vitamin a deficiency disorders in children - home - iapb a deficiency disorders in children clare...

Vitamin A deficiency

disorders in children

Clare Gilbert

Reader in International Eye Health

Vitamin A deficiency disorders

Has been a very important cause of blindness in children: 1999: 350,000 out of 1.4 million (25%)

Poor countries

Declining in many countries

Important cause of child mortality

Common in pregnant and lactating women in developing countries

Other high risk groups: long term prisoners

children in institutions for the multiply handicapped

Vitamin A deficiency - definitions

New terminology: replaces “clinical” and “subclinical” deficiency

reflects the spectrum of deficiency

Vitamin A deficiency (VAD): a state of inadequate vitamin A nutriture

VAD begins when liver stores are below 20g/g

serum levels can often be maintained despite this

serum retinol levels <20g/dL (0.70mol/L) are deficient

Vitamin A deficiency disorders (VADD): physiological disturbances secondary to VAD

subclinical (increased infection; anaemia) and clinical

Xerophthalmia: Ocular signs

Global distribution

Affects poorest communities in poorest countries

Clinically significant public health problem - 39 countries

Serious problem - 11 other countries

Regional or likely problem - 45 countries

At least 140 million preschool age children and >7 million pregnant women suffer from VADD each year

1.2 – 3.0 million children die unnecessarily each year

4.4. million children and 6.2 million women suffer from xerophthalmia

Nearly 50% VAD occurs in South and Southeast Asia.

Prevalence of VADD, West, 2002

Prevalence of VADD, West, 2009

Vitamin A deficiency disorders:

number of children affected

Children : ~150 - 200 mill

Xerophthalmia :

children ~3 million

pregnant women ~3 million

Blindness : ~500,000/ year

Preventable deaths : ~1 - 2.5 mill/ year

Sources of vitamin A

Vitamin A is fat soluble vitamin

Occurs as retinol in animal sources: Breast milk

Egg yolk

Dairy products

Fish liver

Provitamin A precursors found in plant sources (carotenoids e.g. β-carotene): Yellow, orange and red fruits (e.g. mango, papaya)

Yellow and orange vegetables (e.g. squash, carrots)

Dark green leafy vegetables

Red palm oil (West Africa)

>600 identified, but only 10 have pro-vitamin A activity

C40 skeleton with C5 isoprene units

Sources of vitamin A

Foetus acquires retinol across the

placenta

Retinol more biologically active than

provitamin A precursors

Need oil or fat in the diet for absorption

Vitamin A conversion factors

1 µg retinol = 0.00349 µmol retinol

1.15 µg retinyl acetate

1.83 µg retinyl palmitate

3.33 IU retinol

10 I.U provitamin carotenoids 1 Retinol Equivalent (RE)

Retinol Activity Equivalent (RAE)

1 µg retinol

12 µg all trans β-carotene

24 µg other provitamin A carotenoids

Animal Sources

Food source Retinol equivalent (RE);

µg Retinol/100g

Fatty fish liver oils 18,000 to 900,000

Dairy Products Eggs 140

Butter 830

Meat Liver 15,000

Beef 0 – 4

Plant Food Sources

Food source Retinol equivalent (RE);

µg Retinol/100g

Vegetables Red palm oil 30,000

Carrots 2,000

Dark green leafy veg 685

Fruits Buriti palm 3,000

Mango 307

Other Sources Tablets/capsule

Injections

Fortified foods

Vitamin A rich foods – plant sources

Vitamin A rich foods – animal

sources

Liver

Vitamin A – poor sources

Bioavailability

Dietary equivalence (ug)

Retinol equivalents:

= ratio of non-animal sources : animal

sources which give equivalent intake

1989, NRC, traditional 6:1

2001, IOM, US pop 12:1

West, C 21:1

“Vitamin A” in food supply in

different regions

0

200

400

600

800

1000

1200

1400

Europe Africa S America Asia

FAO / WHO (6:1)* IOM (12:1)* C West (21:1)*

Minimum requirement

* Retinol equivalent used to assess content

Recommended daily intake for children (RE)

