Lipid Soluble Vitamins PDF 2024-01

Lipid Soluble Vitamins 2024/01 Dr. Sergio R. Ortiz MD, MPH, CPH Objectives: 01. To know shared characteristics of the lipid soluble vitamins 02. Identify synthesis mechanisms 03. Learn their action mechanisms in the human body 04. Apply knowledge in regards their toxicity and/or deficiency Gene...

Lipid Soluble Vitamins 2024/01 Dr. Sergio R. Ortiz MD, MPH, CPH Objectives: 01. To know shared characteristics of the lipid soluble vitamins 02. Identify synthesis mechanisms 03. Learn their action mechanisms in the human body 04. Apply knowledge in regards their toxicity and/or deficiency Generalities: • • • • • • • • • Vitamins and trace elements are micronutrients essential for metabolism. They participate in the metabolism of carbohydrates, fat, and proteins. A, D, E, and K are the fat-soluble vitamins. A and D vitamins act as hormones. Are associated with body-fat and are often stored in tissues, with circulating concentrations being kept constant. They are not readily absorbed from the diet as are water-soluble vitamins but stored in tissues. Apart from vitamin K, they do not act as coenzymes. All lipid-soluble vitamins in excess cause hypervitaminosis. Recent evidence suggests that only vitamins A and D, but not vitamin E or K, can be toxic in excess. Deficiency: May develop because of inadequate intake/ malnutrition. Poor absorption from the intestinal tract Inefficient utilization or increased loss, or increased demand. May develop as a general cause of malnutrition or illness. During periods of increased demand such as pregnancy, or adolescent growth spurt. As a complication of GI surgery. Multiple micronutrient deficiencies are more common than single ones. Question: A 32-year-old woman presents with night blindness and dry, scaly skin. Upon further examination, conjunctival xerosis is noted. Laboratory tests reveal decreased serum levels of retinol (vitamin A). Which of the following is the most likely cause of her symptoms? a) Excessive dietary intake of vitamin A b) Impaired absorption of fat-soluble vitamins c) Overuse of topical retinoid creams d) Elevated levels of beta-carotene in the diet e) Deficiency of vitamin C 6 Retinoids: • It is a generic term for retinol, retinal, and retinoic-acid. • Retinal and retinoic-acid are active forms. • The term retinoids has been used to define these substances as well as other synthetic compounds associated with vitamin A–like activity. • Retinal can be converted by the body to retinoic acid. • The pro-vitamin of vitamin A is a plant pigment called βcarotene (water soluble and found in plant food). • All dietary forms of vitamin A are converted to retinol. Retinoids: • Retinol, in turn, can be converted to retinal and retinoic acid. • Retinol esters are transported from the intestine to the liver in the chylomicrons and chylomicron remnants (process of fat absorption/ tranport). Food sources: • Free retinol is not generally found in foods. • Retinyl palmitate, a precursor and storage form of retinol, found in animals. (Common vitamin supplement) • Plants contain carotenoids, some of which are precursors for vitamin A (e.g., a-carotene, b-carotene, and b-cryptoxanthin). Yellow and orange vegetables contain significant quantities of carotenoids. Good sources of β-carotene are dark-green and yellow vegetables and tomatoes. Retinoid storage: • Stored in the liver and needs to be transported to its sites of action. • Esterified in the liver by lecithin:retinol acyltransferase and stored in the form of retinyl esters, bound to the cytosolic retinol-binding proteins. • Liver storage can provide approximately 1 year's supply. • Retinol is secreted from the liver bound to serum retinol-binding protein and is taken up by cells via a membrane receptor. • Retinoic acid is a signaling molecule that interacts with RAR (retinoid acid receptors) • RAR binds all-trans and 9-cis-retinoic acid • Rexinoid receptors (RXR) only bind 9-cis form. RXR receptors can also interact with vitamin D3, thyroid hormones, or peroxisome proliferatoractivated receptors (PPAR). Actions: • Retinoic acid is important for growth, differentiation, and proliferation of cells during embryonic development, organogenesis, and also in the maintenance of epithelia. Retinoid deficiency: • Presents as night blindness. • The visual pigment rhodopsin, found in the rod cells of the retina, is formed by the binding of 11- cis -retinal to the apoprotein opsin. • Rod cells are