Vitamin A

Metabolism

Functions of Vitamin A in the Human Body

Vitamin A (retinol) is an essential fat-soluble micronutrient with pleiotropic effects on human physiology. Its functions can be broadly categorized as follows:

• Maintenance of Vision:
  • It is critical for vision in dim light (scotopic vision). Retinol is converted to retinal, which combines with the protein opsin to form rhodopsin (visual purple) in the rod cells of the retina.
  • It is also required for the synthesis of iodopsin in cone cells, which is essential for color vision and bright-light vision.
• Maintenance of Epithelial Integrity:
  • Vitamin A is necessary for the differentiation and maintenance of mucus-secreting epithelial tissues in the eyes, respiratory tract, gastrointestinal tract, and urinary tract.
  • It prevents keratinization (drying and hardening) of these tissues, maintaining a moist barrier against pathogens.
• Immune Function:
  • Often termed the "anti-infective" vitamin, it enhances both cellular and humoral immunity.
  • Deficiency leads to mucosal damage and increased bacterial binding, predisposing the child to severe respiratory and diarrheal infections.
• Growth and Development:
  • It is essential for skeletal growth, regulation of gene expression, and cellular differentiation.
  • It plays a vital role in embryonic development and hematopoiesis.
• Reproduction:
  • Retinol is required for normal reproduction and spermatogenesis.
• Antioxidant Activity:
  • Precursors like beta-carotene function as antioxidants, protecting cells from free radical damage and oxidative stress.

Clinical features of Deficiency

• Xeropthalmia
  • night blindness
  • xerosis
  • ulceration
  • necrosis
• Immunodeficiency
• increased risk of infection especially measles

WHO Classification of Vitamin A Deficiency (Xerophthalmia)

The World Health Organization (WHO) classifies the ocular manifestations of Vitamin A deficiency (Xerophthalmia) as follows:

Treatment Schedule for Managing Xerophthalmia

The management of xerophthalmia (specifically corneal xerosis, ulceration, or keratomalacia) is a medical emergency to prevent permanent blindness. The treatment protocol involves high-dose Vitamin A supplementation and supportive eye care.

1. Vitamin A Supplementation Schedule

A standard three-dose regimen is recommended for all children with corneal ulceration, keratomalacia, or corneal clouding to rapidly replenish liver stores and treat the acute deficiency.

• Timing of Doses:

  • 1st Dose: Immediately upon diagnosis (Day 0 or Day 1).
  • 2nd Dose: The following day (Day 1 or Day 2).
  • 3rd Dose: At least 2 weeks later (Day 14 or 28).

• Dosage by Age and Weight:

• Route of Administration:
  • Oral: This is the preferred route. Oil-based formulations are typically used.
  • Intramuscular (IM): Water-miscible Vitamin A (100,000 IU) can be used if the child has severe vomiting, diarrhea, or septic shock. The dose is usually half the oral dose.

2. Local Eye Care

Supportive care is crucial to save the eye in cases of corneal involvement:

• Antibiotics: Instill broad-spectrum antibiotic eye drops (e.g., Chloramphenicol or Tetracycline) or ointment every 2–3 hours to prevent or treat secondary bacterial infection.
• Atropine: Instill 1% Atropine eye drops (1 drop, three times daily) to relax the ciliary muscle, relieve pain, and prevent the lens from prolapsing through a perforated ulcer.
• Protection: Eye padding or bandaging may be required to protect the eye. If the child sleeps with eyes open, they should be gently closed to prevent drying.

3. Nutritional Rehabilitation

• Protein-Energy Malnutrition: Most children with xerophthalmia also suffer from severe malnutrition. Treatment includes high-protein, high-energy feeding (F-75/F-100 diets) once the child is stabilized.
• Dietary Sources: Encourage the consumption of Vitamin A-rich foods (green leafy vegetables, yellow/orange fruits, liver, egg yolk, dairy) after recovery.

Treatment

Severe deficiency with Xerophthalmia

• Infants : 7,500-15,000 U/day IM f/b oral 5,000 to 10,000 U/day for 10 days
• Children <8 yrs : 5,000 to 10,000 U/kg/day for 5 days or until recovery
• Children >8 yrs : Oral 5,00,000 U/day for 3 days, then 50,000 U/day for 14 days, then 10,000 -20,000 U/day for 2 months

Deficiency without corneal changes

• Infants : 1,00,000 U/day oral q4 to 6 months
• Children <8 yrs : 2,00,000 U/day oral q4 to 6 months
• Children >8 yrs : 1,00,000 U/day for 3 days, then 50,000 U/day for 10 days,

Malabsorption

• Infants : 7,500-15,000 U/day IM f/b oral 5,000 to 10,000 U/day for 10 days
• Children <8 yrs : 5,000 to 10,000 oral U/kg/day for 5 days or until recovery
• Children >8 yrs : Oral 5,00,000 U/day for 3 days, then 50,000 U/day for 14 days, then 10,000 -20,000 U/day for 2 months

Hazards of Vitamin A in Pediatric Practice

While essential, Vitamin A has a narrow therapeutic index. Toxicity (Hypervitaminosis A) can result from excessive intake of preformed vitamin A (retinol), often due to overzealous use of supplements or consumption of liver/fish liver oils,.

