Vitamin E Deficiency

Introduction

• Vitamin E is a group of fat-soluble compounds, primarily tocopherols and tocotrienols.
• Alpha-tocopherol ($\alpha$-tocopherol) is the most biologically potent and widely distributed form in human tissues.
• It was historically referred to as the "anti-sterility factor" in rats or the "shady lady of nutrition" due to the initial ambiguity regarding its precise role in human physiology.
• It is absorbed in the small intestine, a process requiring bile salts and pancreatic enzymes, and is transported via chylomicrons to the liver and peripheral tissues.

Functions of Vitamin E

1. Antioxidant Activity (Primary Function)

• Chain-Breaking Antioxidant: Vitamin E acts as a non-specific chain-breaking antioxidant within the lipid phase of cell membranes.
• Protection of Polyunsaturated Fatty Acids (PUFA): It protects the PUFAs in the phospholipid bilayer of cell membranes from oxidative stress and lipid peroxidation caused by free radicals (Reactive Oxygen Species - ROS).
• Membrane Stability: By preventing peroxidation, it maintains the structural integrity and fluidity of cellular membranes, including those of red blood cells (RBCs) and neurons.
• Synergy: It works synergistically with other antioxidants like Vitamin C (which regenerates Vitamin E), Selenium (a cofactor for glutathione peroxidase), and Beta-carotene to scavenge free radicals.

2. Neurological Function

• Vitamin E is essential for the maintenance of the structure and function of the central and peripheral nervous systems.
• It maintains the integrity of axons and myelin sheaths.
• Deficiency leads to axonal degeneration, particularly affecting the posterior columns of the spinal cord and spinocerebellar tracts.

3. Hematological Role

• RBC Stability: It protects the RBC membrane from oxidative damage and hemolysis.
• Heme Synthesis: It is involved as a cofactor in the synthesis of heme.

4. Immune Function

• Vitamin E enhances immune function, particularly cell-mediated immunity.
• It plays a role in modulation of the inflammatory response.

5. Other Functions

• Gene Expression: It regulates the expression of genes involved in cell proliferation and differentiation.
• Ophthalmic Health: It is highly concentrated in the retina and protects photoreceptors from oxidative damage.
• Cardiovascular Health: Some evidence suggests it may inhibit platelet aggregation and reduce the oxidation of LDL cholesterol, although therapeutic benefits in preventing cardiovascular disease remain debated.

Therapeutic Uses and Indications

1. Premature Infants

• Hemolytic Anemia of Prematurity: Used to prevent or treat hemolytic anemia characterized by reticulocytosis, low hemoglobin, and hyperbilirubinemia appearing at 4–6 weeks of age. Premature infants are born with low stores and often face high oxidative stress.
• Retinopathy of Prematurity (ROP): Due to its antioxidant properties, it has been used to reduce the severity of ROP, although maintaining physiological levels is the current goal.
• Bronchopulmonary Dysplasia (BPD): Used as an antioxidant therapy to potentially mitigate lung injury caused by oxygen toxicity.
• Intraventricular Hemorrhage (IVH): Some studies suggest a role in reduction, though this is not a standard monotherapy.

2. Malabsorption Syndromes

• Therapeutic supplementation is indicated in conditions characterized by chronic steatorrhea (fat malabsorption) where Vitamin E absorption is compromised:
  • Cystic Fibrosis: Pancreatic insufficiency leads to poor absorption.
  • Cholestatic Liver Disease: Decreased bile salts prevent micelle formation necessary for absorption (e.g., Biliary Atresia).
  • Abetalipoproteinemia: Genetic absence of apolipoprotein B prevents the formation of chylomicrons, making Vitamin E transport impossible.
  • Short Bowel Syndrome: Reduced absorptive surface area.
  • Celiac Disease.

3. Genetic Disorders of Transport

• Ataxia with Vitamin E Deficiency (AVED): A rare autosomal recessive disorder caused by mutations in the $\alpha$-tocopherol transfer protein (TTPA) gene. These patients cannot secrete Vitamin E from the liver into the circulation. High-dose therapy is the primary treatment.

