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Vitamins are vital micronutrients that cannot be synthesized endogenously or in insufficient amounts, and the principal means by which we get vitamins is through our diet. Vitamins can be classified as water-soluble or fat-soluble. The fat-soluble vitamins include vitamins A, D, E, and K. Fat-soluble vitamins play integral roles in a multitude of physiological processes such as vision, bone health, immune function, and coagulation. This review discusses the biochemistry, transport, and roles of these vitamins, highlighting deficiency syndromes and potential toxicities.

Deficiency Vitamin A Although rare in developed nations, vitamin A deficiency is a significant health concern in non-industrialized countries. It is responsible for over 500,000 cases of corneal lesions in children per year. In the United States, vitamin A deficiency most commonly results from fat malabsorption syndromes, alcoholism, and liver disease. Vitamin A uptake can also be impaired by iron deficiency, pancreatic insufficiency, and inflammatory bowel disease. Severe deficiency can lead to various ocular signs, notably night blindness (nyctalopia) and xerophthalmia. Keratin accumulation in the conjunctiva causing Bitot’s spots is a pathognomic physical finding. Other ocular manifestations include conjunctival xerosis, corneal drying and ulceration, and follicular hyperkeratosis.[1][9] Due to the role of vitamin A in T-lymphocyte proliferation and differentiation, deficiency also increases the risk of infections. Vitamin A is an effective treatment for measles, decreasing mortality in children and hospitalized patients.[10] Additionally, by inducing differentiation of acute promyelocytic anemia cells, all-trans retinoic acid (ATRA) is an effective treatment for acute promyelocytic leukemia.[11] In outpatient settings, isotretinoin is a common prescription for treating severe acne vulgaris. Vitamin D Vitamin D deficiency has become a global concern with dire health consequences. Common risk factors include old age, exclusively breastfed infants, immobility, reduced kidney function, dark skin, malabsorption syndromes, decreased sunlight exposure, and obesity.[12] Manifestations of deficiency include muscle aches and weakness with bone pain in the back, extremities, and pelvis. In children, vitamin D deficiency leads to impaired cartilage mineralization at growth plates, leading to rickets. Patients with rickets may have a bow-leg deformity, rachitic rosary, stunted growth with short stature, dental deformities, abnormal spinal curvature, craniotabes, and frequent fractures. In adults, low vitamin D levels lead to impaired mineralization of osteoid, leading to osteomalacia. Osteomalacia characteristically demonstrates diffuse bone and joint pain, myopathy, hypocalcemic tetany, and a waddling gait. Vitamin E

Vitamin D deficiency has become a global concern with dire health consequences. Common risk factors include old age, exclusively breastfed infants, immobility, reduced kidney function, dark skin, malabsorption syndromes, decreased sunlight exposure, and obesity.[12] Manifestations of deficiency include muscle aches and weakness with bone pain in the back, extremities, and pelvis. In children, vitamin D deficiency leads to impaired cartilage mineralization at growth plates, leading to rickets. Patients with rickets may have a bow-leg deformity, rachitic rosary, stunted growth with short stature, dental deformities, abnormal spinal curvature, craniotabes, and frequent fractures. In adults, low vitamin D levels lead to impaired mineralization of osteoid, leading to osteomalacia. Osteomalacia characteristically demonstrates diffuse bone and joint pain, myopathy, hypocalcemic tetany, and a waddling gait. Vitamin E Vitamin-E deficiency is extremely rare and principally occurs in individuals with fat malabsorption, abetalipoproteinemia (defect in microsomal transfer protein), and hypobetalipoproteinemia (mutation in apolipoprotein B) disorders. Deficiency symptoms include limb and truncal ataxia, hyporeflexia, and upward gaze limitations. Rarer manifestations are muscle weakness and constriction of visual fields. If left untreated, deficiency can result in blindness, memory impairment, and arrhythmias.[13] Multiple clinical trials have shown that vitamin-E supplementation decreases histological and biochemical evidence of liver dysfunction in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The increased inflammation and oxidative stress observed in obesity theoretically heighten vitamin E requirements in this subset of patients. Additionally, these findings raise whether vitamin E deficiency could exacerbate liver dysfunction.[4] Vitamin K