Acute Hypervitaminosis A

• Pseudotumor Cerebri: Acute toxicity can manifest as signs of increased intracranial pressure, including bulging fontanelle in infants, severe headache, vomiting, irritability, diplopia, and papilledema,,.
• Gastrointestinal Symptoms: Nausea, vomiting, and abdominal pain are early signs of acute ingestion of massive doses,.

Chronic Hypervitaminosis A

Chronic toxicity results from daily ingestion of doses exceeding the Recommended Daily Allowance (e.g., >6,000 µg or ~20,000 IU in children) over weeks or months.

• Dermatological Effects: Dry, itchy, desquamating skin, fissuring at the corners of the mouth, and alopecia (hair loss),.
• Musculoskeletal Effects:
  • Painful swellings over long bones due to cortical hyperostosis (thickening of the bone cortex), particularly affecting the ulna and tibia,.
  • Premature closure of epiphyses and growth arrest may occur.
• Hepatic Effects: Hepatomegaly, splenomegaly, and potential progression to cirrhosis and liver damage,,.
• General Systemic Effects: Anorexia, failure to thrive/lack of weight gain, and irritability.

Teratogenicity

• High doses of preformed Vitamin A (retinol) taken during early pregnancy are teratogenic.
• This can cause congenital malformations, including craniofacial abnormalities and central nervous system defects,,.
• Recommendations limit intake during pregnancy to not exceed 10,000 IU daily to avoid these risks.

Carotenemia (Benign Hazard)

• Excessive intake of carotenoids (provitamin A found in carrots, papaya, etc.) does not cause hypervitaminosis A toxicity because the conversion to retinol is regulated,.
• Clinical Presentation: It causes yellow-orange pigmentation of the skin (carotenodermia), prominently on the palms and soles and nasolabial folds,.
• Differentiation: Unlike jaundice, the sclera remains white. The condition is benign and resolves with dietary modification,.

Vitamin A Supplementation

Vitamin A (retinol) is an essential fat-soluble micronutrient critical for vision, immune function, and epithelial integrity. Vitamin A deficiency (VAD) remains a significant public health problem in developing countries, contributing to preventable blindness and increased mortality from infectious diseases. Supplementation programs are a cornerstone of public health strategies to combat these issues.

1. Physiological Basis for Supplementation

Vitamin A cannot be synthesized de novo by the human body and must be obtained from the diet. Supplementation is necessary when dietary intake is insufficient to meet physiological needs, especially during periods of rapid growth or illness.

• Functions:
  • Vision: Essential for the synthesis of rhodopsin (in rods for night vision) and iodopsin (in cones for color vision). Deficiency leads to night blindness (nyctalopia) and xerophthalmia.
  • Epithelial Integrity: Maintains the integrity of epithelial tissues in the eyes, respiratory tract, gastrointestinal tract, and urinary tract. It regulates glycoprotein synthesis and downregulates keratinization. Deficiency leads to squamous metaplasia and loss of the protective mucosal barrier.
  • Immunity: Enhances both humoral and cell-mediated immunity. It is termed the "anti-infective" vitamin. Supplementation reduces morbidity and mortality associated with measles and diarrhea.
  • Growth and Differentiation: Regulates gene expression via retinoic acid receptors (RAR and RXR), influencing cell differentiation, embryogenesis, and hematopoiesis.

2. Indications for Supplementation

Supplementation strategies are divided into prophylactic (preventive) and therapeutic (curative) interventions.

A. National Prophylaxis Programme (Prevention)

In India, the National Prophylaxis Programme against Nutritional Blindness was initiated in 1970 and later integrated with the Universal Immunization Programme. It targets children aged 9 months to 5 years.

• Target Group: Children 9–59 months.

• Dose Schedule:

  • 1st Dose (9 months): 100,000 IU (1 mL) given orally along with the measles vaccine.
  • 2nd Dose (16–18 months): 200,000 IU (2 mL) given with the DPT booster.
  • Subsequent Doses: 200,000 IU every 6 months until the age of 5 years.
  • Total Doses: A child receives a total of 9 megadoses.

• Current Recommendations for Infants:

  • < 6 months: 50,000 IU (only if clinical signs of deficiency are present or in severe malnutrition).
  • 6–12 months: 100,000 IU.
  • > 12 months: 200,000 IU.