responsible for vision in poor light. • Retinoid deficiency presents as defective night vision, or night blindness (it is the most common symptom of retinoid deficiency in children and pregnant women). • Retinoids affect the growth and differentiation of epithelial cells, its deficiency produces defective epithelialization and corneal softening and opacity (keratomalacia). • Severe retinoid deficiency causes permanent blindness. • Most common cause of blindness in the world. Retinoid deficiency cont. • Pregnant and lactating women are prone to vitamin A deficiency. • The most vulnerable group are premature infants and, in the developing countries, breastfed children of mothers who themselves are retinoid deficient. Note that deficiencies of the vitamins B 12 , E, C, biotin, and the minerals zinc and iron have been linked to problems with vision. This highlights the importance of diet in maintaining optimal vision (Simkin et al.). Toxicity • Retinoid is toxic in excess amounts. • A myriad of symptoms that include increased intracranial pressure, headaches, double vision, dizziness, bone and joint pain, hair loss, dermatitis, hepatosplenomegaly, diarrhea and vomiting. • Increased intake of retinoid is also associated with teratogenicity, and it should be avoided during pregnancy. Question: A 45-year-old man presents with generalized bone pain and muscle weakness. He reports a history of chronic kidney disease and limited sun exposure due to his work schedule. Laboratory results reveal low serum levels of 25-hydroxyvitamin D. Which of the following is the most likely cause of his symptoms? A) Increased dietary intake of calcium B) Hyperparathyroidism C) Excessive sun exposure D) Impaired hepatic hydroxylation of vitamin D E) Renal insufficiency Vitamin D: • Vitamin D 2 (ergocalciferol) is synthesized in the skin by UV radiation of ergosterol • Vitamin D 3 (cholecalciferol) is synthesized in the skin by UV irradiation of 7-dehydrocholesterol. Vitamin D 3 and its hydroxylated metabolites are transported in the plasma bound to a specific globulin, vitamin D–binding protein (DBP). Cholecalciferol is also found in the diet, where its absorption is linked to the absorption of fats. • Absorbed vitamin D is transported to the liver in chylomicrons and is released to the liver, where it is hydroxylated at the 25-position by a hydroxylase designated CYP2R1, forming calcidiol (25hydroxycholecalciferol; 25[OH]D 3 ). • It modulates growth, participates in immune function, and is antiinflammatory. Storage form: • Calcidiol is the storage form of vitamin D • Found in the liver and in the circulation. It is bound to DBP in both compartments. The rate of hydroxylation is regulated by its hepatic content, and its levels in the circulation reflect the size of hepatic stores. A significant proportion of calcidiol is subject to enterohepatic circulation, being excreted in the bile and reabsorbed in the small bowel. Thus, disturbed enterohepatic circulation can cause vitamin D deficiency. Calcidiol • Most potent form of Vitamin D • In the renal tubules, calcidiol (250HD3) is further hydroxylated at the 1position by a hydroxylase designated CYP27B1to form calcitriol (1α,25dihydroxycholecalciferol; 1,25[OH]2D3). The vitamin D–DBP complex is excreted by the tubule and reabsorbed by receptors known as megalin and cubilin. This reaction also takes place in the placenta. • Calcitriol is the most potent of the vitamin D metabolites. The 1αhydroxylase is stimulated by PTH, low plasma concentrations of calcium or phosphate, and calcitonin as well as by estrogens and vitamin D deficiency. It is feedback inhibited by calcitriol, hypercalcemia, high phosphate concentration, and low PTH. • Calcitriol is a hormone. It is transported in plasma bound to DBP. In the intestinal epithelium, analogously to other steroid hormones, it binds to a cytoplasmic receptor. The receptor forms heterodimers with the retinoid X receptor (RXR), and this complex transfers to the nucleus, where it induces gene expression. • Vitamin D upregulates gut Ca 2+ channel TRPV6, the intracellular transporter calbindin D, and the intestinal Ca 2+ ATPase PMCA1b, increasing the transport of Ca 2+ from enterocytes to plasma. • Calcitriol, together with PTH, stimulates osteoclasts and thus bone resorption. Synthesis: 1. Cholecalciferol (D3) is synthesized in the skin by UV irradiation of 7dehydrocholesterol. 2. Vitamin D3 is transported to the liver, where it is hydroxylated at the 25position forming calcidiol (25hydroxycholecalciferol; 25[OH]D3). 