake and growth velocity were evaluated (adjusted for sex, age, baseline
height, energy intake and puberty stage) at 7-year follow-up
Dietary Arginine consumption was associated with
increased growth velocity in children
References: van Vught, Br J Nutr no. 109 (6):1031-9.
Children with an arginine intake between 2.8 and 3.2 g/d grew 0.33 cm/year faster compared
to intake lower than 2.2 g/d (adjusted for confounding factors)
Incremental growth velocity (cm/year) per quintile of mean
arginine intake
MeanGrowthVelocity
(cm/year)
Arginine Intake
(g/d)
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
<2.2 2.2 – 2.5 2.5 – 2.8 2.8 – 3.2 >3.2
Quintiles 1 2 3 4 5

Malnutrition, Immunity & Arginine
• Undernutrition can compromise the immune system
• gut permeability, inflammatory cell in the intestine, B-cells and effector T-cells
• Arginine is reported to impacts immune response
• synthesis of NO and reactive oxygen species
• antimicrobial activity
• secretion of hormones that regulate the metabolism and activity of immunocytes
• maturation and proliferation of T-lymphocytes and B-lymphocytes
• production of cytokines and specific antibodies by T-lymphocytes and B-lymphocytes
• Children: Supplemental arginine (2 gram/ day) increased markers of immune system defense

Role of micronutrients for physical growth &
cognitive function

• It is estimated that, over 50% of apparently healthy-looking children
have subclinical or biochemical deficiencies of vitamins A, K, B2, B6,
folate and vitamin C.
• Over two-third of children have clinical evidences of iron deficiency
while deficiency of trace minerals like iodine and zinc is quite common
in certain populations.
• Micronutrients are required for the integrity and optimal functioning of
immune system.
• Several micronutrients are required for optimal physical growth and
neuromotor development.
• Isolated deficiencies of micronutrients are rare in clinical practice and
usually deficiencies of multiple micronutrients co-exist.

Vitamin K
• A group of fat-soluble
molecules essential to human
health
• Act as cofactors for several
proteins.
• Two main biologically active
forms: K1 & K2

Vitamin Vitamin K1 Vitamin K2 (MK7)
Dietary sources Green leafy vegetables Certain fermented foods
Structure Short chain Long chain
Bioavailability Short half life (3-4 hours) Long half life (3-4 d)
Major uptake tissue Hepatic
Hepatic and Extra hepatic
(e.g. bone)
K2 (MK7) could have a more pronounced impact on bone due to its
longer half life and higher serum circulation level after ingestion
Vitamin K1 vs. Vitamin K2 (MK7)

Osteocalcin
• The 2nd most abundant protein in bone tissue after collagen.
• Produced by osteoblasts and support bone building by
facilitate calcium transportation to bone.
• Used as a marker for the bone formation process.
• Its synthesis is vitamin K dependent.

K1 vs. K2(MK7): Metabolic difference in human
K2 (MK7) supplementation lead to higher and
more stable serum vitamin K level (A) and
induced more complete activation of
osteocalcin (B)
○: K1 supplementation
●: K2 supplementation
▲: no supplementation
References: Schurgers, L. Blood no. 109 (8):3279-83.2007.
SerumvitaminK(μg/L)
differencefrombaseline
A
B
cOC/ucOCratio
differencefrombaseline
8
6
4
2
0
Duration of treatment (days)
0 20 40
Duration of treatment (days)
0 20 40
1
2

Vitamin K facilitates bone building
S u p p o r t b o n e
m i n e r a l i za t i o n f o r s t r o n g
b o n e s
ACTIVE
OSTEOCALCIN
INACTIVE
OSTEOCALCIN K2
Natural Vitamin K2 : Mechanism of Action
• Vitamin K Activates Osteocalcin
• When osteocalcin is fully-activated, it attaches to
calcium and transports it into bone
• Measure of circulating osteocalcin (active and inactive)
is used as a biomarker for vitamin K status
ACTIVE
OSTEOCALCIN bound to Ca

Synergistic effect of Ca, Mg, Vitamin D & K2
Vitamin D Magnesium Vitamin K2
Magnesium
SMALL
INTESTINE BLOOD
BONE
Ca Ca
Helps
calcium
absorption
Helps
bone
formation
Helps
calcium
retention
Ca
A B S O R B B U I L D
S T R E N G T H E N
Calcium from Diet

Take Home Messages
• Undernutrition can have serious consequences for children, including stunting, wasting, poor
cognitive development & illness.
• Addressing undernutrition early to reactivate the growth plate, helps a child reach their full growth
potential.
• ONS may help improve nutrient intake and support absorption and utilization of nutrients to support
growth (height and weight) in the child falling behind.
• Vitamin K2 (MK7) and arginine may further support healthy growth.
o Dietary arginine intake is associated with increased growth velocity in children.
o Vitamin K2 (MK7) is more bioavailable than typical K1 and it supports bone mineralization by
facilitating the transport of calcium into bones.

