| Biochemistry and Physiology | Deficiency [RDA∗] | Toxicity [TUL†] | Assessment of Status |
|---|
| Fat-Soluble Vitamins |
| Vitamin A | A family of the retinoid compounds, each member having biologic activity qualitatively similar to retinol. Carotenoids are structurally related to retinoids. Some carotenoids, most notably β-carotene, are metabolized into compounds with vitamin A activity and are therefore considered to be provitamin A compounds. Vitamin A is an integral component of rhodopsin and iodopsins, light-sensitive proteins in rod and cone cells in the retina. Additional functions: Induction and maintenance of cellular differentiation in certain tissues; signal for appropriate morphogenesis in the developing embryo; maintenance of cell-mediated immunity. 1 μg of retinol = 3.33 IU of vitamin A. | Follicular hyperkeratosis and night blindness are early indicators. Conjunctival xerosis, degeneration of the cornea (keratomalacia), and dedifferentiation of rapidly proliferating epithelia are later indications of deficiency. Bitot spots (focal areas of the conjunctiva or cornea with foamy appearance) are an indication of xerosis. Blindness due to corneal destruction and retinal dysfunction ensues if left uncorrected. Increased susceptibility to infection is also a consequence. [F: 700 μg; M: 900 μg] | In adults, >150,000 μg may cause acute toxicity: Fatal intracranial hypertension, skin exfoliation, and hepatocellular necrosis. Chronic toxicity may occur with habitual daily intake of >10,000 μg: Alopecia, ataxia, bone and muscle pain, dermatitis, cheilitis, conjunctivitis, pseudotumor cerebri, hepatocellular necrosis, hyperlipidemia, and hyperostosis are common. Single, large doses of vitamin A (30,000 μg) or habitual intake of >4500 μg/day in early pregnancy can be teratogenic. Excessive intake of carotenoids causes a benign condition characterized by yellowish discoloration of the skin. Habitually large doses of canthaxanthin, a carotenoid, have the additional capability of inducing a retinopathy. [3000 μg] | Retinol concentration in the plasma and vitamin A concentrations in the milk and tears are reasonably accurate measures of adequate status. Toxicity is best assessed by elevated levels of retinyl esters in plasma. A quantitative measure of dark adaptation for night vision and electroretinography are useful functional tests. |
| Vitamin D | A group of sterol compounds whose parent structure is cholecalciferol (vitamin D3). Cholecalciferol is formed in the skin from 7-dehydrocholesterol (provitamin D3) by exposure to UVB radiation. A plant sterol, ergocalciferol (provitamin D2), can be similarly converted into vitamin D2 and has similar vitamin D activity. The vitamin undergoes sequential hydroxylations in the liver and kidney at the 25 and 1 positions, respectively, producing the most bioactive form of the vitamin, 1,25-dihydroxy vitamin D. Vitamin D maintains intracellular and extracellular concentrations of calcium and phosphate by enhancing intestinal absorption of the two ions and, in conjunction with PTH, promoting their mobilization from bone mineral. It retards proliferation and promotes differentiation in certain epithelia. Purported actions of vitamin D as an anti-diabetes, antiinflammatory, and cancer preventive agent remain controversial and are under investigation. 1 μg = 40 IU. | Deficiency results in decreased mineralization of newly formed bone called rickets in childhood and osteomalacia in adults. Expansion of the epiphyseal growth plates and replacement of normal bone with unmineralized bone matrix are the cardinal features of rickets; the latter feature also characterizes osteomalacia. Deformity of bone and pathologic fractures occur. Decreased serum concentrations of calcium and phosphate may occur. [15 μg, ages 19-70 yr; 20 μg, age >70 yr] | Excess amounts result in abnormally high concentrations of calcium and phosphate in the serum; metastatic calcifications, renal damage, and altered mentation may occur. [100 μg for ages ≥9 yr] | The serum concentration of the major circulating metabolite, 25-hydroxyvitamin D, is the best indicator of systemic status except in advanced kidney disease (stages 4 and 5), in which the impairment of renal 1-hydroxylation results in disassociation of the mono- and dihydroxyvitamin concentrations. Measurement of the serum concentration of 1,25-dihydroxyvitamin D is then necessary. |