Vitamin A g/d

Infants 0-6 months 400

7-12 months 500

Children 1-3 years 300

4-8 years 400

Boys 9-13 years 600

14-18 years 900

Girls 9-13 years 600

14-18 years 700

Safe level needed to sustain health through periods of low intake and stress

Recommended daily intake for dults (RE)

Vitamin A g/d

Men 19->70 years 900

Women 19->70 years 700

Pregnancy 14-18 years 750

19-50 years 770

Lactation 14-18 years 1200*

19-50 years 1300*

Safe level needed to sustain health through periods of low intake and stress

Amount of foods required daily Daily requirement (g) Child Woman Males, lactating

women

Mango 130 162 195

Buriti palm 13 17 20

Red palm oil 1 2 2

Carrot 20 25 30

DGLV 58 73 88

Cod liver oil 2.2 2.8 3.3

Eggs 286 357 429

Liver 2.6 3.3 4

Beef, pork 10,000 12,000 15,000

Food intake for daily requirement

Age group

Carrots Sweet

potatoes

DGLV Mango

Children:

0-5 months

6-11 months

1-2 years

2-6 years

Breast milk

1 ½ tablespoon

1 ½ tablespoon

2 tablespoon

Breast milk

1 tablespoon

1 tablespoon

1 ½ tablespoon

Breast milk

1/3 cup

½ cup

½ cup

Breast milk

½

½

2/3

Females:

Non-pregnant

Pregnant

Lactating

¼ cup

¼ cup

¼ cup

2 ½ tablespoon

2 ½ tablespoon

¼ cup

1 cup

1 cup

1 ½ cup

1

1

2/3

DGLV = dark green leafy vegetables

Digestion and absorption of retinol

Released in stomach by proteolysis

Aggregate with lipids and pass to small intestine

Fat and protein in diet stimulate secretion of bile

through cholecystokinin

Emulsifies lipids to micelles for absorption

Bile salts stimulate pancreatic lipase and

esterases hydrolyse retinyl esters in

enterocytes to retinol

70 – 90% Retinol absorbed by mucosal cells

Digestion and absorption provitamin A

e.g. β-carotene

Most pass through intestinal mucosa and into blood and

lymph unchanged

Some undergo cleavage

β-carotene 2 Retinal Retinyl esters

Digestion and absorption of retinol

Cellular Retinol Binding Protein (CRBP) carries the

lipid-soluble retinol to lecithin:retinol acetyltransferase (LRAT)

Retinol esterified

and delivered

to chylomicrons

Transport to Liver

Chylomicrons carry fat-soluble vitamins through lymphatic system

Chylomicron remnants

containing almost all

retinyl esters are cleared by the liver

Retinyl esters also go to other tissues (and cancer cells) where converted to retinoic acid and used for gene regulation

Metabolism in Liver

Retinyl esters taken up by hepatocytes

Hydrolysed and processed in endosomes

Retinol to endoplasmic reticulum

Binds to retinol binding protein RBP, enters

Golgi apparatus, and is secreted from the cell

50 – 80% vitamin A (retinyl esters) is in the liver,

in the stellate and parenchymal cells

Other storage sites: adipose cells, RPE

Transport to other cells

Retinol is recycled between plasma, liver and other tissues

In plasma, retinol-RBP complex is bound to transthyretin

[RBG] in adult plasma: 1.9 – 2.4 µmol/l

PEM, infections and parasitic infestations lower the concentration

Transport of vitamin A in tissues

Target cell

ROH = Retinol

RA =Retinoic acid

RBP = Retinol binding prot

CRBP = Cellular retinol BP

CRABP = Cellular retinoic acid BP

RXR, RAR = Nuclear receptors

RBP–ROH

Extracellular

Regulated

gene

transcription

DN

A

Receptor

ROH–CRBP

ROH RA Nucleus

RA–RXR RAR–RA

RA

RA–CRABP

Intracellular

Cell membrane and nuclear membrane receptors

Functions of Vitamin A

Gene expression:

