Vit A

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Vitamin A (Retinol)

Overview

Vitamin A is a fat-soluble vitamin that exists in several interconvertible forms:

Retinol - transport and storage form
Retinal - active form in the visual cycle
Retinoic acid - active form for gene regulation and cell differentiation
Retinyl ester - storage form (liver, peripheral tissues)
Beta-carotene - plant-derived provitamin (contributes ~30% of dietary vitamin A)

Dietary Sources

Source Type	Examples
Animal (preformed, retinyl ester)	Liver, fish, eggs, milk, butter
Plant (provitamin, beta-carotene)	Carrots, squash, spinach, yellow/leafy green vegetables

The RDA is expressed in retinol equivalents (RE), which accounts for contributions from both preformed vitamin A and beta-carotene. Conversion: 10,000 IU = 3,000 mcg vitamin A.

Metabolism

Key steps (from Robbins & Kumar Basic Pathology):

Absorption - Requires bile, pancreatic enzymes, and dietary fat. Retinyl esters are cleaved to retinol by pancreatic enzymes; beta-carotene is converted to retinol in intestinal cells.
Transport to liver - Retinol is packaged as retinyl ester in chylomicrons and taken up by the liver via the apolipoprotein E receptor.
Storage - >90% of body's vitamin A is stored in the liver as retinyl ester in perisinusoidal stellate (Ito) cells. Reserves last at least 6 months on adequate diet.
Release - Retinol binds retinol-binding protein (RBP) (synthesized in liver) for circulation. RBP is recycled after retinol delivery to peripheral cells.
In target cells - Retinol is either stored as retinyl ester or oxidized to retinoic acid.

Functions

1. Vision

Vitamin A is a component of four visual pigments:

Rhodopsin (rod cells) - for low-light/dim-light vision
Three iodopsins (cone cells) - for color vision in bright light

Deficiency reduces synthesis of all four, causing night blindness as the earliest sign.

2. Epithelial Differentiation

Retinoic acid binds retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs). The RAR/RXR complex binds retinoic acid response elements (RAREs) on DNA, regulating genes for growth factor receptors, tumor suppressors, and secretory proteins. This governs the orderly differentiation of mucus-secreting columnar epithelium. Without vitamin A, epithelium undergoes squamous metaplasia and keratinization.

3. Metabolic Effects

Retinoids inhibit adipogenesis and stimulate lipid breakdown. RXR forms heterodimers with PPARs and vitamin D receptors, linking vitamin A to lipid and calcium metabolism.

4. Immune Function & Anti-infective

Vitamin A supplementation reduces diarrhea morbidity by ~15% and mortality by ~30%. It promotes regeneration of damaged epithelia and supports immune cell function. In populations where deficiency is prevalent, supplementation reduces overall child mortality by 20-30%.

Deficiency

Causes

Poor nutrition (most common globally, especially in developing countries)
Fat malabsorption: celiac disease, Crohn disease, colitis, biliary atresia, cystic fibrosis
Bariatric surgery
Continuous use of mineral oil laxatives
Infants on non-dairy formula lacking vitamin A

Clinical Features (in order of progression)

Feature	Mechanism
Night blindness	Earliest sign; reduced rhodopsin synthesis
Xerosis conjunctivae	Keratinization of conjunctival epithelium (dry eye)
Bitot spots	White foamy plaques at corneal margin from keratin debris
Keratomalacia	Corneal ulceration, softening, and destruction - leads to blindness
Squamous metaplasia of airways	Predisposes to secondary pulmonary infections
Urinary tract keratinization	Renal/bladder stones from keratin debris
Follicular/papular dermatosis	Hyperkeratinization + plugging of adnexal ducts

Collectively, the eye changes are called xerophthalmia.

Toxicity (Hypervitaminosis A)

Acute Toxicity

Symptoms: headache, dizziness, vomiting, stupor, blurred vision - can mimic a brain tumor (pseudotumor cerebri).

Historical note: first described in 1597 after crew members ate polar bear liver. Polar bear, whale, shark, and halibut liver are all dangerously high in vitamin A.

Chronic Toxicity

Weight loss, anorexia, nausea, vomiting
Bone and joint pain, hyperostoses
Retinoic acid stimulates osteoclast activity → increased bone resorption → fracture risk
Dry, pruritic skin
Pseudotumor cerebri with papilledema

Chronic toxicity threshold: daily intake of >25,000 IU (though most cases involve much higher doses). Average reported toxic dose: ~100,000 IU/day over 7.2 years.

Hepatotoxicity (from Sleisenger & Fordtran's GI and Liver Disease)

Vitamin A is the most important hepatotoxin among vitamin supplements when taken in supratherapeutic doses. Key facts:

Dose- and duration-dependent injury
Liver half-life: 50 days to 1 year - fibrosis may progress even after stopping supplementation
Mechanism: activation of hepatic stellate cells → hyperplasia/hypertrophy → sinusoidal compression → portal hypertension + collagen synthesis
Biopsy: characteristic greenish autofluorescence under UV light; "Swiss cheese/honeycomb" appearance from enlarged stellate cells
Histology: 59% cirrhosis, 34% chronic hepatitis, 21% microvesicular steatosis, 14% perisinusoidal fibrosis, 3% peliosis hepatitis
Water-miscible/emulsified formulations are up to 10x more hepatotoxic than oil-based preparations
Ethanol + beta-carotene combination is particularly hepatotoxic

Severe cases present with hepatomegaly, splenomegaly, ascites, variceal bleeding.

Therapeutic Use & Dosing (Harriet Lane Handbook)

Indication	Dose
Measles supplementation (<6 mo)	50,000 IU/day PO x 2 days
Measles supplementation (6 mo - <1 yr)	100,000 IU/day PO x 2 days
Measles supplementation (1-5 yr)	200,000 IU/day PO x 2 days
Malabsorption prophylaxis (>8 yr, adult)	10,000-50,000 IU/day PO (water-miscible)
Cystic fibrosis (infant)	1,500 IU/day PO
Cystic fibrosis (1-3 yr)	5,000 IU/day PO
Cystic fibrosis (4-8 yr)	5,000-10,000 IU/day PO
Cystic fibrosis (≥9 yr)	10,000 IU/day PO

Formulations: Caps (7,500-25,000 IU), Tabs (10,000-15,000 IU), Oral drops (2,500 IU/0.3 mL), IM injection (Aquasol A: 50,000 IU/mL).

Important: High-dose vitamin A is teratogenic (Category X). Never use above the RDA in pregnancy.

Lab Reference

Normal serum retinol: lower limit 20 mcg/dL
Toxicity suggested: >100 mcg/dL (Bradley & Daroff's Neurology)

Sources:

Robbins & Kumar Basic Pathology, pp. 292-293
Sleisenger & Fordtran's Gastrointestinal and Liver Disease
Bradley and Daroff's Neurology in Clinical Practice
The Harriet Lane Handbook, 23rd ed.

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