• Chemical Properties
• Vitamin A (retinoids) are hydrophobic molecules – contain 6 carbon ring (functional group) with an isoprenoid side chain
• The retinoid can have an alcohol (retinol), aldehyde (retinal) or carboxyl (retinoic acid) as the terminal group at C₁₅
• Isoprenoid side chain consists of many double bonds resulting in many different cis-trans isomers
• Sources
• Vit A is an essential, fat-soluble nutrient synthesized by animals which must be supplied from our diet
• 2 major classes of compounds with activity of Vit A
• retinoids – Isoprenoid compounds in animal products; Source: eggs, whole milk or fortified foods
• carotenoids – Isoprenoid compounds produced by plants; converted to retinoids during absorption; many forms (only 10% are precursors of vit A); Source: green leafy vegetables, orange/yellow fruits and vegetables; in b -carotene (major carotenoid in plants) is converted to retinol with 16% efficiency
• retinol equivalent (RE) – is a measure of this efficiency (1 ug retinol = 1RE = 6 ug beta-carotene)
• Absorption
• (1) Preformed vit A (mostly retinyl palmitate – long chain FA ester of retinol thus needs micelles for absorption) hydrolyzed to retinol in intestine Þ absorbed by mucosal cells Þ re-esterified with long chain saturated FA’s
• (2) b -carotene diffuses into mucosal cells Þ hydrolyzed by carotene cleavage enzyme to form 2 molec of retinal Þ reduced to retinol Þ esterified to retinyl esters
• Metabolism
• after absorption, retinyl esters packaged into lymph chylomicrons Þ into lymphatics Þ into circulation Þ liver Þ retinyl esters hydrolyzed to retinol and bound to retinol binding protein (RBP) Þ stored in stellate cells (major site of liver vit A) or released from liver into circulation
• Thus: most of diet-derived vit A is taken up by hepatic parenchymal cells but most of vit A of liver is in stellate cells!
• Delivery of retinol to extrahepatic tissues
• (1) chylomicron remnants which usually go to liver for processing may also be taken up by muscle, adipose tissue and kidney
• (2) delivery to extrahepatic tissues via RBP (major pathway)
• Transport of Vitamin A from the Liver to Peripheral Tissues: Retinol Binding Protein
• Retinol-RBP in the plasma binds to transthyretin (TTR – pre-albumin; prevents kidney filtration of RBP, increases RBP ½ life from 3hr to 11-16hrs) Þ RBP-receptor-mediated endocytosis of RBP-Retinol complex into peripheral tissues Þ RBP binds the receptor, retinol enters the cell and TTR remains in plasma
• Cellular Retinoid Binding Proteins: Once retinol is delivered to target cells via RBP, it binds intracellular RBP, several forms Þ cellular retinol binding proteins (CRBP); cellular retinaldehyde binding proteins (CRALBP); cellular retinoic acid binding proteins (CRABP)
• Cellular retinoid binding proteins serve as specific chaperones for the retinoids for metabolism and translocation
• Distribution of these binding proteins is tissue specific and developmentally controlled

• Regulation of gene transcription by retinoic acid
• nuclear receptors detected in most cells for retinoic acid – retinoic acid receptors (RAR)
• RARs are transcription factors and members of steroid/thyroid hormone receptor super family
• Retinoic acid binds RAR Þ forms homo or heterodimers with other members of its superfamily (retinoid X receptor, vitamin D receptor, thyroid receptor) Þ bind short DNA sequences (retinoic acid responsive elements – RARE) in the promotor region Þ stimulates or inhibits gene expression depending on the gene
• Genes responsive to retinoic acid include structural proteins (keratins), extracellular matrix proteins (laminins), enzymes (alcohol DH) and retinoid binding proteins and receptors
• Regulation of these genes plays a role in maintenance of epithelial differentiation and immune function – vit A deficiency results in changes in epithelial integrity and suppressed immune function
• Vitamin A and the Visual Process
• Rods are concerned with dim vision and house the pigment rhodopsin which is the fundamental light sensing unit
• Rhodopsin consists of 11-cis retinal bound to the protein opsin
• Photon of light hits rhodopsin Þ catalyzes isomerization of 11-cis-retinal to all trans-retinal (photobleaching)Þ triggers activation of a G protein mediated signaling cascade Þ activates neuronal cells that communicate with the visual cortex
• The all trans-retinal is cleaved from the protein forming all-trans retinaldehyde and opsin Þ aldehyde is reduced to alcohol forming all-trans retinol Þ transported to retinal pigment epith via interstitial retinoid binding protein (IRBP) Þ all-trans-retinol is esterified to retinyl ester Þ isomerized to 11-cis retinol Þ dehydrogenated to 11-cis retinal and transported back to the photoreceptor cells via IRBP Þ ready to bind opsin once again
• Vitamin A Deficiency and Toxicity
• Vit A deficiency Þ night blindness (reversible), Xerophthalmia (irreversible), Bitot’s spots (more about these below)
• WHO includes low serum retinol and low breast milk retinol indicators of public health problems with Vit A
• Vit A excess Þ toxicity seen with overconsumption at 10x the RDA and excessive consumption of liver
• protection against hypervitaminosis – good storage in liver, irreversible oxidation of retinoic acid, relatively inefficient conversion of carotenoids
• Both vitamin A deficiency and excess may have teratogenic effects