During development

Differentiation (epithelial tissues)

Growth

Immune system:

Barrier function

Humoral and cell mediated immunity

Glycoprotein, glycosaminoglycan synthesis

Reproduction (testosterone production)

Functions of vitamin A

Energy Balance: thermogenesis by mitochondria is under

transcriptional regulation by RA

Regulation of dopaminergic system:

Gap junctional communication:

Haemopoesis

Antioxidant

Vision

Visual cycle

Light

Risk factors for

vitamin A deficiency

Risk factors for vitamin A deficiency

Macro-environment

Household

Person

Macroenvironment:

Ecology

Climate

Political

Infrastructure

Cultural practices and taboos

Structure of society

Inadequate health services

Factors leading to poverty


Household:

Poor water supply

Inadequate sanitation

Dirty local environment

Lack of female literacy

Large family sizes

Over crowding

Lack of land ownership


Children:

measles and other febrile illnesses

malabsorption (diarrhoea, infestations)

malnutrition

Adults:

pregnancy and lactation

alcoholism

wars and conflicts (malnutrition)

prisoners

diseases with malabsorption (coeliac disease)


Children are at higher risk:

Liver stores relatively low at birth

Breast milk supplies adequate retinol for 6 months

High requirement because of growth

High rate of infection and diarrhoea after weaning

Measles infection after the age of 6 months

Totally dependant on adults


Children can develop VADD even if vitamin A rich foods are available and affordable: Inadequate breast feeding

Complimentary and weaning foods low in vitamin A

Feeding practices and taboos

Food preferences

Over cooking

Inadequate preservation methods

DGLV not mashed


Pathology in vitamin A deficiency

Dedifferentiation of epithelial cells:

Loss of goblet cells

Low mucin production

Squamous metaplasia

Eye

Respiratory tract

[Skin and hair]

Loss of barrier function

Vicious cycle in vitamin A deficiency

Infection

Vitamin A

deficiency

Loss of barrier function

Reduced immunity

Increased demand

Increased loss

Lower RBP

Acute phase proteins

Manifestation of vitamin A deficiency

Morbidity:

Ocular

Other

Mortality

Xerophthalmia

Relationship between blindness due to

VAD and Human Development Index

0

10

20

30

40

50

60

70

0.25 0.35 0.45 0.55 0.65 0.75 0.85 0.95

Human Development Index

% b

lin

dn

ess d

ue

to

VA

D

Xerophthalmia - classification

Night Blindness XN

Conjunctival Xerosis X1A

Bitot’s Spots X1B

Corneal Xerosis X2

Corneal Ulceration <1/3 X3A

Corneal Ulceration >1/3 X3B

Corneal Scar XS

Xerophthalmic Fundus XF

NB This is not a chronological classification

Courtesy A Sommer

Night blindness (XN)

Conjunctival xerosis (X1A)

Difficult sign to elicit C Gilbert

Bitot’s spot (X1B)

Courtesy A Sommer

Bitots spot (X1B)

Pathognomonic of vitamin A deficiency

Accumulations of keratin, acted on by bacteria. Can be wiped off.

Disappear when vitamin A status improves C Gilbert

Corneal (and conjunctival) xerosis (X2)

Courtesy A Sommer

Keritinsation, xerosis and scarring

C Gilbert

Corneal ulcer <1/3 cornea (X3A)

Corneal ulcer <1/3 cornea (X3A)

A Foster

Courtesy A Sommer

Before….

