VITAMIN A & VISUAL CYCLE

VITAMIN A & VISUAL CYCLE
MODERATOR-DR SUDHA SEETHARAM
PRESENTER-DR RAVNEET CHADHA

INTRODUCTION
 VITAMINS:-
Vitamins may be regarded as organic
compounds required in the diet in small
amounts to perform specific biological
functions for normal maintenance of optimum
growth and health of the organism.

WHAT IS VITAMIN A?
• The term “vitamin A” makes it sound like there is one
particular nutrient called “vitamin A”, but this is not true.
It is a broad group of related nutrients.
• Vitamin A is a broad term for group of unsaturated
nutritional organic compounds, that
includes retinol, retinal, retinoic acid, and
several provitamin A carotenoids, among which beta-
carotene is the most important.

THUS,
VITAMIN A IS AN Essential fat soluble vitamin occuring in
the following forms:
 Preformed
 Retinoids (retinal, retinol, retinoic acid)
 Found in animal products
 Provitamin A
 Carotenoids
 Must be converted to retinoid form
 Found in plant products

HISTORY
 It is recorded in history that HIPPOCRATES cured night
blindness(about 500 B.C)
 He prescribed to the patients Ox liver(in honey)which is
now known to contain high quantity of vitamin A.
 By 1917, Elmer McCollum et al at the University of
Wisconsin–Madison, studied the role of fats in the diet
and discovered few accessory factors. These "accessory
factors" were termed "fat soluble" in 1918 and later
"vitamin A" in 1920.

 In 1919, Harry Steenbock (University of Wisconsin)
proposed a relationship between yellow plant pigments
(beta-carotene) and vitamin A.
 In 1931, Swiss chemist Paul Karrer described the
chemical structure of vitamin A.
 Vitamin A was first synthesized in 1947 by two Dutch
chemists, David Adriaan van Dorp and Jozef Ferdinand
Arens.

Structure of vitamin A
NOMENCLATURE
PROVITAMIN A : β-Carotene
VITAMIN A1 : Retinol ( Vitamin A alcohol)
VITAMIN A2 : 3 –Dehydro-retinol
VITAMIN A ALDEHYDE : Retinal
VITAMIN A ACID : Retinoic acid
VITAMIN A ESTER : Retinyl ester
NEO VITAMIN A : Stereoisomer of Vitamin A1, has 70
–80% of biological activity of Vitamin A1.

 CHEMISTRY
• Vitamin A is composed of ‘β-IONONE RING’ (CYCLOHEXENYL)
to which ‘POLY ISOPRENOID SIDE CHAIN’ is attached
 Polyisoprenoid chain –all trans configuration, contains 4
double bonds, has 2 methyl groups with terminal carbon
having ‘R’ group
 ‘R’ Group –alcohol/aldehyde/acid
 β-Ionone ring –contains 1 double bond with 3 methyl
groups

Retinol: -(CH2OH)
-found in animal tissues as
‘Retinyl esters’ with long
chain fatty acids
•Retinal: -(CHO)
-Aldehyde derived from
oxidation of retinol by ‘retinal
reductase’ requiring
NAD/NADP
-Retinol & Retinal are inter-
convertible

•Retinoic acid : -(COOH)
-Acid derived from oxidation of
retinal
-Retinoic acid cannot be
reduced in body therefore
cannot form retinal or retinol.
•β-Carotene :
-Hydrolysed by β-carotene
dioxygenase in presence of
oxygen & bile salts to two
molecules of retinal.

Sources of vitamin A
• Animal : Fish Liver oil, Butter, Milk, Cheese,
Egg Yolk
• Plant : All Yellow –Orange –Red –Dark Green
fruits & vegetables like Tomatoes, Carrots,
Spinach, Papayas, Mangoes, corn, sweet
potatoes.

RECOMMENDED DIETARY
ALLOWANCE
 Unit of activity is expressed as ‘RETINAL
EQUIVALENT’ (R.E.) / ‘INTERNATIONAL UNIT’ (I.U.)
1 Retinal Equivalent = 1μg of Retinol OR 6 μg of β-
carotene
1 I.U. = 0.3 μg of Retinol OR 0.34 μg of Retinyl acetate
OR 0.6 μg of β-carotene
Infants & Children : 400 t0 600 μg/day
Adults (Men & Women) : 600 to 800 μg/day
Pregnancy & Lactation : 1000 to 1200 μg/day

ABSORPTION,TRANSPORT AND STORAGE OF VITAMIN A

VISUAL CYCLE
 The term “visual cycle” was coined by George Wald in the
mid 1900’s to describe the ability of the eye to “re-cycle”
vitamin A for the synthesis of visual pigments(wald,1968)
 As originally proposed (Wald,1968),the rod visual cycle
requires the involvement of both retina and the retinal
pigment epithelium(RPE) in order to properly process the
retinal chromophore released from bleached rod
pigment(or rhodopsin)