3. In the renal tubules, calcidiol (25[OH]D3) is further hydroxylated at the 1-position to form calcitriol (1α,25dihydroxycholecalciferol; 1,25[OH]2D3). Synthesis: • • • The synthesis of 1,25(OH)2D3 from 25(OH)D3 is stimulated by Parathyroid hormone (PTH) and suppressed by Ca2+, Pi and 1,25(OH)2D3 itself. The 1α-hydroxylase is stimulated by PTH, by low plasma concentrations of calcium or phosphate, and by calcitonin as well as by estrogens and vitamin D deficiency. Feedback is inhibited by calcitriol, hypercalcemia, high phosphate concentration, and low PTH. Factors influencing Vitamin D levels Both, UVB intensity and skin pigmentation level contribute to the rate of D3 formation. Melanin in the skin blocks UVB from reaching 7-DHC, thus limiting D3 production, as do clothing and sun-screen. 1. Where you live. 2. Air quality. 3. Use of sunscreen. 4. Skin color. Vitamin D actions: Although vitamin D is considered a major player in bone development and homeostasis, it has other physiological roles as well… Non-classical actions • immune function, autoimmune diseases, & allergies • certain cancers, such as breast, colon, and prostate • cardiovascular & metabolic diseases • neurological disorders Vitamin D3 functions: • Calcitriol, together with PTH, stimulates bone resorption by osteoclasts. • Calcitriol deficiency disrupts the mineralization of newly formed osteoid as a result of decreased calcium and phosphate availability and reduced osteoblast function, leading to the development of rickets in children and osteomalacia in adults. This increases plasma concentrations of calcium and phosphate. Rickets • Rickets develops when growing bones fail to mineralize. • Nutritional rickets can be caused by inadequate intake of vitamin D; however, it is not uncommon in children who have limited sun exposure and in infants who are breastfed exclusively. Pregnancy: • Vitamin D status becomes crucial for maternal health, fetal skeletal growth, and optimal maternal and fetal outcomes. • Vitamin D deficiency is common in pregnant women (550%) and in breastfed infants (10-56%). • Adverse health outcomes such as preeclampsia, low birth weight, neonatal hypocalcemia, poor postnatal growth, bone fragility, and increased incidence of autoimmune diseases have been linked to low vitamin D levels during pregnancy and infancy. Toxicity • • • • Stored as 25-OHD3 with a half-life of 20 to 29 days. Doses 10 times higher than the recommended dose can be toxic. Excessive exposure to sunlight does not lead to overproduction. High doses result in hypervitaminosis à deposition of Ca2+ in soft tissue (kidney, heart, lungs and vasculature), hypercalcinuria, and possible kidney stones. • Overconsumption is a contributing factor of atherosclerosis lesions of the vasculature, because calcium deposits cause damage especially to elastic tissue and to smooth muscle cells. • Arterial thrombosis can also be induced with excessive vitamin D. 30 Question: A 28-year-old woman presents with a history of ataxia and impaired proprioception. Neurological examination reveals decreased deep tendon reflexes and loss of vibratory sensation. Further investigation reveals a reduced concentration of alpha-tocopherol in the serum. Which of the following is the most likely cause of her symptoms? a) Excessive dietary intake of vitamin E b) Chronic alcoholism c) Malabsorption syndrome d) Overuse of antioxidant supplements e) Prolonged sun exposure 31 Tocopherol • Known as vitamin E • • Is a mixture of several compounds. 90% of vitamin E present in human tissues is in the form of αtocopherol. Absorbed from the diet in the small intestine with lipids. • • It is packed into the chylomicrons, and in the circulation, it is associated with lipoproteins. Antioxidant qualities of Vitamin E: • Vitamin E is the most abundant natural antioxidant, and because of its lipid solubility, it is associated with all lipidcontaining structures: membranes, lipoproteins, and fat deposits. • It protects lipids from oxidation by the reactive oxygen species (ROS). • It is also involved in immune function, cellular signaling, and gene expression. • α-Tocopherol inhibits the activity of protein kinase C and affects cell adhesion as well as arachidonic acid metabolism. • A 6-month-old infant is brought to the pediatrician due to a history of recurrent episodes of bleeding, including blood-streaked stools and oozing from a recent minor