Vitamin-E deficiency is extremely rare and principally occurs in individuals with fat malabsorption, abetalipoproteinemia (defect in microsomal transfer protein), and hypobetalipoproteinemia (mutation in apolipoprotein B) disorders. Deficiency symptoms include limb and truncal ataxia, hyporeflexia, and upward gaze limitations. Rarer manifestations are muscle weakness and constriction of visual fields. If left untreated, deficiency can result in blindness, memory impairment, and arrhythmias.[13] Multiple clinical trials have shown that vitamin-E supplementation decreases histological and biochemical evidence of liver dysfunction in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The increased inflammation and oxidative stress observed in obesity theoretically heighten vitamin E requirements in this subset of patients. Additionally, these findings raise whether vitamin E deficiency could exacerbate liver dysfunction.[4] Vitamin K Vitamin K deficiency is clinically significant due to its prevalence in various patient populations. Risk factors include antibiotic use, which interferes with vitamin K production in the gut, nutritional deficiency, and high ingestion of vitamins A and E. Newborns are also at risk for deficiency due to immature gut flora, poor placental transfer, and low content in breast milk. The risk in newborns becomes further increased with a maternal history of anticonvulsant and anticoagulant use. A common clinical syndrome that results from vitamin-K deficiency is a hemorrhagic disease of the newborn, a life-threatening bleeding condition in neonates. Neonates with this condition present with failure to thrive, low birth weight, and excessive bleeding from the umbilical stump and mucous membranes. They are at higher risk for intracranial hemorrhage. This condition is treated prophylactically through vitamin K injections at birth. In adults, deficiency can also cause easy bleeding and bruising with an elevated PT. Toxicity Vitamin A

Vitamin K deficiency is clinically significant due to its prevalence in various patient populations. Risk factors include antibiotic use, which interferes with vitamin K production in the gut, nutritional deficiency, and high ingestion of vitamins A and E. Newborns are also at risk for deficiency due to immature gut flora, poor placental transfer, and low content in breast milk. The risk in newborns becomes further increased with a maternal history of anticonvulsant and anticoagulant use. A common clinical syndrome that results from vitamin-K deficiency is a hemorrhagic disease of the newborn, a life-threatening bleeding condition in neonates. Neonates with this condition present with failure to thrive, low birth weight, and excessive bleeding from the umbilical stump and mucous membranes. They are at higher risk for intracranial hemorrhage. This condition is treated prophylactically through vitamin K injections at birth. In adults, deficiency can also cause easy bleeding and bruising with an elevated PT. Toxicity Vitamin A Vitamin A toxicity is most commonly the result of over-supplementation, wild game liver consumption, and isotretinoin therapy. Hypervitaminosis A leads to intracranial swelling, which manifests as headaches, papilledema, and seizures. Other findings include arthralgias, alopecia, dry mucous membranes, skin desquamation, hypercalcemia, and liver damage. Isoretinoic acid, an acne treatment, is contraindicated in women who are pregnant or may become pregnant due to a risk of spontaneous abortion and birth defects in the fetus.[14] Vitamin D Vitamin D toxicity, although rare, can occur in individuals taking large doses of vitamin D supplements with a heavy intake of fortified foods. Most symptoms of hypervitaminosis D stem from hypercalcemia caused by excessive calcium absorption in the duodenum and distal convoluted tubule. Clinical manifestations include gastrointestinal issues such as decreased appetite, diarrhea, nausea, vomiting, and constipation. Hypercalcemia can result in polyuria, polydipsia, pruritus, and the development of kidney stones. Bone, muscle, and joint pain are also common manifestations.[12] Vitamin E Hypervitaminosis E is most commonly a result of over-supplementation and is otherwise very rare. Since high doses of Vitamin E (800 mg per day) inhibit platelet aggregation, it is contraindicated in patients on anticoagulants.[15] Vitamin K

Vitamin D toxicity, although rare, can occur in individuals taking large doses of vitamin D supplements with a heavy intake of fortified foods. Most symptoms of hypervitaminosis D stem from hypercalcemia caused by excessive calcium absorption in the duodenum and distal convoluted tubule. Clinical manifestations include gastrointestinal issues such as decreased appetite, diarrhea, nausea, vomiting, and constipation. Hypercalcemia can result in polyuria, polydipsia, pruritus, and the development of kidney stones. Bone, muscle, and joint pain are also common manifestations.[12] Vitamin E Hypervitaminosis E is most commonly a result of over-supplementation and is otherwise very rare. Since high doses of Vitamin E (800 mg per day) inhibit platelet aggregation, it is contraindicated in patients on anticoagulants.[15] Vitamin K Vitamin K toxicity is uncommon but is more prevalent in formula-fed infants and those receiving menadione injections, a water-soluble synthetic vitamin K precursor. Symptoms of hypervitaminosis K include hemolytic anemia, jaundice in newborns with hyperbilirubinemia, and liver damage.