| Vitamin E | A group of at least eight naturally occurring compounds, some of which are tocopherols and some of which are tocotrienols. At present, the only dietary form that is thought to be biologically active in humans is α-tocopherol. Vitamin E acts as an antioxidant and free radical scavenger in lipophilic environments, most notably in cell membranes. It acts in conjunction with other antioxidants, such as selenium. | Deficiency due to dietary inadequacy is rare. It is usually seen in premature infants, individuals with fat malabsorption, and individuals with abetalipoproteinemia. Red blood cell fragility occurs and can produce a hemolytic anemia. Neuronal degeneration produces peripheral neuropathies, ophthalmoplegia, and destruction of posterior columns of spinal cord. Neurologic disease is frequently irreversible if deficiency is not corrected early enough. May contribute to the hemolytic anemia and retrolental fibroplasia seen in premature infants. Reported to suppress cell-mediated immunity. [15 mg] | Depressed levels of vitamin K-dependent procoagulants and potentiation of oral anticoagulants have been reported, as has impaired WBC function. Doses of 800 mg/day have been reported to increase slightly the incidence of hemorrhagic stroke. [1000 mg] | Plasma or serum concentration of α-tocopherol is most commonly used. Additional accuracy is obtained by expressing this value per milligram of total plasma lipid. RBC peroxide hemolysis test is not entirely specific but is a useful functional measure of the antioxidant potential of cell membranes. |
| Vitamin K | A family of naphthoquinone compounds with similar biologic activity. Phylloquinone (vitamin K1) is derived from plants; a variety of menaquinones (vitamin K2) are derived from bacterial and animal sources. Vitamin K serves as an essential cofactor in the posttranslational γ-carboxylation of glutamic acid residues in many proteins. These proteins include several circulating procoagulants and anticoagulants as well as proteins in a variety of tissues. | Deficiency syndrome is uncommon except in breast-fed newborns, in whom it may cause “hemorrhagic disease of the newborn”; in adults with fat malabsorption or who are taking drugs that interfere with vitamin K metabolism (e.g., coumarin, phenytoin, broad-spectrum antibiotics); and in individuals taking large doses of vitamin E and anticoagulant drugs. Excessive hemorrhage is the usual manifestation. [F: 90 μg; M: 120 μg] | Rapid intravenous infusion of K1 has been rarely associated with dyspnea, flushing, and cardiovascular collapse; this is likely related to the dispersing agents in the solution. Supplementation may interfere with coumarin-based anticoagulation. Pregnant women taking large amounts of the provitamin menadione may deliver infants with hemolytic anemia, hyperbilirubinemia, and kernicterus. [no TUL established] | Prothrombin time is typically used as a measure of functional K status; it is neither sensitive nor specific for vitamin K deficiency. Determination of fasting plasma vitamin K is an accurate indicator of status. Undercarboxylated plasma prothrombin is also an accurate metric, but only for detecting the deficient state, and is less widely available than plasma vitamin K. |
| Water-Soluble Vitamins |
| Thiamin (vitamin B1) | A water-soluble compound containing substituted pyrimidine and thiazole rings and a hydroxyethyl side chain. The coenzyme form is thiamin pyrophosphate (TPP). Thiamin serves as a coenzyme in many α-ketoacid decarboxylation and transketolation reactions. Inadequate thiamin availability leads to impairments of these reactions, resulting in inadequate adenosine triphosphate synthesis and abnormal carbohydrate metabolism, respectively. It may have an additional role in neuronal conduction independent of the aforementioned actions. | Classic deficiency syndrome (beriberi) is described in Asian populations consuming a polished rice diet. Alcoholism, chronic renal dialysis, and persistent nausea and vomiting after bariatric surgery are also common precipitants. High carbohydrate intake increases need for B1. Mild deficiency: Irritability, fatigue, and headaches. More severe deficiency: Combinations of peripheral neuropathy, cardiovascular dysfunction, and cerebral dysfunction. Cardiovascular involvement (wet beriberi): Congestive heart failure and low peripheral vascular resistance. Cerebral disease: Nystagmus, ophthalmoplegia, and ataxia (Wernicke encephalopathy); hallucinations, impaired short-term memory, and confabulation (Korsakoff psychosis). Deficiency