References
• Son’kin V, Tambovtseva R. Energy metabolism in children and adolescents. In, Bioenergetics, 2012. Ed, Dr. Kevin Clark. Intech Press.
Chapter 5: 121-142
• https://www.unicef.org/publications/files/UNICEF_Breastfeeding_A_Mothers_Gift_for_Every_Child.pdf
• WHO Multicenter Growth Reference Study Group (2006). Acta Paediatr Suppl 450: 56-65
• Leroy JL, Ruel M, Habicht JP, Frongillo EA. Linear growth deficit continues to accumulate beyond the first 1000 days in low- and
middle-income countries: global evidence from 51 national surveys. J Nutr. 2014 Sep;144(9):1460-6. doi: 10.3945/jn.114.191981.
Epub 2014 Jun 18. PMID: 24944283.
• Robert Murray RD. Starting strong: Dietary, behavioral, and environmental factors that promote “strength” from conception to age 2
years. Pediatr Ann 2018;47:e465-e469
• Malnutrition: The Child At-Risk, Robert Murray MD, FAAP Professor of Pediatrics, The Ohio State University, March 2016
• Lindsey RC, Mohan S. Skeletal effects of growth hormone and insulin-like growth factor-I therapy. Mol Cell Endocrinol. 2016 Sep
5;432:44-55. doi: 10.1016/j.mce.2015.09.017. Epub 2015 Sep 25. PMID: 26408965; PMCID: PMC4808510.
• Millward DJ. Nutrition, infection and stunting: the roles of deficiencies of individual nutrients and foods, and of inflammation, as
determinants of reduced linear growth of children. Nutr Res Rev. 2017 Jun;30(1):50-72. doi: 10.1017/S0954422416000238. Epub
2017 Jan 23. PMID: 28112064.
• Gat-Yablonski G, Phillip M. Nutritionally-induced catch-up growth. Nutrients. 2015 Jan 14;7(1):517-51. doi: 10.3390/nu7010517.
PMID: 25594438; PMCID: PMC4303852
• Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC Growth
Charts for the United States: methods and development. Vital Health Stat 11. 2002 May;(246):1-190. PMID: 12043359

References
• Alarcon PA, et al. Effect of Oral Supplementation on Catch-Up Growth in Picky Eaters. Clin Pediatr. 2003;42:209-217
• Huynh et al, Longitudinal growth and health outcomes in nutritionally at‐risk children who received long‐term nutritional intervention. Journal of human nutrition and dietetics.
Volume28, Issue6. March 2015 https://doi.org/10.1111/jhn.12306.
• Dieu T. T. Huynh, Elvira Estorninos, Maria Rosario Capeding, Jeffery S. Oliver, Yen Ling Low, Francisco J. Rosales, Impact of long-term use of oral nutritional supplement on nutritional
adequacy, dietary diversity, food intake and growth of Filipinopreschool children, Journal of Nutritional Science, 10.1017/jns.2016.6, 5, (2016).
• Tapiero H, Mathé G, Couvreur P, Tew KD. I. Arginine. Biomed Pharmacother. 2002 Nov;56(9):439-45. doi: 10.1016/s0753-3322(02)00284-6. PMID: 12481980.
• Semba RD, Shardell M, Sakr Ashour FA, Moaddel R, Trehan I, Maleta KM, Ordiz MI, Kraemer K, Khadeer MA, Ferrucci L, Manary MJ. Child Stunting is Associated with Low Circulating
Essential Amino Acids. EBioMedicine. 2016 Apr;6:246-252. doi: 10.1016/j.ebiom.2016.02.030. Epub 2016 Feb 19. PMID: 27211567; PMCID: PMC4856740.
• van Vught AJ, Dagnelie PC, Arts IC, Froberg K, Andersen LB, El-Naaman B, Bugge A, Nielsen BM, Heitman BL. Dietary arginine and linear growth: the Copenhagen School Child
Intervention Study. Br J Nutr. 2013 Mar 28;109(6):1031-9. doi: 10.1017/S0007114512002942. Epub 2012 Oct 10. PMID: 23046689.
• Jiang MY, Cai DP. Oral arginine improves linear growth of long bones and the neuroendocrine mechanism. Neurosci Bull. 2011 Jun;27(3):156-62. doi: 10.1007/s12264-011-1051-3.
PMID: 21614098; PMCID: PMC5560364.
• Baligan, M., Giardina, A., Giovannini, G., Laghi, M. G., & Ambrosioni, G. (1997). [L-arginine and immunity. Study of pediatric subjects]. MinervaPediatr, 49(11), 537-542.
• Karpinski, M. et al. 2017. J Am Coll Nutr no. 36 (5):399-412. doi: 10.1080/07315724.2017.1307791.
• van Summeren MJ, van Coeverden SC, Schurgers LJ, Braam LA, Noirt F, Uiterwaal CS, Kuis W, Vermeer C. Vitamin K status is associated with childhood bone mineral content. Br J
Nutr. 2008 Oct;100(4):852-8. doi: 10.1017/S0007114508921760. Epub 2008 Feb 18. PMID: 18279558.
• Popko, J.; Karpiński, M.; Chojnowska, S.; Maresz, K.; Milewski, R.; Badmaev, V.; Schurgers, L.J. Decreased Levels of Circulating Carboxylated Osteocalcin in Children with Low Energy
Fractures: A Pilot Study. Nutrients 2018, 10, 734.
• Schurgers LJ, Teunissen KJ, Hamulyák K, Knapen MH, Vik H, Vermeer C. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived
menaquinone-7. Blood. 2007 Apr 15;109(8):3279-83. doi: 10.1182/blood-2006-08-040709. Epub 2006 Dec 7. PMID:

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