.. and after

treatment

Corneal ulcer >1/3 cornea (X3B)

L Gordillo

Keratomalacia

Courtesy A Sommer

Corneal scarring

C Gilbert

Peak age for different eye signs

Grade of xerophthalmia Peak age group affected

XN Night blindness 2-6 yrs, women

X1A Conjunctival xerosis 3-6 years

X1B Bitot’s spot 3-6 years

X2 Corneal xerosis 1-4 years

X3A C ulcer/keratomalacia <1/3 cornea 1-4 years

X3B C ulcer/keratomalacia 1/3 cornea 1-4 years

XS Corneal scarring (from X3) 1-4 years +

XF Xerophthalmic fundus Adults

Management of xerophthalmia

Optical iridectomy [corneal grating]

C Gilbert

Management of xerophthalmia

Timing Malnutrition Measles Xerophth.

Infants and children:

- 0-5 months

- 6-11 months

- males >12 months

- females>12 mo-12 ys; >49 ys

Day 1

Day 1

Day 1

Day 1

Day 1, 2

Day 1, 2

Day 1, 2

Day 1, 2

Day 1,2 and 14

Day 1,2 and 14

Day 1,2 and 14

Day 1,2 and 14

Women (aged 13-49 years)

- XN and/or Bitots spot

- X3a or X3b (rare)

10,000 daily for 3 mo

or

25,000 weekly for 3

mo

200,000 day 1,2,14

Corneal grafting

Indications: – To maintain integrity of the eye

– To restore visual function, but very

challenging in children, particularly

those blind from VADD: • very poor families

• very poor follow up

• failure to use medication

• early onset visual loss, so amblyopia

• rejection

• astigmatism

Other morbidity

Other morbidity

More difficult to assess

Fewer studies

Conflicting results

Childhood mortality in vitamin A

deficiency

Mortality in children with xerophthalmia

Ocular status Child

intervals

Deaths Mortality

rate

per 1,000

Relative

risk

No xerophthalmia 19,889 108 5.4 1.0

Night blindness only 547 8 14.6 2.7

Bitots spot only 269 6 35.5 6.6

Night blindness + B spot 215 10 46.5 8.6

Clinical trials – childhood mortality

Community based trials:

– 8 randomised, double masked trials in Africa and Asia

– different doses and schedules

– different baseline levels of xerophthalmia

– 6 showed vitamin A supplementation significantly

reduces all cause child mortality

Meta analysis:

– 23% reduction in all trials

– 34% reduction in Asian trials

Mortality prevention trails

Study (Year) Country Vit. A Supplement Mortality

reduction

Relative Risk

(95% CI)

Aceh 1986 Indonesia Large dose 6 monly 34% 0.74 (0.54-0.99)

Bogor 1988 Indonesia Vit.A fortified MSG 45% 0.69 (0.57-0.84)

NNIPS 1991 Nepal Large dose 4 mly 30% 0.70 (0.56-0.88)

Jumla 1992 Nepal One and 5 monly 29% 0.55 (0.99)0.74)

Tamil Nadu 1990 India Small Weekly doses 54% 0.46 (0.29-0.71)

Hyderabad 1990 India Large doses 6 monly 6%(NS) 1.00 (0.64-1.55)

Khartoum 1992 Sudan Large doses 6 monly 6%(NS) 1.06 (0.82(-1.37)

VAST1993 Ghana Large doses 4 monly 19% 0.80 (0.29-0.98)

Cochrane Systematic Reviews Vitamin A supplementation for the prevention of morbidity and mortality in

infants six months of age or less. Gogia S, Sachdev HS.

Cochrane Database Syst Rev. 2011 Oct 5;(10):CD007480. Review.

Neonatal vitamin A supplementation for the prevention of mortality and

morbidity in term neonates in developing countries. Haider BA, Bhutta ZA.

Cochrane Database Syst Rev. 2011 Oct 5;(10):CD006980. Review.

Vitamin A supplements for preventing mortality, illness, and blindness in

children aged under 5: systematic review and meta-analysis. Mayo-Wilson E,

Imdad A, Herzer K, Yakoob MY, Bhutta ZA.

BMJ. 2011 Aug 25;343:d5094. doi: 10.1136/bmj.d5094. Review.