syndrome responds within 24 hr to parenteral thiamin but is partially or wholly irreversible after a certain stage. [F: 1.1 mg; M: 1.2 mg] | Excess intake is largely excreted in the urine, although parenteral doses of >400 mg/day are reported to cause lethargy, ataxia, and reduced tone of the gastrointestinal tract. [TUL not established] | The most effective measure of B1 status is the erythrocyte transketolase activity coefficient, which measures enzyme activity before and after addition of exogenous TPP; RBCs from a deficient individual express a substantial increase in enzyme activity with addition of TPP. Thiamin concentrations in blood or urine are also used. |
| Riboflavin (vitamin B2) | Consists of a substituted isoalloxazine ring with a ribitol side chain. Riboflavin serves as a coenzyme for a diverse array of biochemical reactions. The primary coenzymatic forms are flavin mononucleotide and flavin adenine dinucleotide. Riboflavin holoenzymes participate in oxidation-reduction reactions in myriad metabolic pathways. | Deficiency is usually seen in conjunction with deficiencies of other B vitamins. Isolated deficiency of riboflavin produces hyperemia and edema of nasopharyngeal mucosa, cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and a normochromic, normocytic anemia. [F: 1.1; M: 1.3] | Toxicity is not reported in humans. [TUL not established] | The most common method of assessment is to determine the activity coefficient of glutathione reductase in RBCs (the test is invalid for individuals with glucose-6-phosphate dehydrogenase deficiency). Measurements of blood and urine concentrations are less desirable methods. |
| Niacin (vitamin B3) | Refers to nicotinic acid and the corresponding amide, nicotinamide. The active coenzymatic forms are composed of nicotinamide affixed to adenine dinucleotide, forming NAD or NADP. More than 200 apoenzymes use these compounds as electron acceptors or hydrogen donors, either as a coenzyme or as a co-substrate. The essential amino acid tryptophan is a precursor of niacin; 60 mg of dietary tryptophan yields approximately 1 mg of niacin. Dietary requirements thus depend partly on tryptophan intake. Requirement is often determined on basis of calorie intake (i.e., niacin equivalents/1000 kcal). Large doses of nicotinic acid (1.5-3 g/day) effectively lower low-density lipoprotein cholesterol and elevate high-density lipoprotein cholesterol. | Pellagra is the classic deficiency syndrome and is often seen in populations in which corn is the major source of energy; it is still endemic in parts of China, Africa, and India. Diarrhea, dementia (or associated symptoms of anxiety or insomnia), and a pigmented dermatitis that develops in sun-exposed areas are typical features. Glossitis, stomatitis, vaginitis, vertigo, and burning dysesthesias are early signs. It is reported occasionally to occur in carcinoid syndrome because tryptophan is diverted to other synthetic pathways. [F: 14 mg; M: 16 mg] | Human toxicity is known largely through studies examining hypolipidemic effects. Includes vasomotor phenomenon (flushing), hyperglycemia, parenchymal liver damage, and hyperuricemia. [35 mg] | Assessment of status is problematic; blood levels of the vitamin are not reliable. Measurement of urinary excretion of the niacin metabolites N-methylnicotinamide and 2-pyridone is thought to be the most effective means of assessment at present. |
| Vitamin B6 | Refers to several derivatives of pyridine, including pyridoxine, pyridoxal, and pyridoxamine, which are interconvertible in the body. The coenzymatic forms are pyridoxal-5-phosphate (PLP) and pyridoxamine-5-phosphate. As a coenzyme, B6 is involved in many transamination reactions (and thereby in gluconeogenesis), in the synthesis of niacin from tryptophan, in the synthesis of several neurotransmitters, and in the synthesis of Δ-aminolevulinic acid (and therefore in heme synthesis). It also has functions unrelated to coenzymatic activity: Pyridoxal and PLP bind to hemoglobin and alter oxygen affinity; PLP also binds to steroid receptors, inhibiting receptor affinity to DNA and thereby modulating steroid activity. | Deficiency is usually seen in conjunction with other water-soluble vitamin deficiencies. Stomatitis, angular cheilosis, glossitis, irritability, depression, and confusion occur in moderate to severe depletion; normochromic, normocytic anemia has been reported in severe deficiency. Abnormalities on electroencephalography and, in