{
  "id": "vitamin",
  "title": "Vitamin",
  "lang": "en",
  "source_lang": "en",
  "summary": "Vitamins are organic micronutrients that the body needs in small amounts, mostly for enzyme cofactors, antioxidant protection, and hormone-like regulation. Deficiency and excess both cause disease.",
  "category": "health",
  "subcategory": "public-health",
  "type": "concept",
  "aliases": [
    "Vitamins"
  ],
  "generated_at": "2026-10-08",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/vitamin/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/vitamin/",
      "json": "https://aiwiki.page/zh/vitamin.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "A Vitamin is an organic compound that an organism needs in small amounts for normal metabolism and growth but cannot make in sufficient quantity, so it must come from food or supplements. Most vitamins act as precursors of cofactors for enzymes, as antioxidants, or as signaling molecules that regulate gene expression. The term was coined in the early twentieth century for \"vital amines,\" although many vitamins are not amines, and the name has been kept. Vitamins are not a source of energy in the way carbohydrates or proteins are, and they differ from minerals in being carbon-based. Vitamin research has shaped modern nutrition, public-health policy, and the study of metabolism.\n\nThe thirteen vitamins recognized in humans fall into two solubility groups: four fat-soluble vitamins (A, D, E, K) and nine water-soluble vitamins (eight B vitamins and vitamin C). Their chemical diversity, biological roles, storage patterns, and toxicity profiles differ widely, so the entry treats each vitamin family in turn after introducing the shared principles. The article covers how vitamins were discovered, how the body absorbs, transports, and excretes them, and what happens in deficiency and excess. It then considers dietary reference values, supplementation, fortification, and therapeutic uses, and it ends with unresolved questions in the field."
    },
    {
      "heading": "Definition and Biological Role",
      "text": "A vitamin is an organic compound that the body needs in small amounts, cannot make in adequate quantities, and requires to prevent a specific deficiency disease. The last criterion is the most practical one. A substance qualifies when its absence produces a recognizable disorder that is prevented or cured by supplying it. By this standard, humans rely on thirteen compounds: vitamins A, D, E, and K, vitamin C, and the eight B vitamins. The definition is not rigid. Humans make some vitamin D in the skin, obtain part of their niacin from tryptophan, and receive some vitamin K from gut bacteria. Whether a person must rely on the diet therefore depends on diet, sun exposure, and the intestinal microbiota.\n\nVitamins differ from the minerals in the same micronutrient category in two main ways. Minerals are inorganic elements such as calcium, iron, and zinc, whereas vitamins are carbon-based molecules that can be broken down by heat, light, or oxidation. Vitamins also supply no energy. The energy-yielding macronutrients are carbohydrates, proteins, and fats, and vitamins do not provide calories when they are metabolized. Their value lies in enabling chemical reactions rather than in serving as fuel.\n\nBiochemically, vitamins work in three broad ways. The first is as precursors of coenzymes. Several B vitamins are converted into the working forms of cofactors that enzymes require: thiamine becomes thiamine pyrophosphate, riboflavin becomes flavin coenzymes, niacin becomes NAD and NADP, pantothenic acid becomes coenzyme A, and pyridoxine becomes pyridoxal phosphate. Vitamin K and vitamin C, by contrast, often act directly as cofactors. The second is as antioxidants. Vitamin E interrupts chain reactions of lipid peroxidation in membranes, and vitamin C scavenges reactive oxygen species and helps regenerate other antioxidants. Both processes are forms of oxidation–reduction chemistry. The third is in the regulation of gene expression. Retinoic acid binds nuclear receptors of the retinoic acid receptor family, and calcitriol binds the vitamin D receptor. Once bound, these ligand–receptor complexes influence the transcription of target genes, which links these vitamins to growth, differentiation, and mineral homeostasis.\n\nMany vitamins are obtained not in their active form but as provitamins, which the body converts. The best-known provitamin A compound is beta-carotene, a plant pigment that is cleaved in the intestinal lining to yield retinal, which is then reduced to retinol or oxidized to retinoic acid. The efficiency of this conversion varies widely with the food matrix, dietary fat, and individual genetics. The second major example is 7-dehydrocholesterol, an intermediate in cholesterol synthesis that accumulates in the skin. When exposed to ultraviolet B radiation, it is converted to previtamin D3, which then isomerizes to vitamin D3 (cholecalciferol). Because of this, a vitamin's dietary intake and its endogenous production together determine whether a person is adequately supplied.\n\nUnderstanding these categories matters because most vitamins cannot be stored in large amounts. Some, such as vitamins A, D, and B12, accumulate in the liver, while others must be obtained more continuously. This explains why the consequences of deficiency vary so much between vitamins, a topic developed in the sections on classification and deficiency diseases."