Routine vitamin A supplementation for the prevention of blindness due to

measles infection in children. Bello S, Meremikwu MM, Ejemot-Nwadiaro RI,

Oduwole O. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD007719. Review.

http://www.ncbi.nlm.nih.gov/pubmed/21975770










• Vitamin A supplementation for preventing morbidity and mortality in

children from 6 months to 5 years of age. Imdad A, Herzer K, Mayo-

Wilson E, Yakoob MY, Bhutta ZA. Cochrane Database Syst Rev.

2010 Dec 8;(12):CD008524. Review.

• Vitamin A supplementation during pregnancy for maternal and

newborn outcomes. Van an den Broek N, Dou L, Othman M, Neilson

JP, Gates S, Gülmezoglu AM. Cochrane Database Syst Rev. 2010

Nov 10;(11):CD008666. Review.

• Vitamin A supplementation for postpartum women. Oliveira-

Menegozzo JM, Bergamaschi DP, Middleton P, East CE. Cochrane

Database Syst Rev. 2010 Oct 6;(10):CD005944. Review.

• Vitamin A for preventing acute lower respiratory tract infections in

children up to seven years of age. Chen H, Zhuo Q, Yuan W, Wang

J, Wu T. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006090.

Review.

Cochrane Systematic Reviews








Impact on mortality in trials

Different age groups of children

Mortality and/or morbidity

Impact on infants of supplementing

mothers

Maternal deaths

More trials on-going....

Clinical trials have studied:

Assessing vitamin A deficiency

in the community

Hidden iceberg of VADD in the

community

Xerophthalmia

VADD i.e. deficient but no eye signs

Higher risk of mortality

Increased risk of infection

Blind, or at high risk

At very high risk of dying

Measles

Malabsorption

Malnutrition

Prevalence of VAD of public health

significance

Criterion Prevalence (%)

Clinical in children aged 2-5 years:

Night blindness XN

Bitot’s spot XB

C ulcers/keratomalacia X2, X3A & B

Xerophthalmia related corneal scars XS

Clinical in women of child bearing age:

Night blindness during a recent pregnancy XN

Biochemical:

Serum retinol < 0.7 mol/L (20g/dL)

>1.0

>0.5

>0.01

>0.05

>5.0

>15.0

Assessing vitamin A deficiency as

a public health problem

Recently simplified (Annency Accords):

Uses under 5 mortality rates:

>50 / 1,000 = highly likely

20 – 50/1,000 = focal; needs confirming

<20/1,000 = unlikely

Distribution of VADD 2009

Under 5 mortality rates in 2007

Control of vitamin A deficiency


Short term:

– Intermittent supplementation with high dose vitamin A

Medium term:

– Dietary diversification / food supplementation programmes

– Food fortification

Long term:

– Address underlying causes

– Change eating and food preparation behaviours

Courtesy A Sommer

Supplementation with high dose

retinal palmitate

Seasonality of xerophthalmia in India children


- vitamin A supplementation

Population Amount of vitamin A to be

administered

Time of administration

Infants aged 0-5

months

3 doses of 50,000 IU, with at least a

1 month interval between doses

At each DTP immunization contact

(6, 10, and 14 weeks after birth)

(otherwise at other opportunities)

Infants aged 6-11

months

100,000 IU as a single dose every 4-

6 months

At any opportunity (e.g. with

measles immunization)

Children aged 12 – 72

months

200,000 IU as a single dose every 4-

6 months

At any opportunity

Postpartum women 400,000 IU as two doses of 200,000

IU at least 1 day apart;

and/or 10,000 daily or 25,000 IU

weekly*

- As soon after delivery as possible

but not more than 6 weeks after

delivery*

- and/or during the first 6 months

after delivery

* as high dose vitamin A is teratogenic vitamin A should not be given during pregnancy, or when a pregnancy is possible


