The Curious Case of an aspiring model

17 year old girl who wants to be a fashion model presents to the ophthalmologist with the complaint of difficulty seeing at night. She is extremely thin with a BMI of 18.5. She is very worried that she is becoming blind. She follows a low fat low calorie diet. She loves raw carrots, carrot juice and has it regularly in her diet plan

Vitamin A

By: Dr. Beenish Zaki

Objectives:At the end of the class the student will be able to:

Outline the various forms, sources, metabolism, deficiency and toxicity of vitamin A

Correlate the structure of Vitamin A as a function of visual pigment and changes in the visual cycle.

Comprehend various biochemical steps of dimlight vision and colour vision and be able to apply the knoweledge in analyzing the defects in vision in case of Vitamin A deficiency.

Analyse the relationship between Rhodopsin, G protein and vision.

Interpret the molecular changes in colour blindness.

Chemistry Fat soluble vitamin.

Active form only present in animal tissue

The pro-vitamin Beta carotene is present in plant tissues.

Compounds with vitamin A activity are referred to as Retinoids.

Chemistry cont’d Three different compounds with Vitamin A

activity are: Retinol (Alcohol) Retinal (Aldehyde) Retinoic acid (Acid)

The conversion of Retinol to Retinal is a reversible reaction.

Conversion of Retinal to Retinoic acid is irreversible reaction.

Chemistry Cont’d The common form of Vitamin is Vitamin A1

which is chemically all-trans retinal.

Vitamin A2 is found in fish oils which has an extra double bound present in the ring.

Biologically important form is 11-cis-retinal

Dietary Sources of Vitamin A Animal sources:

Dairy Liver Fish liver oil.

Plant sources: Carrots Papaya Mango Pumpkins

During cooking the activity is not destroyed.

Vitamin A metabolismAbsorption:

In the intestinal mucosa, requires bile salts.

Beta-carotene cleaved Retinal reduced

Retinol

Within the mucosa the retinol is re-esterified and transported to liver.

Stored in the liver in the form of Retinol Palmitate

Vitamin A metabolism cont’dTransport: Transported to peripheral tissues as trans-retinol.

It is bound to Retinol binding protein.

Uptake by the Tissues: The retinol binding protein does not enter the

tissues.

Binds to specific receptors on tissues such as retina, skin

Vitamin A metabolism Cont’dUptake by the tissues:

The vitamin binds to cellular retinoic acid binding proteins.

From here it is transported to the Hormone responsive elements of the DNA.

Genes are activated by Vitamin A.

Biochemical Role of Vitamin A Wald’s visual Cycle.

Growth and differentiation of tissues.

Normal reproduction.

Anti-oxidant property.

Normal skin and epithelium production.

Vitamin A uses in Clinical medicine

Isoretinone a synthetic variant of vitamin A

Reduces sebaceous secretions.

Used for treatment of Acne.

Normal Vitamin A level

25-50 microgram/dl

The recommended daily allowance for :• Children: 400-600 microgram/day• Men: 750-1000 microgram/day• Women=750 microgram/day• Pregnancy= 1000 microgram/day

Vitamin A toxicity

Excess vitamin A results in condition called Hypercarotenemia.

Vitamin A is stored in the body and hence can become toxic.

Symptoms of toxicity: Anorexia Peeling of skin Vomiting Signs of increased intracranial pressure.

Causes of Vitamin A deficiency

Decreased intake.

Obstructive jaundice

Cirrhosis

Severe malnutrition.

Deficiency manifestation of Vitamin AEYE CONDITIONS

Reversible conditions: Night blindness: Dark adaptation is decreased.

Xeropthalmia: The conjunctiva becomes dry thick and wrinkled, loosing normal transparency.

Bitot’s spots: These are seen as greyish- white triangular plaques adherent to conjunctiva.

Irreversible condition: Keratomalacia: Softening of the cornea, degeneration of

corneal epithelium. Later leads to ulceration and perforation of cornea.

Bitot’s Spot

Keratomalacia

Deficiency manifestation of Vitamin A

Skin Manifestation

Hyperkeratosis: Increased keretinisation of epithelium lining of follicles. Skin becomes rough and susceptible to infections.

Assessment of Deficiency

Dark adaptation test

Decreased Retinol binding protein.

Decreased Vitamin A serum level.

Biochemical Role of Vitamin A Wald’s visual Cycle.

Growth and differentiation of tissues.

Normal reproduction.

Anti-oxidant property.

Normal skin and epithelium production.

Photoreceptors

Structure of Rods and Cones

RODS

The Retina is made up 2 two types of photoreceptors cells:• Rods• Cones.

Rods are responsible for perception in dim light; do not perceive color.

Rods contains a membrane protein called Rhodopsin.

Rhodopsin is made up of Opsin and 11-cis-retinal.

When light falls on retina, 11-cis-retinal isomerizes to all-trans-retinal.

Cones Cones are responsible for vision in bright

light as well as color vision.

They contain photosensitive proteins called Conopsin.

Conospin is made up of 3 different types of photoreceptor protein and 11-cis-retinal.

There are 3 types of photoreceptor protein sensitive to a different color are as follows:• Blue- Cyanopsin• Green- Iodopsin• Red-Prophyropsin

Wald’s Visual Cycle

Wald’s Visual CycleActivation The key to initiation of visual cycle is the

availability of 11-cis-retinal and hence vitamin A.

Light absorption results in the isomerization of 11-cis retinal to all-trans form.

This leads to the conversion of Rhodopsin Bathorhodopsin Metarhodopsin II

Opsin+ All trans retinal.

Wald’s Visual Cycle Cont’d This causes activation of the G protein called

Transducin.

Leading to closing of C-GMP gated ion channels which leads to neuronal signaling.

This process causes amplification of signal resulting in hyper polarization of membrane

Wald’s Visual Cycle Cont’d Deactivation

Rhodopsin Kinase which deactivates Rhodopsin.

The activated Rhodopsin binds to Arrestin to cause deactivation.

Transducin is bound to phosphodiester to return to inactive state.

Colour blindness

Colorblind visual PerceptionNormal Person’s Perception

Colorblind Person’s Perception

Color Blindness

Color blindness is because of :

Reduction in number of cones

Or

Reduction of cone proteins.

Genetics of Color blindness The gene for green and red pigments lies adjacent to

each other on X chromosomes.

These genes are 98% identical in nucleotide sequence.

Recombination can take place either between or within transcribed region of the chromosomes.

One chromosome will lose a gene and thus may lack the gene for example of green pigment.

This person will have difficulty distinguishing between red and green.

The Curious Case of an aspiring model

17 year old girl who wants to be a fashion model presents to the ophthalmologist with the complaint of difficulty seeing at night. She is extremely thin with a BMI of 18.5. She is very worried that she is becoming blind. She follows a low fat low calorie diet. She loves raw carrots, carrot juice and has it regularly in her diet plan

Any Question

References Textbook of Biochemistry;DM Vasudevan,

Sreekumari S; 5th Edition; Jaypee.

Biochemistry;John L. Tymoczko, Jeremy M. Berg, Lubert Stryer; 5th Edition;

Harper’s Illustrated Biochemsitry;Daryl K. Granner, Peter A. Mayes, Victor W. Rodwell, Robert K. Murray;26th Edition; Lange