    },
    {
      "heading": "Classification and Chemical Diversity",
      "text": "Vitamins are conventionally divided into two groups according to whether they dissolve in lipids or in water. The division follows from chemical structure, and it determines how each vitamin is absorbed, transported, stored and excreted. The fat-soluble vitamins (A, D, E and K) are largely nonpolar molecules built from isoprenoid or steroid-derived skeletons with few polar groups. They are absorbed together with dietary fat and can accumulate in the liver and adipose tissue. The water-soluble vitamins are the eight B vitamins and vitamin C. They carry polar or ionizable groups, such as carboxylic acid, amine, phosphate and hydroxyl groups, that allow them to dissolve in plasma and cytoplasm. Most are stored only in small amounts, so surplus is usually excreted in urine through the kidneys. Vitamin B12 is a notable exception because the liver holds a substantial reserve.\n\nFat-soluble families\n\nVitamin A comprises the retinoids, which share a β-ionone ring and an isoprenoid side chain. Retinol, retinal and retinoic acid belong to this family. Provitamin A carotenoids, such as β-carotene, are C40 tetraterpenes whose central cleavage yields retinal. Vitamin D belongs to the secosteroids, which form when the B ring of a sterol is broken open. Vitamin D2 (ergocalciferol) derives from plant ergosterol, and vitamin D3 (cholecalciferol) derives from the sterol 7-dehydrocholesterol in animal tissue and skin. Vitamin E is a set of tocopherols and tocotrienols. Both share a chromanol ring with a hydrophobic side chain: the tocopherols have a saturated tail, whereas the tocotrienols have three double bonds in theirs. Vitamin K is represented by phylloquinone (K1) and the menaquinones (K2 series). Both contain a 2-methyl-1,4-naphthoquinone ring, and they differ in the length of the isoprenoid side chain. The letter K comes from the German word Koagulation, reflecting its role in clotting.\n\nWater-soluble families\n\nThe B vitamins are structurally diverse, and they are often grouped together only because they were discovered in the same nutritional context. Thiamine (B1) contains a thiazolium ring linked to an aminopyrimidine. Riboflavin (B2) has an isoalloxazine ring with a ribityl side chain. Niacin (B3) includes nicotinic acid and nicotinamide, both pyridine derivatives. Pantothenic acid (B5) is an amide of pantoic acid and β-alanine. Vitamin B6 exists as pyridoxine, pyridoxal and pyridoxamine, which are interconvertible forms of one vitamer family. Biotin (B7) is a sulfur-containing bicyclic ring with a valeric acid side chain. Folate (B9) is built from a pteridine ring, para-aminobenzoic acid and one or more glutamate residues. Cobalamin (B12) has a corrin ring that holds a central cobalt ion. Vitamin C, or ascorbic acid, is a lactone of a six-carbon sugar acid and contains an enediol group that gives it reducing properties. Its chemistry is therefore quite distinct from that of the B vitamins, despite the shared solubility.\n\nWhy the B vitamins are numbered as they are\n\nThe letter names date from the early 20th century, when researchers distinguished an unknown fat-soluble factor from a water-soluble one. The water-soluble factor was initially treated as a single substance called vitamin B, and it was later resolved into several components. Each component was assigned a number, usually in the order it was characterized, which is why the numbers do not reflect chemical relationships or metabolic function. When a substance was shown to be non-essential, to be synthesized by the body, or to be identical to a compound already named, its number was withdrawn and was not reused. This produced the gaps in the sequence. Vitamin B4 (adenine) and vitamin B8 are examples of withdrawn designations, and B10 (para-aminobenzoic acid) was dropped because it is not a vitamin for humans, although it is a building block of folate. The letter F was once used for what are now recognized as essential fatty acids, and it too was eventually removed from the vitamin list. Similarly, biotin was known as vitamin H before its place in the B series was assigned. These revisions mean that the historical numbering is a record of research sequence rather than a coherent system, and that the currently recognized set is smaller than the original list."
