Vitamin a

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Vitamin A

Overview

Vitamin A is a fat-soluble vitamin - a collective term for a family of structurally related compounds called retinoids. It exists in several biologically active forms and is obtained from both animal and plant sources.

Chemistry and Forms

Form	Source / Role
Retinol	Principal circulating form; transport and storage (as retinyl ester)
Retinal (retinaldehyde)	Active in vision (component of rhodopsin)
Retinoic acid	Active in gene regulation and differentiation
Retinyl esters	Storage form (especially retinyl palmitate in liver)
β-carotene	Provitamin A (plant source); cleaved to yield retinol

The 20-carbon structure contains a β-ionone ring and an isoprenoid side chain. About 1,000 carotenoid compounds exist, but only ~50 have provitamin A activity - the main ones are β-carotene, α-carotene, and β-cryptoxanthin.

Conversion: 10,000 IU = 3,000 mcg retinol activity equivalents (RAE)

Dietary Sources

Preformed vitamin A (retinol): Liver, fish oils, egg yolk, dairy (milk, butter, cream)
Provitamin A (carotenoids): Carrots, pumpkin, squash, sweet potato, spinach, apricots, grapefruit, green leafy vegetables
In the US diet, ~75% comes from preformed retinol and ~25% from carotenoids

Metabolism

Absorption: Requires bile salts, pancreatic lipase, and dietary fat. β-carotene is converted to retinol in the intestinal wall.
Transport: Retinol is packaged into chylomicrons and transported via lymphatics to the liver.
Storage: >90% of body stores are in the liver (predominantly in perisinusoidal stellate/Ito cells as retinyl esters). Sufficient reserves for at least 6 months.
Release: Bound to retinol-binding protein (RBP), which is synthesized in the liver. Peripheral tissues take it up via RBP surface receptors; RBP is then recycled.
Activation: Retinol → retinal (reversible) → retinoic acid (irreversible)

Functions

1. Vision

Retinal combines with opsin to form visual pigments: rhodopsin (in rods, for dim light) and iodopsins (3 types in cones, for color vision)
Deficiency reduces synthesis of all four pigments

2. Epithelial Differentiation

Maintains mucus-secreting columnar epithelium throughout the body
Without vitamin A, epithelium undergoes squamous metaplasia → keratinization
Acts through retinoic acid receptors (RARs) forming heterodimers with retinoid X receptors (RXRs), which bind retinoic acid response elements (RAREs) in gene regulatory regions

3. Immune Function

Supplementation reduces diarrhea morbidity by ~15% and mortality by ~30%
Promotes regeneration of damaged epithelia; required for optimal immune function
In deficient populations, supplementation reduces overall mortality by 20-30%

4. Cell Growth and Differentiation

RAR/RXR heterodimers regulate expression of growth factor receptors, tumor suppressor genes, and secreted proteins
Controls cell-cycle progression

5. Metabolic Effects

Retinoids inhibit adipogenesis and stimulate lipid breakdown
RXR forms heterodimers with PPARs and vitamin D receptors

6. Reproduction and Fetal Development

Essential for spermatogenesis, fetal organogenesis, and normal embryonic development

Deficiency

Causes: Poor dietary intake (most common worldwide), fat malabsorption (celiac disease, Crohn disease, colitis), bariatric surgery, continuous use of mineral oil laxatives.

Clinical Manifestations

Ocular (xerophthalmia) - progression:

Night blindness - earliest sign; impaired rhodopsin synthesis
Xerosis conjunctivae - dryness of conjunctiva (lacrimal/mucus epithelium replaced by keratinized epithelium)
Bitot spots - keratin debris plaques on conjunctiva
Keratomalacia - softening and destruction of the cornea → irreversible blindness

Other manifestations:

Squamous metaplasia of respiratory epithelium → loss of mucociliary clearance → recurrent pulmonary infections
Desquamation of keratin debris in urinary tract → renal/bladder stones
Follicular/papular dermatosis (hyperkeratosis of skin with plugging of adnexal ducts)
Impaired immune function and increased susceptibility to infections

Toxicity (Hypervitaminosis A)

Vitamin A is a dose- and duration-dependent hepatotoxin. Only preformed retinol causes toxicity - β-carotene does not (excess causes carotenodermia, not toxicity).

Acute Toxicity

Caused by single massive dose (e.g., polar bear liver - historically well known):

Headache, dizziness, vomiting, stupor, blurred vision
Can mimic a brain tumor (pseudotumor cerebri / raised ICP)

Chronic Toxicity

Typical dose in reported liver disease cases: ~100,000 IU/day over ~7.2 years (mean cumulative dose 229 million IU). Liver injury reported at 10,000-45,000 IU/day; cirrhosis at 25,000 IU/day for ≥6 years:

Weight loss, anorexia, nausea, vomiting
Bone and joint pain; increased fracture risk (osteoclast stimulation by retinoic acid)
Hepatotoxicity - from stellate cell hyperplasia/hypertrophy → sinusoidal obstruction → portal hypertension → cirrhosis
Skin and CNS involvement

Liver biopsy findings:

Greenish autofluorescence under UV light (characteristic)
Enlarged stellate cells in space of Disse → "Swiss cheese" / honeycomb appearance
Perisinusoidal fibrosis, microvesicular steatosis
Cirrhosis (59%), chronic hepatitis (34%), perisinusoidal fibrosis (14%), peliosis (3%)

Important note: Water-miscible preparations are up to 10x more toxic than oil-based forms due to higher peak plasma and hepatic levels.

Teratogenicity: High-dose vitamin A is category X in pregnancy - causes craniofacial, cardiac, CNS, and thymic malformations.

Reference Ranges and Dosing

Population	Value
Normal serum retinol	1.05-2.09 µmol/L (30-60 µg/dL)
US RDA (adults)	700-900 mcg RAE/day
Tolerable upper intake level	3,000 mcg RAE/day (10,000 IU)

Pediatric dosing for measles (Harriet Lane):

<6 months: 50,000 IU/day × 2 days
6 months to <1 year: 100,000 IU/day × 2 days
1-5 years: 200,000 IU/day × 2 days

Clinical Uses

Measles - reduces complications and mortality in deficient/at-risk children
Synthetic retinoids (tretinoin, isotretinoin) - acne, psoriasis, acute promyelocytic leukemia (APL)
Malabsorption syndromes - prophylaxis (10,000-50,000 IU/day water-miscible form)
Cystic fibrosis - supplementation to prevent deficiency

Sources: Robbins & Kumar Basic Pathology, p. 292-293 | Sleisenger & Fordtran's GI & Liver Disease | Tietz Textbook of Laboratory Medicine, 7th Ed. | Harriet Lane Handbook, 23rd Ed.

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