4. Other Potential Uses

• Hemolytic Anemias: Used as an adjunct in G6PD deficiency and Thalassemia to reduce oxidative hemolysis.
• Skin Conditions: Topical or oral use for wound healing and reduction of scarring (e.g., phrynoderma).
• Fatty Liver: Investigated for use in Non-Alcoholic Fatty Liver Disease (NAFLD).

Clinical Features of Deficiency

Deficiency is rare in healthy individuals consuming a varied diet. It is almost exclusively seen in premature infants and children with malabsorption.

1. Hematological Manifestations (Infants)

• Hemolytic Anemia: Occurs in preterm infants (<34 weeks) around 6–10 weeks of age.
• Features: Hemoglobin 7–9 g/dL, reticulocytosis, thrombocytosis, and edema (often affecting the legs and labia).
• Aggravating Factors: High intake of PUFAs (which increases antioxidant demand) and iron supplementation (which acts as a pro-oxidant) without adequate Vitamin E can precipitate hemolysis.

2. Neurological Manifestations (Older Children/Chronic Deficiency)

• A progressive spinocerebellar degeneration syndrome that resembles Friedreich's ataxia.
• Hyporeflexia/Areflexia: Loss of deep tendon reflexes is often the first sign.
• Ataxia: Truncal and limb ataxia, wide-based gait, intention tremor.
• Sensory Loss: Loss of proprioception (position sense) and vibration sense due to posterior column involvement.
• Ophthalmoplegia: Limitation of upward gaze, strabismus, and nystagmus.
• Muscle Weakness: Proximal muscle weakness and myopathy.
• Pigmentary Retinopathy: Can progress to visual field constriction and blindness.

Management of Vitamin E Deficiency

1. Prevention

• Premature Infants:
  • Routine supplementation is recommended for low birth weight (<1500 g) and preterm infants.
  • Avoidance of formulas with excessively high PUFA content unless balanced with antioxidants.
  • Delaying aggressive iron supplementation until antioxidant status is improved.
• Dietary Sources: Encouraging intake of vegetable oils (corn, soy, safflower), nuts, seeds, whole grains, and green leafy vegetables.

2. Treatment Regimens

• Hemolytic Anemia in Preterms:
  • Dose: 20–50 IU/day (or 15–25 IU/kg/day) orally.
  • Duration: Typically given for 1 week or until the deficiency is corrected.
  • Parenteral administration may be used if oral intake is not feasible.
• Chronic Malabsorption (Cholestasis, Cystic Fibrosis):
  • Oral Dosage: 15–25 IU/kg/day. Doses may need to be titrated significantly higher (up to 100–200 IU/kg/day) based on serum levels.
  • Water-Soluble Forms: In severe cholestasis, water-soluble forms like TPGS (Tocopherol Polyethylene Glycol-1000 Succinate) are preferred as they can be absorbed without bile salts.
• Abetalipoproteinemia and AVED:
  • Requires massive doses, often 100 mg/kg/day or 5000–10,000 IU/day, to achieve therapeutic serum levels through passive diffusion.

3. Monitoring

• Serum Vitamin E Levels:
  • Normal range: 0.5–1.5 mg/dL (11.6–34.8 $\mu$mol/L).
  • Deficiency: <0.5 mg/dL.
• Vitamin E to Lipid Ratio:
  • Because Vitamin E circulates bound to lipids, serum levels can be artificially elevated in hyperlipidemia and low in hypolipidemia.
  • The ratio of Serum Vitamin E (mg) to Total Serum Lipids (g) is the most accurate index.
  • Normal Ratio: >0.8 mg/g (adults/older children) and >0.6 mg/g (infants).

Hypervitaminosis E (Toxicity)

• Vitamin E is generally considered relatively non-toxic compared to vitamins A and D.
• Upper Limit: The tolerable upper intake level is set at 1000 mg/day for adults.
• Adverse Effects:
  • Bleeding Diathesis: Very high doses can antagonize Vitamin K, leading to prolonged prothrombin time and increased risk of bleeding (especially in patients on anticoagulants).
  • Necrotizing Enterocolitis (NEC): Historically associated with high-dose oral hyperosmolar Vitamin E preparations in preterm infants.
  • Sepsis: Some reports suggest an increased risk of sepsis with high-dose supplementation in neonates.
  • GI Symptoms: Nausea, diarrhea, and cramps at mega doses.