- short term

Intermittent supplementation with high

dose vitamin A:

targeted

vertical programme

integrated programme – with MCH; EPI

43 countries combining vitamin A

supplementation with immunization


- medium term

Food supplementation: Preferred strategy in India through Anganwadi

(kindergarten programme)

Food fortification: Artificially increases the vitamin A content of foods

Must not alter the colour, taste, shelf life, cost

Must be consumed in small amounts on a regular basis by the target population

Examples: rice, cooking oil, monosodium glutamate

Challenges

Genetic modification – “golden rice”

Fortified foods

“Golden rice” Fortified sugar

Biofortification: cross breeding


- long term

Address underlying causes:

– Alleviation of poverty

– Improved water and sanitation

– Improve environmental hygiene

– Female education

– Home gardening

– Health education

– Nutrition education

– Improve primary health care, and health services


- long term

Change foods eaten:

– Availability

– Cost

– Cultural factors

– Beliefs and taboos

Change food preparation:

– Solar drying out of UV light

– Reduce cooking


- preferred strategies

Vitamin A supplementation

Food diversification

Food fortification

Impact of control of vitamin A

deficiency

Marked decline in xerophthalmia in many

developing countries

Anecdotal evidence of fewer children with

bilateral corneal ulceration

Decline in scarring as a cause of blindness in

some countries (Uganda)

Lower rates of corneal blindness in younger

children than in older children

Change in the prevalence of clinical vitamin

A deficiency in children aged <6years

0

0.5

1

1.5

2

2.5

3

3.5

Phillipines Niger India Bhutan Sri Lanka Indonesia Ethiopia Nepal

Pre

va

len

ce

(%

)

Baseline

After 10 yrs

UN ACC/SCN 1997

Change in VAD in Asian and African

children (% change / 10 years)

UN ACC/SCN 1997 -100

-80

-60

-40

-20

0

20

40

60

80

Phillip

ines

Sri L

anka

Indon

esia

India

Bhuta

n

Eth

iopia

Nep

al

Nig

er

Ch

an

ge

in p

rev

ale

nce

/ 1

0 y

ears

(%

)

Estimated change in number of children

with clinical VAD 1985-1995 (million)

1985 1995

South Asia 2.67 1.58

East Asia/Pacific 0.66 0.40

L America/Caribbean 0.17 0.12

East/S Africa 0.69 0.53

West/Central Africa 0.53 0.45

Middle East/N Africa 0.24 0.12

Total: 5.00 3.30

UN ACC/SCN 1997

VADD in Sub-Saharan Africa • Data from 11 surveys between 1997 and 2003, and the measured effects of

vitamin A deficiency on child mortality were combined to estimate the prevalence

of children at risk for vitamin A deficiency in sub-Saharan Africa and the potential

child-survival benefits of effective and sustained policies and programs for the

control of vitamin A deficiency in this region.

• In the absence of effective and sustained policies and programs for the control

of vitamin A deficiency, an estimated 42.4% of children 0 to 59 months of age in

sub-Saharan Africa (43.2 million children) are at risk for vitamin A deficiency.

Such effective and sustained policy and program action for the control of vitamin

A deficiency can bring about a potential 25% reduction in mortality in children 0

to 59 months with respect to 1995 mortality levels (i.e., before the onset of large-

scale vitamin A supplementation programs in sub-Saharan Africa

Vitamin A deficiency and child survival in sub-Saharan Africa: A reappraisal of

challenges and opportunities Victor M. Aguayo and Shawn K. Baker. Food and

Nutrition Bulletin, 2005 26 348-355.

The State of the Worlds Children (2008)

• >40 countries in Africa have under 5 mortality

rates (U5MR) above the level used to indicate

that VADD is a public health problem (i.e.

>50/1,000 live births),

• 37 countries have U5MRs >100/1,000

• Coverage with supplements:

o poor data in many countries

o probably not as good as anticipated

o much more to be done

VADD in Sub-Saharan Africa

vitamin a deficiency disorders in children - home - iapb a deficiency disorders in children clare...

Documents