Vitamin A Deficiency – Xerophthalmia

• Vit A deficiency is very common – annually affects 5-10 million children (mostly in the developing world)
• Xerophthalmia = "dry eye"
• symptoms = night blindness; retinopathy; conjuctival and corneal xerosis; corneal ulceration and melting
• Egyptians 1000’s of years ago treated it with Liver (contains vit A)
• In general, nutritional blindness means Xerophthalmia
• Can occur at any age, but children are more susceptible (rapid growth rate depletes the stores)
• Seen today especially in rice eating areas of SE Asia, Africa, Latin America, and Mediterranean
• Keratomalacia = liquifactive necrosis of the cornea (often most severe stage of Vit A deficiency)
• Xerophthalmia and Keratomalacia are most common ocular diseases due to Vit A deficiency
• Clinical classification – ocular changes occur in a regular sequence
• XIA Conjunctival Xerosis
• Patch of dry unwettable conjuctiva (mostly temporal side, may be nasal side)
• Results from loss of goblet cells as columnar epith changes to stratified squamous
• XIB Bitot’s spot (reversible)
• Foamy cheesy accretion of keratin (and saprophytic bacilli) overlying conjuctival xerosis
• X2 Corneal Xerosis (reversible)
• Is the beginning of eye sight loss
• Is usually present in most patients with night blindness and Bitot’s spots
• The area of involvement spreads to the entire cornea and edema develops
• X3 Corneal Destruction
• Ulceration of cornea occurs – iris often plugs the hole
• Eyes from Vit A deficiency are "white and quiet", unlike eyes with infective diseases
• XF Xerophthalmic Fundus (reversible)
• In older patients
• Loss of retinal Pigment epith (RPE) – presents as small, white blister-like intraretinal dots in the periphery
• May see dense scotomas
• XN Night Blindness (reversible)
• Early sign – Interference with dark adaptation and scotopic vision
• Takes an unusually long time for eye to adapt to the dark light
• Risk increases with age – no test for it
• Mechanism – Vit A is essential part of rhodopsin (pigment needed for rod functioning) Þ If Vit A deficient, rhodopsin malfunctions Þ retina cannot attain its normal dark-adapted sensitivity
• Blindness Across the Globe (80% is avoidable)
• 4 major causes – trachoma, cataract, Xerophthalmia, Onchocerciasis
• Global blindness rate = 10.5 blind per 1,000 – (15 blind per 1,000 in developing countries)
• Contrary to popular belief, Measles does not cause blindness
• Vit A deficiency and Xerophthalmia are very rare occurrences in the US
• Treatment for Vit A deficiency – administration of Vit A (enteral is fine)

• Leads to irreversible blindness (not curable) – common in the US
• Affects older people >65 years but is not an inevitable consequence of getting old
• Slowly progresses to binocular loss due to degeneration of the retinal pigment epithelium (RPE)
• No known risk factors or preventable measures
• laser surgery is effective in retarding the macular degeneration but does not halt the process
• First findings = Drusen – small, yellow-white dots that don’t affect vision Þ they become confluent and the overlying RPE becomes atrophic Þ central vision is gradually lost
• Nutrition may play a role in this process via RPE senescence
• UV may increase risk of macular degeneration development
• Antioxidants, Vit C, Vit E, carotenoids may have a protective effect
• In 10% of patients with acute macular degeneration (AMD), blood vessels from choroid burrow into the retina and cause bleeding Þ eventual scarring (laser surgery can prevent the process by zapping away the blood vessels)
• Can cause a marked sudden fall in visual acuity (may occur overnight)