Vitamin D, E, and K: Functions, Sources, and Deficiencies

Vitamins Overview

Fat Soluble Vitamins

Vitamin D

• Definition: D vitamins are a group of sterols with a hormone-like function.

• Active Form: The active form is 1,25-dihydroxycholecalciferol (1,25(OH)2-D3) or calcitriol.

• Mechanism:
    - Binds to intracellular receptor proteins.
    - The calcitriol-receptor complex interacts with DNA in the nucleus of target cells, similar to vitamin A, affecting gene transcription.

• Functions:
    - Regulates plasma levels of calcium and phosphorus.

Distribution of Vitamin D

1. Sources:
      - Endogenous:
        - Cholesterol → 7-Dehydrocholesterol → cholecalciferol (vitamin D3) in the skin/dermis from UV light.
      - Dietary Sources:
        - Ergocalciferol (vitamin D2) in plants, cholecalciferol (vitamin D3) in animal tissues.
        - Packaged into chylomicrons and transported via lymphatics to blood.

• Transport:
    - Vitamin D3 binds to the Vitamin D-binding protein which transports it to the liver for metabolism.

Metabolism of Vitamin D

• Activation Process:
    - Formation of 1,25(OH)2-D3 (Calcitriol):
      1. Non-active forms D2 & D3 are converted via two sequential hydroxylation reactions.
         - First Hydroxylation:
           - Occurs in the liver at the 25-position:
           - Produces 25-hydroxycholecalciferol (the predominant form in plasma).
         - Second Hydroxylation:
           - Occurs in the kidney at position 1:
           - Produces 1,25-(OH)2-D3 by 1-α-hydroxylase enzyme.

• Enzymes:
    - Both 1-hydroxylase and 25-hydroxylase are cytochrome P450 (CYP) proteins.

Regulation of Vitamin D Metabolism

• 1-α-Hydroxylase Regulation:
    - The activity of this enzyme is controlled by plasma phosphate and calcium levels.
    - Increased by low plasma phosphate or indirectly through PTH release due to low plasma calcium.
    - Calcitriol’s Role:
      - Inhibits synthesis of PTH, providing feedback inhibition and also inhibits the activity of 1-α-hydroxylase.

Functions of Vitamin D

• Calcium Regulation:
    - Works with PTH to increase plasma calcium levels:
      - Decreases calcium excretion in kidneys, increases calcium reabsorption.
      - Increases mobilization of calcium and phosphate from bones (in need of PTH).
      - Enhances intestinal calcium absorption by increasing synthesis of calcium-binding proteins.

• Cellular Functions:
    - Important for cell differentiation.

Distribution & Requirement of Vitamin D

• Natural Sources:
    - Found in fatty fish, liver, and egg yolk.

• Dietary Supplementation:
    - Adult requirement: approximately 100 IU/day.
    - Increased requirement for pregnant and lactating mothers, infants, and children to about 220 IU/day.

Clinical Aspects

• Vitamin D Deficiency:

1. Nutritional Rickets:
      - Results from Vitamin D deficiency leading to bone demineralization.
      - Symptoms include inadequate calcification, misshapen and deformed bones, and lax muscles leading to spasms.
      - Bowing of legs is typical.

2. Osteomalacia:
      - Characterized by demineralization of bones which leads to softness and deformation, pain, weakness, and higher fracture risk.
      - High-risk groups include infants and the elderly lacking sunlight exposure and adequate Vitamin D intake.

3. Renal Osteodystrophy:
      - Chronic kidney disease reduces ability to form active vitamin D and enhances phosphate retention, causing hyperphosphatemia and hypocalcemia.
      - Treatment includes supplementation with calcitriol alongside phosphate reduction strategies.

4. Hypoparathyroidism:
      - Lack of PTH leads to hypocalcemia and hyperphosphatemia; treatment includes calcitriol and calcium.

Vitamin D Toxicity

• Characteristics:
    - Vitamin D is fat-soluble, stored in the body; slow to metabolize.
    - High doses (e.g., 100,000 IU/day) for prolonged periods result in loss of appetite, nausea, thirst, and neurological symptoms.
    - Increased calcium uptake leads to hypercalcemia, causing deposition of calcium in organs, mainly arteries and kidneys.
    - Toxicity is generally associated with supplements only.