    },
    {
      "heading": "Discovery and Early Research",
      "text": "Long before the word \"vitamin\" existed, physicians and sailors recorded diseases that a change in diet could prevent or cure. Night blindness was treated with liver in ancient Egyptian medicine, and the Ebers Papyrus, from about 1550 BCE, is often cited for this. Scurvy struck crews on long sea voyages, and beriberi, a paralytic and cardiac illness, was endemic in parts of Asia where polished white rice was a staple. In the 1880s the Japanese naval physician Takaki Kanehiro reduced beriberi among sailors by changing their rations, although his explanation was incomplete. Such observations established that disease could follow from what people ate, but they did not identify the missing factor.\n\nEijkman's Chicken Experiments\n\nThe decisive laboratory work was done by Christiaan Eijkman, a Dutch physician who went to the Dutch East Indies (now Indonesia) in the late 1880s to study beriberi. Sources differ on the exact start date, with some giving 1886 and others 1889. Eijkman first suspected a microbe, but his chickens developed a polyneuritis resembling beriberi. He traced the outbreak to a change in the chickens' feed: when they ate polished white rice from the military kitchen, they fell ill, and when they were given unpolished rice, they recovered. Eijkman concluded that the outer layers of the rice contained a protective \"anti-beriberi factor.\" He initially believed the rice acted by neutralising a toxin. His successor Gerrit Grijns later argued that the protective substance was used directly by the body and that ordinary food must therefore contain other essential substances. This reasoning, more than Eijkman's own, pointed toward the modern concept of dietary essentials.\n\nHopkins and \"Accessory Food Factors\"\n\nIn England, Frederick Gowland Hopkins approached the problem through feeding experiments with purified diets made of protein, fat, carbohydrate and salts. Animals on such diets failed to grow properly, which suggested that foods contained additional substances that were indispensable but needed in tiny amounts. In 1906 Hopkins described these as \"accessory food factors.\" During the First World War he examined the nutritional value of margarine and found that it lacked the fat-soluble vitamins A and D present in butter, a finding that led to vitamin-enriched margarine being introduced in 1926. Eijkman and Hopkins shared the 1929 Nobel Prize in Physiology or Medicine, Eijkman for \"his discovery of the antineuritic vitamin\" and Hopkins for \"his discovery of the growth-stimulating vitamins.\" Funk and Grijns were not included.\n\nFunk's Term and the Isolation of Vitamins in the 1910s and 1920s\n\nCasimir Funk, a Polish biochemist working in Europe, extracted an active substance from rice polishings in 1911 or 1912. He combined \"vital\" and \"amine,\" because the compound he had isolated was a nitrogen-containing molecule, and proposed the word \"vitamine\" for a class of essential food substances. He also suggested that scurvy, pellagra and rickets were vitamine-deficiency diseases. Funk's extract was not the pure anti-beriberi factor; one common account holds that he had mainly isolated nicotinic acid. When it became clear that the new substances were not all amines, the final \"e\" was dropped. Thiamine was crystallised only in 1926 by the Dutch chemists Barend Jansen and Willem Donath, and it became the first vitamin to be isolated in pure form. Meanwhile, the American researchers Elmer McCollum and Marguerite Davis separated a fat-soluble factor from a water-soluble one in the 1910s, the fat-soluble factor later named vitamin A, and vitamin D was recognised in the 1920s as the substance that prevented rickets. Vitamin C was identified in the 1920s and 1930s through the work of Albert Szent-Györgyi, who isolated a sugar-like acid that was later shown to be ascorbic acid.\n\nStructural Elucidation and Synthesis, 1930s–1940s\n\nOnce the substances could be isolated, chemists worked out their structures and made them in the laboratory. Paul Karrer determined the structure of carotene, the main precursor of vitamin A, in 1930, and reported vitamin A's own structure and synthesis shortly after, and he went on to work on riboflavin and vitamin E. Norman Haworth, with Edmund Hirst, determined the structure of ascorbic acid and synthesised it. Sources give different years for the synthesis, 1932 in one account and 1934 in another. Vitamin C was the first vitamin to be made artificially, and this made it cheap enough for widespread medical use. Robert Williams characterised the structure of thiamine and synthesised it in 1936. The 1937 Nobel Prize in Chemistry was shared by Haworth, \"for his investigations on carbohydrates and vitamin C,\" and Karrer, \"for his investigations on carotenoids, flavins and vitamins A and B2.\" The same year, the Nobel Prize in Physiology or Medicine went to Szent-Györgyi for work on biological oxidation with special reference to vitamin C. Together, these achievements turned the vitamin concept from an inference about diet into a body of chemistry that could be tested directly."
