Vitamin A

Overview

• Vitamin A is a fat soluble micronutrient that cannot be synthesized in vivo and must be obtained from dietary sources
  
• The term "Vitamin A" refers to a group of compounds (retinyl esters, retinol, retinal, retinoic acid)
  
• All-trans retinoic acid - (most bioactive form) Cell differentiation and regulation of gene transcription
  
• 11-cis retinal - required for vision as the light absorbing chromophore (light sensing receptor) of the visual pigments rhodopsin (rods) and iodopsin (cones)
  
• Metabolism
• Vitamin A compounds in foods (preformed Vitamin A) are digested and retinyl esters are hydrolyzed in the intestinal lumen which liberates unesterified retinol to be absorbed across the mucosal barrier
• In the enterocyte, most retinol is reesterified creating new retinyl esters to be included in chylomicrons
• 70-90% of dietary preformed Vitamin A is absorbed if there is >10g fat in the meal (less fat means less Vitamin A can be absorbed
• Provitamin-A carotenoids have specific transporters to take them from the intestinal lumen into the enterocyte. They can be incorporated intact into the chylomicrons or they can be cleaved to form retinal (a precurser for retinol). beta-carotene is cleaved to become  retinol by the cleavage enzyme beta-carotene monooxygenase
  
• 20-50% of  carotenoids are absorbed
  
• Absorption also depends on the bodys Vitamin A status

Dietary Needs

• Retinol (vitamin A 1 ); 1 µg retinol = 3.3 IU vitamin A = 1 RAE
  
• Provitamins A: the plant pigments α-, β-, and γ-carotenes and cryptoxanthin have partial retinol
• Activity: 12 µg β-carotene, or 24 µg other provitamin A carotenoids = 1 µg retinol
  

Age	RDA	Upper Level	Note
0-6 mo	400	600	micrograms of retinol activity equivalents per day
7-12 mo	500	600
1-3 yr	300	600	Upper levels only apply to preformed vit A (retinol)
4-8 yr	400	900
9-13 yr	600	1700
14-18 yr	900/700	2800	900 -male; 700 -female

Dietary Sources

• Retinyl esters: animal origin primarily
• Organ meats (esp liver, kidney but other meats, milk, and cheese have moderate amounts)
• Liver, fish liver oils
• Dairy products, except skim milk
• Egg yolk, fortified margarine, fortified skim milk
• Carotenoids from plants: green vegetables, yellow fruits, and vegetables
• Provitamin A carotinoids
• fruits and vegetables (esp yellow-orange veggies: pumpkin, squash, sweet potato)
• Leafy green veggies (chard, spinach, broccoli)
• Beta-Carotene
• cultivars or biofortified forms of sweet potatoes
• Alpha-Carotene and oxygenated carotenoids (e.g. beta-cryptoxanthin found in oranges)
  
• have lower bioactivity of vitamin A

Physiology

• Absorbed in the Upper small intestine
• Fat-soluble; heat-stable; destroyed by oxidation, drying
• Bile necessary for absorption
• Stored in liver
• Protected by vitamin E

Biochemical action

• Retinal: In vision, for synthesis of the visual pigments rhodopsin and iodopsin
• Retinoic Acid acts as a ligand for specific nuclear transcription factors, regulating genes involved in many fundamental cellular processes:
• growth
• reproduction
• embryonic and fetal development
• bone growth
• immune functions
• epithelial functions - maintains epithelial integrity
  
• See: https://courses.lumenlearning.com/wm-biology2/chapter/transduction-of-light/
  
• https://www.sciencedirect.com/science/article/pii/S0005272813001461
  

Deficiency

• Nyctalopia - inability to see dim light or at night
  
• Photophobia, xerophthalmia***, Bitôt spots (preschool age children), conjunctivitis, keratomalacia leading to blindness, corneal ulceration, (rare cause - bone overgrowth pressing on the optic nerve)
  
• Faulty epiphyseal bone formation
• Defective tooth enamel
• Keratinization of mucous membranes and skin
• Retarded growth
• Impaired resistance to infection, anemia, reproductive failure, fetal abnormalities

    Eye lesions are most specific, but typically occur late in prgression and rarely occur before 2 years of age. A symptom that may appear earlier is delayed Dark Adaption (nyctalopia, night blindness) due to the reduced resynthesis of rhodopsin. Retinal pigment epithelium (RPE) is a structural element of the retina. If it undergoes keratinization, the rods and cones have no support and eventially disintigrate resulting in blindness.
    Vitamin A deficiency is seen in epithelial cell changes: mucous producing goblet cells are affected. epithelial barrier function is affected in the intestines leading to diarrhea. absence of mucous secretion in the respiratory tract leads to inability to remove inhaled pathogens and toxins. Proliferation of basal cells, hyperkeratosis, formation of stratified cornified squamous epithelium, typically seen on the shoulders, arms, legs, and buttocks. Squamous metaplasia of the renal pelves, ureters, vaginal epithelium, and the pancreatic and salivary ducts (increased infection in these areas possible). Pyuria, hematuria in bladder.
   *** note: Xerophthalmia is a very characteristic lesion of Vit A deficienct

Dx:

• Eye Exam
• Less severe deficiency - conjunctival impression cytology, relative dose response, and modified relative dose reponse tests
• Plasma retinol is not an accurate inficator of Vit A status
• <0.35umol/L -very deficient
• 0.35-0.7umol/L - deficient
• 0.7-1.05umol/L - marginal
• >1.05umol/L - adequate
• Liver Vit A Concentration >20ug/g is needed to support a normal rate of secretion of Retinol- Retinol Binding Protein (RBP) into plasma - indicating normal delivery of retinol to peripheral tissues
  

Treatment

• Treating with vitamin A up to the stage of keratomalacia is effective in preserving vision
• Daily supplement of  1500ug of Vit A
• 30-60mg of retinol (100k-200k IU/child) given once or twice under careful monitoring to avoid toxicity
• Xeropthalmia - 1500ug/kg orally for 5 days followed by 7,500ug IM Vit A in oil until recovery
  

Toxicity

• Anorexia
  
• slow growth
  
• drying and cracking of skin
  
• enlargement of liver and spleen
  
• swelling and pain of long bones
  
• bone fragility
  
• increased intracranial pressure
  
• alopecia
  
• carotenemia
• Fetal abnormalities

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Ref:

1. embedded links
2. Nelsons Textbook of Pediatrics