infants, convulsions have also been observed. Some sideroblastic anemias respond to B6 administration. Isoniazid, cycloserine, penicillamine, ethanol, and theophylline can inhibit B6 metabolism. [Ages 19-50 yr: 1.3 mg; >50 yr: 1.5 mg for women, 1.7 mg for men] | Long-term use with doses exceeding 200 mg/day (in adults) may cause peripheral neuropathies and photosensitivity. [100 mg] | Many useful laboratory methods of assessment exist. The plasma or erythrocyte PLP levels are most common. Urinary excretion of xanthurenic acid after an oral tryptophan load and activity indices of RBC alanine or aspartate transaminase are functional measures of B6-dependent enzyme activity. |
| Folate | A group of related pterin compounds. More than 35 forms of the vitamin are found naturally. The fully oxidized form, folic acid, is not found in nature but is the pharmacologic form of the vitamin. All folate functions relate to its ability to transfer one-carbon groups. It is essential in the de novo synthesis of nucleotides and in the metabolism of several amino acids; it is an integral component for the regeneration of the “universal” methyl donor, S-adenosylmethionine. Inhibition of bacterial and cancer cell folate metabolism is the basis for the sulfonamide antibiotics and chemotherapeutic agents, such as methotrexate and 5-fluorouracil, respectively. | Women of childbearing age are most likely to be deficient. Classic deficiency syndrome: Megaloblastic anemia, diarrhea. The hematopoietic cells in bone marrow become enlarged and have immature nuclei, reflecting ineffective DNA synthesis. The peripheral blood smear demonstrates macro-ovalocytes and polymorphonuclear leukocytes with an average of more than 3.5 nuclear lobes. Megaloblastic changes also occur in other epithelia that proliferate rapidly (e.g., oral mucosa and gastrointestinal tract, producing glossitis and diarrhea, respectively). Sulfasalazine and diphenytoin inhibit absorption and predispose to deficiency. [400 μg of dietary folate equivalents (DFE); 1 DFE = 1 μg food folate = 0.6 μg folic acid] | Doses >1000 μg/day may partially correct the anemia of B12 deficiency and may therefore mask (and perhaps exacerbate) the associated neuropathy. Large doses are also reported to lower seizure threshold in individuals prone to seizures. Parenteral administration is rarely reported to cause allergic phenomena, which is probably due to dispersion agents. [1000 μg] | Serum folate measures short-term folate balance, whereas RBC folate is a better reflection of tissue status. Serum homocysteine rises early in deficiency but is nonspecific because B12 or B6 deficiency, renal insufficiency, and older age may also cause elevations. |
| Vitamin C (ascorbic and dehydroascorbic acid) | Ascorbic acid readily oxidizes to dehydroascorbic acid in aqueous solution. Dehydroascorbic acid can be reduced in vivo, so it possesses vitamin C activity. Total vitamin C is therefore the sum of ascorbic and dehydroascorbic acid content. Vitamin C serves primarily as a biologic antioxidant in aqueous environments. Biosyntheses of collagen, carnitine, bile acids, and norepinephrine as well as proper functioning of the hepatic mixed-function oxygenase system depend on this property. Vitamin C in foodstuffs increases the intestinal absorption of nonheme iron. | Overt deficiency is uncommon in developed countries. The classic deficiency syndrome is scurvy: Fatigue, depression, and widespread abnormalities in connective tissues, such as inflamed gingivae, petechiae, perifollicular hemorrhages, impaired wound healing, coiled hairs, hyperkeratosis, and bleeding into body cavities. In infants, defects in ossification and bone growth may occur. Tobacco smoking lowers plasma and leukocyte vitamin C levels. [F: 75 mg; M: 90 mg; increase requirement for cigarette smokers by 35 mg/day] | ≥500 mg/day (in adults) may cause nausea and diarrhea. >1 g/day modestly increases risk for oxalate kidney stones. Supplementation may interfere with laboratory tests based on redox potential (e.g., fecal occult blood testing, serum cholesterol, and glucose). Withdrawal from chronic ingestion of high doses of vitamin C supplements should be done gradually because accommodation appears to occur, raising a concern of “rebound scurvy.” [2 g] | Plasma ascorbic acid concentration reflects recent dietary intake, whereas WBC levels more closely reflect tissue stores. Women’s plasma levels are approximately 20% higher than men’s for any given dietary intake. |