    },
    {
      "heading": "Vitamin A and Carotenoids",
      "text": "Vitamin A is a collective term for retinoids: retinol, its aldehyde retinal, retinoic acid, and synthetic analogues. Plant, fungal, and bacterial carotenoids can also serve as sources, because they can be metabolized to retinol and are thus vitamin A vitamers. The compound has two main lines of activity. One is the light-sensing function of retinal in the eye, and the other is a signalling function carried out largely by retinoic acid.\n\nIn the retina, dietary retinol is processed through a sequence of steps known as the visual cycle. In the retinal pigment epithelium, LRAT converts all-trans-retinol to all-trans-retinyl ester, which is then converted through a series of enzymatic steps involving RPE65, RDH5, and RDH11 to the 11-cis-retinal chromophore. The chromophore is moved to the photoreceptor outer segments, where it binds the opsin protein to form the visual pigment Rhodopsin. When a photon strikes the complex, the chromophore changes shape and separates from opsin. Light stimulation causes isomerization of the chromophore from cis to trans, a conformational change of the opsin, and dissociation of all-trans-retinal from the opsin. Because the pigment must be rebuilt after each bleaching event, the supply of retinal limits how quickly the eye recovers. Without sufficient vitamin A, rhodopsin regeneration is compromised, leading to decreased ability to see in dim light, a condition known as night blindness.\n\nMost of vitamin A's broader biological effects are attributed to all-trans-retinoic acid. Retinal is oxidized to this acid by retinal dehydrogenase, and the acid acts as a signalling molecule rather than a visual pigment precursor. Retinoic acid receptors (RARs) belong to the nuclear receptor family, and they form heterodimers with retinoid X receptors (RXRs), which bind to DNA and function as ligand-activated transcription factors. Through this mechanism, retinoic acid affects gene-expression on a large scale; one review notes that by regulating the expression of over 500 retinoid-responsive genes, retinoic acid isomers play major roles in cellular proliferation and differentiation. The receptor pathway is therefore comparable in principle to that of other hormones acting through transcription-factors, and it underlies the vitamin's influence on the growth and specialization of cells in epithelia, the immune system, and reproduction.\n\nThe provitamin A carotenoids form a second route to retinoids. The most important is beta-carotene, which is cleaved to yield retinal. In order to be converted to vitamin A the carotenoid must contain at least one unsubstituted β-ring. Hydroxylated carotenoids, called xanthophylls, lack this capacity, although the two that accumulate in the macula, zeaxanthin and lutein, have a separate protective role in the retina. Conversion efficiency is limited and variable. Preformed vitamin A is effectively absorbed, stored, and hydrolyzed to form retinol, while provitamin A carotenoids like β-carotene are less easily digested and absorbed. The efficiency of this conversion can vary widely among individuals. Reference values therefore use conversion factors. The US National Academies, for example, assume that dietary beta-carotene is roughly half as potent as retinol per unit of retinol activity equivalents, though the exact factors differ across food matrices, cooking, and fat intake.\n\nSevere deficiency produces visible and systemic damage. Symptoms of deficiency include vision related disorders such as xerophthalmia and night blindness; dry skin and dry mucous membranes; retarded development and growth; and sterility in male animals. Xerophthalmia progresses from night blindness to dryness of the conjunctiva and cornea, and it can lead to corneal ulceration and blindness if untreated. Because deficiency is most common where diets are poor in animal foods and orange or green vegetables, it remains a major nutritional problem, particularly in the developing world."
