Fat-soluble vitamins A, D, E, and K are hydrophobic compounds that require dietary fat and bile salts for absorption. They are transported in chylomicrons, stored in the liver and adipose tissue, and can accumulate to toxic levels with excessive intake.
Vitamin A
Vitamin A refers to retinol, retinal, and retinoic acid. Beta-carotene, a provitamin carotenoid found in plants, is cleaved by beta-carotene dioxygenase to produce retinal. Retinol is the transport form, retinal is essential for vision, and retinoic acid regulates gene expression through nuclear retinoic acid receptors and retinoid X receptors.
In vision, 11-cis-retinal is the chromophore of rhodopsin in rod photoreceptors. Light absorption isomerizes 11-cis-retinal to all-trans-retinal, triggering a signaling cascade that results in a nerve impulse. Retinoic acid regulates gene expression in embryonic development, immune function, and cell differentiation. Vitamin A is found in liver, dairy products, and fortified foods, while carotenoids are abundant in orange and green vegetables.
Night blindness is the earliest symptom of deficiency, followed by xerophthalmia, Bitot spots, and corneal ulceration. Vitamin A deficiency is a leading cause of preventable blindness in children. Excess vitamin A causes hypervitaminosis A with headache, liver damage, and teratogenicity.
Vitamin D
Vitamin D is produced in the skin from 7-dehydrocholesterol, an intermediate in cholesterol metabolism, upon ultraviolet B exposure or obtained from dietary sources. It is converted to 25-hydroxyvitamin D in the liver and to the active form 1,25-dihydroxyvitamin D in the kidney. Cholecalciferol is the form produced in skin, while ergocalciferol comes from plant sources.
Active vitamin D binds the vitamin D receptor, a nuclear receptor that regulates calcium and phosphate homeostasis. It increases intestinal absorption of calcium and phosphate, promotes bone mineralization, and regulates parathyroid hormone secretion. Vitamin D also has immunomodulatory and anti-proliferative effects.
Deficiency causes rickets in children, characterized by soft, deformed bones, and osteomalacia in adults with bone pain and weakness. Vitamin D insufficiency is widespread and contributes to osteoporosis risk. Toxicity causes hypercalcemia, nephrocalcinosis, and kidney stones.
Vitamin E
Vitamin E includes eight tocopherols and tocotrienols, with alpha-tocopherol having the highest biological activity. It is the major lipid-soluble antioxidant, protecting polyunsaturated fatty acids in membranes from lipid peroxidation. Vitamin E donates a hydrogen atom to lipid peroxyl radicals, terminating the chain reaction of lipid peroxidation.
Vitamin E is found in vegetable oils, nuts, seeds, and green leafy vegetables. Deficiency is rare but occurs in fat malabsorption syndromes and in genetic disorders affecting the alpha-tocopherol transfer protein. Deficiency causes peripheral neuropathy, muscle weakness, and hemolytic anemia. High doses are well tolerated but can interfere with vitamin K metabolism.
Vitamin K
Vitamin K is a cofactor for gamma-glutamyl carboxylase, which converts specific glutamate residues to gamma-carboxyglutamate in vitamin K-dependent proteins. This modification is essential for calcium binding by these proteins. Vitamin K-dependent proteins include the blood clotting factors II, VII, IX, and X, and the anticoagulant proteins C and S. Osteocalcin, a bone matrix protein, also requires gamma-carboxylation.
Phylloquinone from green leafy vegetables and menaquinones from bacterial synthesis in the gut provide vitamin K. Warfarin and related anticoagulants inhibit vitamin K epoxide reductase, blocking recycling of vitamin K and impairing clotting factor synthesis. Newborns receive vitamin K prophylaxis to prevent hemorrhagic disease because of sterile guts and low stores. Deficiency causes easy bruising, bleeding, and impaired bone mineralization.