Vitamin E

• Definition:
    - Consists of eight naturally occurring tocopherols, α-tocopherol is the most active.

• Dietary Sources:
    - Rich in polyunsaturated plant oils; moderate amounts found in liver & eggs.

• Recommended Dietary Allowance (RDA):
    - 15 mg/day for adults, increases with intake of polyunsaturated fatty acids to limit fatty acid peroxidation.

Functions of Vitamin E

• Role:
    - Functions primarily as an antioxidant.

• Mechanism:
    - Stabilizes cell membranes, regulates oxidation reactions, protects polyunsaturated fatty acids and vitamin A from oxidative damage.

• Importance:
    - Essential for proper nerve and muscle function.

• Antioxidants Include:
    - Vitamins E & C, carotenoids, flavonoids, and selenium.

Vitamin E Toxicity

• Toxicity Profile:
    - Very minimal; no toxicity observed at doses of 300 mg/day.

• Deficiency & Associated Risks:
    - Generally restricted to premature infants. Adults show deficiency due to malabsorption (biliary, pancreatic, intestinal diseases).
    - Symptoms:
      - Hemolytic anemia (sensitivity of RBCs to peroxides), nerve damage, muscle weakness, atherosclerosis, and increased cancer risks.

Vitamin K

• Definition:
    - Refers to a group of fat-soluble vitamins important for blood clotting.

• Synthesis:
    - Produced ~75% by intestinal bacteria.

• Absorption:
    - Requires healthy liver and gall bladder; not stored in the body necessitating daily supply.

• Function:
    - Required for synthesis of proteins necessary for blood coagulation and bone calcium-binding proteins.

Forms of Vitamin K

1. Vitamin K1 (phylloquinone):
      - Produced by plants.

2. Vitamin K2 (menaquinone):
      - Produced by intestinal bacteria; more active, 15 times more potent than K1.

3. Vitamin K3 (menadione):
      - Synthetic water-soluble derivative for therapy; can be converted to K2.

Functions of Vitamin K

1. γ-Carboxyglutamate Formation:
      - Involved in the synthesis of clotting factors II, VII, IX, and X.
      - Carboxylation of glutamic acid residues needs vitamin K as a coenzyme for γ-glutamyl carboxylase.
      - Inhibited by anticoagulants like dicumarol & warfarin.

2. Prothrombin-Membrane Interaction:
      - Gla residues help binding calcium ions, crucial for blood clotting processes.

3. Other Functions:
      - Integration of calcium into bones.
      - Preventing vascular calcification and maintaining elasticity of blood vessels.

Vitamin K & Anticoagulants

• Interaction:
    - Warfarin blocks the regeneration of active vitamin K.
    - Antibiotics may reduce intestinal flora, impacting vitamin K synthesis.

Sources of Vitamin K & Deficiency

• Dietary Sources:
    - Cabbage, cauliflower, spinach, egg yolk, and liver.

• Deficiency Causes:
    - Antibiotics affecting intestinal bacteria can lower vitamin K synthesis.
    - Warfarin effects leading to decreased active vitamin K levels.

• High-Risk Groups:
    - Newborns (especially premature), requiring prophylactic vitamin K at birth.
    - People with fat malabsorption or consumption of unabsorbed lipids.

Effects of Vitamin K Deficiency

• Symptoms:
    - Prolonged prothrombin time, leading to bleeding disorders.
    - Poor bone development and osteoporosis.
    - Increased cardiovascular disease risks.

Vitamin K Toxicity

• Toxicity Profile:
    - Risk of hemolytic anemia and jaundice in infants from large doses of synthetic vitamin K.
    - No established upper limit for vitamin K.

Summary of Fat Soluble Vitamins

Summary of Deficiency and Toxicity in Fat Soluble Vitamins

• Note:
    - Vitamin D is not a true vitamin as it can be synthesized in the skin, and its synthesis can be affected by sunscreen application or darker skin tones.
    - Vitamin K is synthesized by intestinal bacteria and its deficiency is common in newborns, necessitating IM treatment at birth.
    - The benefits of Vitamin E supplementation have not been validated in controlled trials and are generally not recommended unless necessary.