    },
    {
      "heading": "Vitamin D and Calcium Homeostasis",
      "text": "Cutaneous synthesis and the factors that limit it\n\nMost of the vitamin D in the human body is made in the skin rather than taken in with food. Ultraviolet B light acts on 7-dehydrocholesterol, a sterol in the epidermis, opening one of its rings to form previtamin D3. Previtamin D3 is formed from 7-dehydrocholesterol by absorbing a single photon of ultraviolet sunlight, and its conversion to vitamin D3 is governed by body heat, taking several days. The usable wavelengths are narrow: UV radiation above 315 nm is unable to produce previtamin D3 in human skin.\n\nThis narrow band explains why synthesis depends on geography and season. The shortest terrestrial solar wavelengths reaching the surface are about 295 nm, and the 295–320 nm range makes up roughly 4% of solar UV irradiance. At high latitudes, and during winter months when the sun is low, little of this band reaches the ground. Melanin in darker skin competes with 7-dehydrocholesterol for UVB photons, so longer exposure is needed to produce the same amount of vitamin D. Clothing and sunscreen also reduce synthesis. Dietary sources such as oily fish, egg yolk, and fortified foods supply the remainder.\n\nTwo hydroxylation steps and the active hormone\n\nVitamin D3 is biologically inactive when it is first formed. It is transported to the liver and is metabolised to calcidiol 25(OH)D by 25 hydroxylases and then calcitriol 1α,25(OH)2D3 by 1α-hydroxylase in the kidney. The liver product, 25-hydroxyvitamin D, is the main circulating form and the usual clinical marker of vitamin D status, although it has only modest activity itself. The renal step generates calcitriol, the most potent form. Calcitriol is thought to generate the main biological effects by binding to the vitamin D receptor. The receptor is a nuclear transcription factor, so calcitriol acts by altering gene expression in target cells.\n\nThe renal enzyme is itself regulated. The conversion to 1,25-dihydroxyvitamin D is regulated by its own concentration, parathyroid hormone (PTH), and serum concentrations of calcium and phosphate.\n\nRegulation of calcium and phosphate\n\nCalcitriol raises blood calcium and phosphate through several routes. Calcitriol increases renal tubular reabsorption of calcium, which reduces the loss of calcium in the urine. Calcitriol also increases the intestinal absorption of calcium and phosphate. Without enough vitamin D, the gut absorbs very little of the diet's calcium and phosphate. One review cites figures under which only 10% to 15% of dietary calcium and 60% of phosphorus are absorbed in the absence of adequate vitamin D.\n\nBone mineralization depends on this supply. Calcium and phosphate are needed to build the mineral phase of bone once the organic matrix has been laid down, so a shortfall of either produces defective mineralization.\n\nParathyroid hormone feedback\n\nThe parathyroid glands sense blood calcium and respond quickly to falls in it. Parathyroid hormone is secreted in response to low blood calcium levels, and it stimulates the resorption of calcium and a small amount of phosphate from the bone and into the bloodstream. PTH also feeds back on vitamin D metabolism. Parathyroid hormone can boost 1-alpha-hydroxylase activity, which forms more active vitamin D, increasing gut absorption of calcium. In the kidney, parathyroid hormone increases calcium reabsorption and reduces the reabsorption of phosphate, so more phosphate is excreted through the urine. Calcitriol in turn suppresses PTH secretion, closing the loop.\n\nDeficiency: rickets and osteomalacia\n\nVitamin D deficiency therefore disturbs calcium and phosphate handling at several points at once. Vitamin D deficiency causes hypocalcemia, which stimulates production of parathyroid hormone (PTH), causing hyperparathyroidism. Hyperparathyroidism increases absorption, bone mobilization, and renal conservation of calcium but increases excretion of phosphate. As a result, the serum level of calcium may be normal, but because of hypophosphatemia, bone mineralization is impaired. This is why blood calcium alone can look acceptable while the skeleton is still affected.\n\nThe classic outcomes are rickets in children and osteomalacia in adults. Both reflect the same underlying defect: failure of calcification of osteoid, which is the matrix of bone. Nutritional deficiency remains the leading cause worldwide, and it responds well to vitamin D supplementation.\n\nHistorically, the link between these bone diseases and diet or sunlight was made in the early twentieth century. Edward Mellanby's 1919 experiments in dogs associated cod liver oil with the prevention of rickets, and around the same time physicians showed that artificial ultraviolet light could also heal the condition. Elmer McCollum's 1922 work led to the name \"vitamin D.\" These observations later explained why sun exposure and oily fish both protected against the disease."