| Vitamin B12 | A group of closely related cobalamin compounds composed of a corrin ring (with a cobalt atom in its center) connected to a ribonucleotide through an aminopropanol bridge. Microorganisms are the ultimate source of all naturally occurring B12. The two active coenzyme forms are deoxyadenosylcobalamin and methylcobalamin. These coenzymes are needed for the synthesis of succinyl CoA, which is essential in lipid and carbohydrate metabolism, and for the synthesis of methionine. The synthesis of methionine is essential for amino acid metabolism, for purine and pyrimidine synthesis, for many methylation reactions, and for the intracellular retention of folates. | Dietary inadequacy is a rare cause of deficiency except in strict vegetarians. Most deficiencies arise from loss of intestinal absorption, which may occur with pernicious anemia, pancreatic insufficiency, atrophic gastritis, small bowel bacterial overgrowth, or ileal disease. Megaloblastic anemia and megaloblastic changes in other epithelia (see “Folate”) are the result of sustained depletion. Demyelination of peripheral nerves, posterior and lateral columns of spinal cord, and nerves within the brain may occur. Altered mentation, depression, and psychoses occur. Hematologic and neurologic complications may occur independently. Folate supplementation, in doses of 1000 μg/day, may partly correct the anemia, thereby masking (or perhaps exacerbating) the neuropathic complication. [2.4 μg] | A few allergic reactions have been reported to crystalline B12 preparations and are probably due to impurities, not the vitamin. [TUL not established] | Serum or plasma concentrations are generally accurate. Subtle deficiency with neurologic complications, as described in the Deficiency column, can best be established by concurrently measuring the concentration of plasma B12 and serum methylmalonic acid, which is a sensitive indicator of cellular deficiency. |
| Biotin | A bi-cyclic compound consisting of a ureido ring fused to a substituted tetrahydrothiophene ring. Endogenous synthesis by intestinal flora may contribute significantly to biotin nutriture. Most dietary biotin is linked to lysine, a compound called biotinyl lysine, or biocytin. The lysine must be hydrolyzed by an intestinal enzyme called biotinidase before intestinal absorption occurs. Biotin acts primarily as a coenzyme for several carboxylases; each holoenzyme catalyzes an adenosine triphosphate-dependent carbon dioxide transfer. The carboxylases are critical enzymes in carbohydrate and lipid metabolism. | Isolated deficiency is rare. Deficiency in humans has been produced by prolonged total parenteral nutrition lacking the vitamin and by ingestion of large quantities of raw egg white, which contains avidin, a protein that binds biotin with such high affinity that it renders it biounavailable. Alterations in mental status, myalgias, hyperesthesias, and anorexia occur. Later, a seborrheic dermatitis and alopecia develop. Deficiency is usually accompanied by lactic acidosis and organic aciduria. [30 μg] | Toxicity has not been reported in humans with doses as high as 60 mg/day in children. [TUL not established] | Plasma and urine concentrations of biotin are diminished in the deficient state. Elevated urine concentrations of methyl citrate, 3-methylcrotonylglycine, and 3-hydroxyisovalerate are also observed in deficiency. |
| Pantothenic acid | Consists of pantoic acid linked to β-alanine through an amide bond. Pantothenic acid is an essential component of CoA and phosphopantetheine, which are essential for synthesis and β-oxidation of fatty acids as well as for synthesis of cholesterol, steroid hormones, vitamins A and D, and other isoprenoid derivatives. CoA is also involved in the synthesis of several amino acids and Δ-aminolevulinic acid, a precursor for the corrin ring of vitamin B12, the porphyrin ring of heme, and of cytochromes. CoA is also necessary for the acetylation and fatty acid acylation of a variety of proteins. | Deficiency is rare; it has been reported only as a result of feeding of semisynthetic diets or an antagonist to the vitamin. Experimental, isolated deficiency in humans produces fatigue, abdominal pain, vomiting, insomnia, and paresthesias of the extremities. [5 mg] | In doses of 10 g/day, diarrhea is reported to occur. [TUL not established] | Whole blood and urine concentrations of pantothenate are indicators of status; serum levels are not thought to be accurate. |