INTRODUCTION
 The visual cycle is the biological conversion of a photon into
an electrical signal in the retina.
 The processing of visual information begins in the retina with
the detection of light by photoreceptor cells.
 The photoreceptor cells involved in vision are :
1. rods.
2. cones.
 Both the rods and cones contain chemicals that decompose
on exposure to light and in the process, excite the nerve fibres
leading from the eye.
 light sensitive chemical in the rods is called rhodopsin and
that in the cones is called cone pigments/colour pigments

Anatomy of photoreceptors
RODS:-
 Cylindrical stuctures
 Length:40-60 microns
 Diameter:2 micron
 For peripheral vision and
scotopic vision
 Contain visual purple
(Rhodopsin)
 120 million
 Absent in fovea

Each rod is composed
of four structures
namely:
1. outer segment
2. Inner segment
3. Cell body
4. Synaptic terminal

Outer segment : Outer
segment is cylindrical,
transversely striated and
contains rhodopsin
The photosensitive pigment
rhodopsin is present in
membranous discs.
There are about 1000 discs in
each rod.
The outer segment of rod cell
is constantly renewed by the
formation of new discs.(3-4/hr)

 Inner segment: connected to outer
segment by means of modified cilium.
 Contains organelles with large number
of mitochondria.
 Cell body: also called rod granule,
contains the nucleus.
 Synaptic terminal: synapses with
dendrites of bipolar cells and horizontal
cells. Synaptic vesicles present in the
synaptic terminal contain the
neurotransmitter glutamate.

CONES:
 Central and colour vision
 Length :35-40 microns
 Diameter: 5microns
 Contain Iodopsin
 6.5 million
 Highest density in fovea
(199000 cones /mm2)

 Each cone is composed
of four structures
namely:
1. outer segment
2. Inner segment
3. Cell body
4. Synaptic terminal

 Outer segment: smaller and
conical
 Contains saccules (infoldings
of cell membrane)
counterparts of rod discs.
 Renewal of outer segment of
cone is a slow process and it
differs form that in rods.
.

Inner segment: connected to
outer segment with modified
cilium. Contain organelles and
mitochondria.
Cell body: also called cone
granule, possesses the nucleus.
Synaptic terminal: synaptic
vesicle present in the synaptic
terminal possess the
neurotransmitter, glutamate

50.4 Membranuous structures of the outer
segments of a rod and cone

Physiology of vision
 The main mechanisms are:
1. Initiation of vision(phototransduction)
2. Processing and transmission of visual sensations
3. Visual perception

Photochemistry of vision
 Will be discussed under the following headings:
1. Rhodopsin-retinal visual cycle in the rods.
• Rhodopsin and its decomposition by light energy.
• Reformation of rhodopsin.
• Role of vitamin A in the formation of rhodopsin.
• Excitation of rod when rhodopsin is activated.
2. Colour vision in the cones.

Chemical basis of visual process
 The photopigments present in the rods and cones
decompose on exposure to light, in the process, excite
the nerve fibers through generation of electrical activity
and impulses in the retina.
 Photopigments:
 Rhodopsin/visual purple present in rods.
 Colour pigments/cone pigments(porphyropsin,iodopsin
and cyanopsin) present in cones.

Rhodopsin –retinal visual cycle in the rods.
Rhodopsin and its decomposition by light energy:
• The outer segment of the rod that projects into the
pigment layer of retina has a concentration of about 40%
of light sensitive pigments called Rhodopsin or visual
purple.
• Rhodopsin = scotopsin(protein) + retinal(carotenoid
protein).
• Retinal is present in the form of 11-cis retinal known as
retinene.
• cis form of retinal is important because only this form can
bind with scotopsin to synthesize rhodopsin.

Photochemical changes in rhodopsin:
1.Bleaching of rhodopsin:
 When exposed to light, the colour of rhodopsin changes
from red to yellow by a process known as bleaching.
 Bleaching occurs in a few milliseconds and many unstable
intermediates are formed during the process.
2. Reformation of rhodopsin:

changes occuring in rhodopsin
 Light rhodopsin barthorhodopsin
lumirhodopsin
RHODOPSIN BLEACHING
metarhodopsin I
metarhodopsin II
scotopsin
11-cis retinal isomerase all-trans retinal
REFORMATION
11-cis retinol isomerase all trans retinol

Phototransduction
The transduction of light into a neural signal takes
place in the outer segment of a retinal rod or cone
photoreceptor

