Biochemistry Exam - Vitamin A Deficiency (Long Essay Answer)

Clinical Scenario Summary

(i) Most Likely Diagnosis — 2 Marks

• Difficulty seeing in dim light = night blindness (nyctalopia) - the earliest ocular sign of vitamin A deficiency
• Dryness of eyes = conjunctival xerosis
• Bitot's spots on conjunctiva = pathognomonic triangular, foamy, pearly-white deposits on the bulbar conjunctiva, confirming vitamin A deficiency

Park's Textbook of Preventive and Social Medicine: "The signs of vitamin A deficiency are predominantly ocular. They include nightblindness, conjunctival xerosis, Bitot's spots, corneal xerosis and keratomalacia."

(ii) Biochemical Basis for the Patient's Symptoms — 2 Marks

1. Rhodopsin = 11-cis retinal + the protein opsin (a G protein-coupled receptor)
2. When light strikes rhodopsin, a photochemical isomerization occurs: 11-cis retinal → all-trans retinal, causing rhodopsin to bleach and opsin to be released
3. This activates the G protein transducin, triggering a nerve impulse transmitted via the optic nerve to the brain
4. Regeneration of rhodopsin requires isomerization of all-trans retinal back to 11-cis retinal; all-trans retinal is first reduced to all-trans retinol, then esterified and isomerized to 11-cis retinol, which is oxidized to 11-cis retinal to recombine with opsin

• Vitamin A (as retinoic acid) regulates gene expression via nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs)
• These RAR complexes bind DNA response elements and regulate transcription of keratin and mucus-secretory genes in epithelial cells
• In deficiency: epithelial cells undergo squamous metaplasia - mucus-secreting goblet cells are replaced by keratinizing squamous cells
• The conjunctival epithelium loses its mucus-secreting ability → dryness and keratinization → Bitot's spots (accumulation of keratin debris with Corynebacterium xerosis colonisation)

Lippincott's Biochemistry: "Severe deficiency leads to xerophthalmia, a pathologic dryness of the conjunctiva and cornea, caused, in part, by increased keratin synthesis."

Harper's Biochemistry: "Retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes... retinoids control the expression of the gene for keratin in most epithelial tissues."

(iii) Inactive Dietary Precursor, Its Conversion, and Why This Patient Developed It After Intestinal Surgery — 1M + 1M + 2M

Inactive Dietary Precursor:

Conversion to Active Form:

• Beta-carotene is a symmetric molecule consisting of two retinyl units joined at the center
• It is cleaved centrally in the intestinal mucosa (small intestinal villous cells) by the enzyme beta-carotene-15,15'-dioxygenase (also called beta-carotene monooxygenase) to yield 2 molecules of retinal (all-trans retinal)
• Retinal is then reduced to retinol by retinal reductase (using NADH/NADPH)
• Retinol is esterified to retinyl esters (e.g., retinyl palmitate) for transport via chylomicrons through lymphatics into the bloodstream
• In the liver, retinyl esters are stored or converted back to retinol, which binds retinol-binding protein (RBP) complexed with transthyretin (TTR) for systemic transport
• In target cells: retinol is oxidized to retinal and then to retinoic acid, the active form that regulates gene transcription

Park's Textbook: "1 μg of β-carotene = 0.167 μg of Retinol Equivalent (RE)... Carotenes are converted to vitamin A in the small intestine."

Lippincott's: "The RDA for adults is 900 RAE for males and 700 RAE for females. 1 RAE = 1 μg retinol, 12 μg β-carotene, or 24 μg of other carotenoids."

Why Did This Patient Develop Deficiency After Intestinal Resection?

1. Intact small intestinal mucosa - the primary site of beta-carotene cleavage and retinol absorption
2. Bile salts - required for micelle formation to solubilize fat-soluble vitamins
3. Adequate absorptive surface area - provided by intestinal villi

• Reduced mucosal surface area impairs both retinol absorption (from animal foods) and beta-carotene conversion and absorption (from plant foods)
• The enzyme beta-carotene dioxygenase is located in intestinal villous cells - resection removes this enzymatic capacity
• Fat malabsorption (common post-resection) further impairs absorption of all fat-soluble vitamins
• Poor diet compounded this by providing insufficient vitamin A/beta-carotene intake

Harrison's: "Vitamin A deficiency most often occurs in patients with malabsorptive diseases (e.g., celiac sprue, short-bowel syndrome) who have abnormal dark adaptation or symptoms of night blindness..."

(iv) Dietary Sources and RDA — 2 Marks

Dietary Sources:

• Liver (ox liver: ~16,500 RE/100g) - richest
• Fish liver oils (cod liver oil: ~18,000 RE/100g)
• Egg yolk (~140 RE/100g)
• Butter (~825 RE/100g)
• Whole milk, cheese, fish, meat

• Dark green leafy vegetables: spinach (~607 RE/100g), amaranth (~515 RE/100g)
• Yellow/orange vegetables and fruits: carrot (~1,167 RE/100g), pumpkin, mango (~313 RE/100g), papaya (~118 RE/100g)
• Tomato (~84 RE/100g)
• The darker the green leaf, the higher the carotene content

RDA (Recommended Dietary Allowance):

• Adult males: 900 μg RAE/day (Retinol Activity Equivalents)
• Adult females: 700 μg RAE/day
• Alternatively expressed as: 750-1000 μg retinol equivalent (RE)/day

Lippincott's Biochemistry: "The RDA for adults is 900 retinol activity equivalents (RAE) for males and 700 RAE for females."

(v) Different Vitamers of This Nutrient — 2 Marks

• RAR (Retinoic Acid Receptors): bind all-trans-retinoic acid or 9-cis-retinoic acid
• RXR (Retinoid X Receptors): bind 9-cis-retinoic acid; form heterodimers with vitamin D and thyroid hormone receptors

Harper's Biochemistry: "All-trans-retinoic acid and 9-cis-retinoic acid regulate growth, development, and tissue differentiation... the retinoic acid receptors (RAR) bind all-trans-retinoic acid or 9-cis-retinoic acid, and the retinoid X receptors (RXR) bind 9-cis-retinoic acid."

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