cut. The infant has been exclusively breastfed, and the mother reports a limited intake of green leafy vegetables during pregnancy and lactation. The physical examination is notable for pallor, and laboratory studies reveal a prolonged prothrombin time (PT) and an elevated international normalized ratio (INR). Which of the following is the most likely diagnosis? a) Hemophilia A b) von Willebrand disease c) Vitamin K deficiency d) Factor V Leiden mutation e) Thrombocytopenia Deficiency • Malabsorption of fat and abetalipoproteinemia may lead to vitamin E deficiency. • Deficiency may also develop as a result of low vitamin E intake in pregnancy and newborn infants (mostly in preterm infants fed with formula milk with low vitamin E content). • In premature infants, this causes hemolytic anemia, thrombocytosis, and edema, as well as peripheral neuropathy, myopathy, and ataxia. Vitamin K: Vitamin K is a group of compounds that vary in the number of isoprenoid units in their side chain. Vitamin K circulates as phylloquinone (vitamin K1), and its hepatic stores are in the form of menaquinones (vitamin K2). Functions of Vitamin K • Vitamin K is required for post-translational modification of coagulation factors (factors II, VII, IX, and X). • All of these proteins (coagulation factors) are synthesized by the liver as inactive precursors and are activated by the carboxylation of specific glutamic acid residues by a vitamin K–dependent enzyme. • Prothrombin (factor II) contains 10 of these carboxylated residues, and all are required for this protein's specific chelation of Ca2+ ions during its function in the coagulation process. Deficiency: • Vitamin K supply by the intestinal microflora virtually ensures that dietary deficiency does not occur in humans, except for newborn infants. • Rarely, deficiency may develop in those with liver disease or fat malabsorption. • The deficiency is associated with bleeding disorders. Infants and Vitamin K • Premature infants are at particular risk of deficiency and may develop hemorrhagic disease of the newborn. • Placental transfer of vitamin K to the fetus is inefficient. Immediately after birth, the circulating concentration decreases. The gut of the newborn is sterile, therefore there is no source of vitamin K. • Usually, the concentration normalizes when the • absorption of food starts, but this might be • delayed in preterm infants. Inhibitors of Vitamin K • Inhibitors of vitamin K action are valuable antithrombotic drugs. • Specific inhibitors of vitamin K–dependent carboxylation are used in the treatment of thrombosis-related diseases - for example, in patients with deep vein thrombosis and pulmonary thromboembolism or those with atrial fibrillation who are at risk of thrombosis. • These are the drugs of the dicoumarin group (e.g., warfarin), which inhibit the action of vitamin K. Summary Vitamin Retinol (retinal & retinoic acid) A Cholecalciferol (Calcitriol & Calcidiol) D Function • • • • Antioxidant Visual pigment Epithelial differentiation *Tx. Acne & APL Deficiency • • • • • Night blindness Skinà dry scaly Keratomalacia Immunosuppression *Bitot spots Excess • • • • Intestinal absorption of Ca & Po • Bone mineralization & resorption • *TIGHT REGULATORY MEHCANISM (PTH, Ca, Po & negative feedback) • Rickets • Osteomalacia • Hypocalcemia Caused by • Malabsorption • Low sun exposure • Poor diet • Kidney disease • • • • • Nausea, vomiting, vertigo, blurred vision Alopecia, dry skin, hepatic toxicity and hepatomegaly. *TERATOGENIC Hypercalcemia Hypercalciuria Loss appetite Stupor *Granulomatous diseases (epithelioid macrophages) Summary Vitamin Tocopherol (α-tocopherol) E Phylloquinone, menaquinone K Function Deficiency • Antioxidant (protects cell membranes) • Inhibitor of vitamin E (at high doses supplementation) • • • • Hemolytic anemia Acanthocytosis Muscle weakness Demyelination disorders Carboxylation of glutamic residues (Ca binding proteins) Coagulation (maturation clotting factors II, VII, IX, X, protein C & S) *Synthesized by intestinal flora *Warfarin (INHIBITOR) • Hemorrhagic disease of the newborn • Bruises • Increased prothrombin time Excess • Enterocolitis in infants • Increased risk of bleeding • Rare • Liver related References: 1. 2. Baynes, J., & Dominiczak, M. H. (2019). Medical biochemistry. Elsevier Health Sciences. Chapter 7, 75-91 Bikle, D. D. (2014). Vitamin D metabolism, mechanism of action, and clinical applications. Chemistry & biology, 21(3), 319-329.