Fig. 50.6 Movement of sodium and potassium ions through
the inner and outer segments of the rod

VISUAL CYCLE-COLOUR VISION
Cones are specialised in bright & colour vision
 Colour vision is governed by 3 colour sensitive pigments :
 -Porphyropsin (Red)
 -Iodopsin (Green)
 -Cyanopsin (Blue)
 All these are retinal-opsin complexes
 When bright light strikes the retina →one or more of these
pigments are bleached, depending on the colour of light
→pigment (s) dissociating into All-trans-retinal & Opsin
 Differential bleaching
 Nerve impulse generated by visual cascade causes perception
of specific colour

 Receptor potential of the photoreceptors is locally graded
potential i.e it does not propagate
 The receptor potential does not follow all or none law .
 The receptor potential generated in the photoreceptors
is transmitted by electronic conduction to the other cells
of retina i.e horizontal cells,bipolar cells,amacrine cells
and ganglion cells
 The ganglion cells transmit the visual signals by means of
action potential

FUNCTIONS OF VITAMIN A
 VISION
 GENE TRANSCRIPTION
 IMMUNE FUNCTION
 EMBRYONIC DEVELOPMENT AND REPRODUCTION
 BONE METABOLISM
 HAEMATOPOESIS
 SKIN AND CELLULAR HEALTH
 ANTIOXIDANT ACTIVITY

VITAMIN A DEFICIENCY
 Most susceptible populations:
 Preschool children with low F&V intake
 Urban poor
 Older adults
 Alcoholism
 Liver disease (limits storage)
 Fat malabsorption

Vitamin A deficiency may result from :
 -Dietary insufficiency of Vitamin A / Precursors
 -Interference with absorption from intestines
 eg: diarrhoea, malabsorption syndrome, bile salt
deficiency
 -Defect in the transport due to protein malnutrition –
‘Kwashiorkar’
 -Defect in the storage due to diseases of liver

Tissues chiefly affected –‘Epithelial’ principally which
are not normally keratinised
Includes epithelium of respiratory tract,
gastrointestinal tract, genitourinary tract, eye &
paraocular glands, salivary glands, accessory glands
of tongue & buccal cavity and pancreas
Fundamental change: Metaplasia of normal non-
keratinised living cells into keratinising type of
epithelium

OCULAR MANIFESTATIONS OF
VITAMIN A DEFICIENCY
 XEROPHTHALMIA
The term xerophthalmia was given by a joint WHO and
USAID committee in 1976 to cover all the ocular
manifestations of vitamin A deficiency including the
structural changes affecting the conjunctiva, cornea and
retina and also the biophysical disorders of retinal rods
and cones functions.

WHO CLASSIFICATION (1982)
XEROPHTHALMIA CLASSIFICATION(modified)
 XN Night blindness
 X1A Conjunctival xerosis
 X1B Bitot’s spots
 X2 Corneal xerosis
 X3A Corneal ulceration /keratomalacia affecting less than
1/3rd corneal surface
 X3B Corneal ulceration /keratomalacia affecting more
than 1/3rd corneal surface
 XS Corneal scar due to xerophthalmia.
 XF Xerophthalmic fundus.

XN :NIGHT BLINDNESS(Nyctalopia)
 Earliest symptom of xerophthalmia in children
 Diminished visual acuity in ‘dim light’(Insufficient
adaptation to darkness)
 Defective rhodopsin function.

X1A CONJUNCTIVAL XEROSIS
Characterised by:
 One or more patches of dry, lustreless,nonwettable
conjunctiva.
 Interpalpebral conjunctiva(commonly temporal
quadrants)
 Severe cases involves the entire bulbar conjunctiva.
 Desribed as ‘emerging like sand banks at receding
tide’when child ceases to cry
 Can lead to conjunctival thickening,wrinkling and
pigmentation.

X1B BITOT’S SPOTS
 Bilateral
 Bulbar conjunctiva in the interpalpebral area
 Commonly in temporal quadrant.
 Triangular greyish/silvery white spots/plaques.
 Firmly adherent to conjunctiva
 Foamy keratinised epithelium(corynebacterium xerosis)

X2 CORNEAL XEROSIS
 Dry lustreless appearance of cornea
 Earliest change is punctate keratopathy
 Begins in the lower nasal quadrant
 Bilateral punctate corneal epithelial erosions
 Can progress to epithelial defects
 Reversible on treatment

X3A & X3B CORNEAL ULCERATION
/KERATOMALACIA
 Stromal defects occur in late stages due to colliquative
necrosis leading to corneal ulceration ,softening (melting)
and destruction of cornea(keratomalacia)
 Corneal ulcers may be small or large
 Stromal defects involving less than 1/3rd cornea usually
heal leaving some useful vision
 Large stromal defects commonly result in blindness.