B. Therapeutic Supplementation (Treatment of Deficiency)

According to the WHO/UNICEF/IVACG Task Force, specific schedules are required for treating active xerophthalmia (e.g., Bitot’s spots, corneal xerosis) and severe malnutrition.

• Schedule: Three doses are administered to replenish liver stores.

  • Dose 1: Immediately on diagnosis.
  • Dose 2: The next day.
  • Dose 3: After 2–4 weeks.

• Dosage by Age/Weight:

  • < 6 months: 50,000 IU.
  • 6–12 months (or < 8 kg): 100,000 IU.
  • > 1 year (or > 8 kg): 200,000 IU.

C. Specific Clinical Scenarios

• Measles: Vitamin A significantly reduces mortality in measles. All children with measles should receive Vitamin A therapy (doses as per age above).
• Severe Acute Malnutrition (SAM): All children with SAM receive a stat dose of Vitamin A on Day 1 unless there is evidence they received a dose in the last month.
  • If eye signs (xerophthalmia) are present, the 3-dose schedule (Day 1, 2, and 14) is mandatory.
• Persistent Diarrhea: A single large dose is recommended if not recently received.
• Neonates/Preterms: Preterm infants have low stores. Supplementation (oral multivitamin drops) providing ~1000 IU/day is often recommended. Routine high-dose supplementation for all neonates is not currently standard unless specific deficiency risks exist.

3. Sources and Forms of Supplement

• Oral Concentrate: The most common form used in public health is an oil-based solution (retinyl palmitate or acetate).
  • Standard strength: 100,000 IU per mL (often supplied with a spoon or dispenser).
• Injectable: Water-miscible preparations (e.g., Aquasol A) are available for cases of severe malabsorption or persistent vomiting.
  • Note: Parenteral administration should be followed by oral dosing when possible to ensure adequate liver storage, as water-soluble injections may not be stored efficiently.
• Dietary Sources: Supplementation programs must be complemented by dietary diversification.
  • Animal sources (Preformed Vitamin A): Liver, fish liver oils, egg yolk, milk fat.
  • Plant sources (Provitamin A/Carotenoids): Green leafy vegetables (spinach), yellow/orange vegetables (carrots, pumpkin, sweet potato), and fruits (papaya, mango).

4. Benefits of Supplementation

• Prevention of Blindness: Reverses night blindness, conjunctival xerosis, and Bitot’s spots. It can heal corneal ulcers (keratomalacia) if treated early, preventing permanent scarring and blindness.
• Reduction in Mortality: Supplementation reduces all-cause mortality in children aged 6–59 months by approximately 23–30%.
• Morbidity Reduction: Reduces the severity of diarrhea and measles. It boosts immunity by stabilizing lysosomal membranes and augmenting antibody responses.

5. Toxicity (Hypervitaminosis A)

While beneficial, Vitamin A has a narrow therapeutic window. Toxicity usually results from excessive intake of preformed Vitamin A, not carotenoids.

• Acute Toxicity: Can occur after a massive single dose.
  • Signs: Nausea, vomiting, irritability, headache.
  • CNS: Signs of raised intracranial pressure (Pseudotumor cerebri) such as bulging fontanelle in infants, diplopia, and stupor.
• Chronic Toxicity: Due to prolonged excessive intake (>6,000 µg/day in children).
  • Signs: Anorexia, dry itchy skin, alopecia (hair loss), fissuring of lips (cheilitis), and tender swelling of long bones (hyperostosis, typically ulna and tibia).
• Teratogenicity: High doses (>10,000 IU/day) in early pregnancy can cause congenital malformations (craniofacial, CNS, cardiac defects). Therefore, massive doses are contraindicated in pregnant women; safer daily doses (<10,000 IU) are recommended if deficiency is suspected.

6. Assessment of Vitamin A Status

Public health decisions regarding supplementation are based on the prevalence of deficiency signs in the community.

• Clinical Signs: Night blindness (>1%), Bitot’s spots (>0.5%), Corneal xerosis/ulceration (>0.01%) indicate a public health problem.
• Biochemical: Serum retinol < 20 µg/dL (<0.70 µmol/L) indicates deficiency. Levels < 10 µg/dL (<0.35 µmol/L) indicate severe deficiency.
• Functional Tests: Dark adaptometry and Conjunctival Impression Cytology (CIC).

7. Programmatic Issues and Current Strategy

• Integration: The prophylaxis program is integrated with the Village Health and Nutrition Days (VHND) and immunization sessions to ensure high coverage.
• Dietary Diversification: While supplements are a short-term measure ("medicalization"), the long-term goal is "nutritionalization"—improving dietary intake through education and food fortification (e.g., milk, oil).
• Double Fortified Salt: Research into salt fortified with both iodine and micronutrients like iron (and potentially vitamin A in some contexts) helps address multiple deficiencies simultaneously.