 Small ulcers
 1-3mm
 Occur peripherally
 Circular
 Steep margins and
sharply demarcated
 Large ulcers
 More than 3mm
 Occur centrally
 Involve entire cornea

XS CORNEAL SCAR
 Healing of stromal defects results in corneal scarring
 Size of the corneal scar depends on the size and density
of corneal defect.

XF XEROPHTHALMIC FUNDUS
 Uncommon in occurance
 Typical seed like lesions
 Whitish/yellow
 Raised
 Scattered uniformly over part of fundus
 At the level of optic disc.
 FFA reveals these dots to be focal retinal pigment
epithelial defects

CONTND
 Rarely these patients can present with scotomas
corresponding to the area of retinal involvement
 Respond to vitamin A therapy with scotoma disappearing
in 1-2 weeks and retinal lesions fading in 1-4 months.

AGE GROUP DOSE DURATION
1.All patients above
one year
2.<1 yr of age or <8
kg weight
3.Women of
reproductive age
group
-less severe
- severe
2,00,000 IU
Half the dose i.e
1,00,000 IU
10,000 IU
2,00,000 IU
Day of presentation,
next day and 2-3
weeks later
2 weeks
VITAMIN A THERAPY
 Treatment schedules apply to all stages of active
xerophthalmia
1. Oral therapy (Recommended)

2. Parenteral therapy: IN CASES OF
-severe disease
-unable to take oral feeds
-Repeated vomiting and diarrhoea
-malabsorption
 Intramuscular injections of water miscible vit A
preparation
 Dose – 1,00,000 IU(Half the oral dose)

 Local ocular therapy-
 Intense lubrication-instilled every 3-4 hours
 Topical retinoic acid
 Treatment of keratomalacia and corneal ulcer
 Treatment of corneal perforation

PROPHYLAXIS AGAINST XEROPHTHALMIA
 1.Short term approach
-Periodic administration of vitamin A supplements
-WHO recommended ,universal distribution schedule of vit A
for prevention is as follows:
i) Infants <6months (not being breastfed)—50,000 IU
ii)Infants 6-12 months and any child <8kg – 1,00,000 IU
every 3-6months
iii)Children over 1 year and under 6 years --- 2,00,000 IU orally
every 6 months
iv)Lactating mothers – 2,00,000 IU orally once at delivery or
during next 2 months to maintain level of vitamin A in breast
milk

PROPHYLAXIS
1.Infants <1 year
(not being
breastfed)
2.Infants 6-12
months and any
child <8kg
3. Children > 1
year and < 6
years
4. Lactating
mothers
50,000 IU
1,00,000 IU
2,00,000 IU
2,00,000 IU
Every 3-6 months
Every 6 months
once at delivery
or during next 2
months to
maintain level of
vitamin A in
breast milk

ctnd
 Under vitamin A supplementation program through
Reproductive and child health program(RCH) and now
National Rural Health Mission(NRHM)
-- Children between 9 and 36 months of age are to be
provided with vitamin A solution every 6 months starting
with 1,00,000 IU at 9 months of age along with measles
vaccination and subsequently 2,00,000 IU every 6 months
till 36 months of age.

 2.Medium term approach-
- fortification of food with Vit A
 3. Long term approach-
- Promotion of adequate intake of Vit A rich foods in high
risk groups particularly preschool aged children on a
periodic basis and to mothers within 6-8 weeks after
childbirth
- Other measures like nutritional education,social
marketing,home or community garden programs and
measures to improve food security.

HYPERVITAMINOSIS A
 Ingestion of large amounts of preformed vitaminA from
the diet,supplement intake or medications
 Acute:
 Single doses of >3,00,000 IU
 Headache ,Blurred vision,nausea
,vomiting,drowsiness,irritability i.e signs of raised
ICP(Benign intracranial hypertension)
 Serum vit a values-200-1000 IU/dl

Benign intracranial hypertension
 Increased intracranial pressure
 Idiopathic
 Headache (m.c),vomiting,pulsatile tinnitus
 Diplopia(compression of 6th nerve)
 Rarely compression of 3rd n 4th nerve
 Papillaedema
 visual field defects
 Long standing pappilledema leads to optic atrophy.

 Chronic – long-term megadose; possible permanent
damage ( >50,000 IU/day for several wks)
 Bone and muscle pain
 Loss of appetite
 Skin disorders
 Headache
 Dry skin
 Hair loss
 Increased liver size
-Manifestations reversible when vitamin A discontinued

VITAMIN A & VISUAL CYCLE

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VITAMIN A & VISUAL CYCLE