    },
    {
      "heading": "Vitamin E and Antioxidant Protection",
      "text": "Eight fat-soluble molecules, four tocopherols (alpha, beta, gamma and delta) and four tocotrienols, form the group that nutritionists call vitamin E tocochromanols describes a family of eight fat-soluble molecules with antioxidant activities. Among them, alpha-tocopherol alone covers the human requirement Only one form, α-tocopherol, meets human vitamin E requirements. The selectivity happens in the liver. Once the α-tocopherol transfer protein (α-TTP) captures alpha-tocopherol, it loads the molecule onto lipoproteins that carry it to other tissues α-Tocopherol is the form of vitamin E that is preferentially bound to α-tocopherol transfer protein (α-TTP) and incorporated into lipoproteins that transport α-tocopherol in the blood. Dietary beta-, gamma- and delta-tocopherols are instead routed out of the body through bile and stool Most of the ingested β-, γ-, δ-tocopherols are secreted into the bile or not taken up and excreted in the feces.\n\nThe best-established function is as a chain-breaking antioxidant inside membranes. Membrane lipids rich in polyunsaturated fatty acids are vulnerable to attack by free radicals, which initiates lipid peroxidation. A hydrogen atom from the phenolic group of alpha-tocopherol neutralises a lipid peroxyl radical it can rapidly transfer the phenolic H atom onto a lipid peroxyl radical (LOO●). The tocopheroxyl radical left behind is sluggish and does not reattack oxygen or unsaturated lipids the tocopheroxyl radical (T●) is unreactive towards O_2_ or polyunsaturated lipids, so the chain stops. The spent molecule can be regenerated: ascorbate and coenzyme Q return it to its active phenol form reduced back to phenol by co-antioxidants (e.g., ascorbic acid, β-carotene, or coenzyme Q). This regeneration links vitamin E to vitamin C status. Because the protection extends to the bilayer as well as the enzymes and membrane proteins embedded in it, the effect is considered basic to cell integrity. Researchers have also debated whether vitamin E has further biological activities beyond radical trapping, without a conclusive resolution the possibility that the vitamin possesses additional biological activities has been postulated and debated in the literature without conclusive resolution. One example is a reported dampening of protein kinase C activity through reduced membrane diacylglycerol Protein kinase C inhibition by α-tocopherol is in part attributable to its attenuating effect on the generation of membrane-derived diacylglycerol.\n\nOvert vitamin E deficiency is uncommon. Where diets are poor, the shortfall is typically dietary, while in food-secure countries deficiency arises mainly from problems with fat absorption or from inherited disorders Dietary vitamin E deficiency is common in countries with high rates of food insecurity; deficiency among adults in other countries is uncommon and usually due to fat malabsorption. Conditions that impair fat digestion and uptake include cystic fibrosis, cholestatic liver disease, pancreatitis, short bowel syndrome and abetalipoproteinemia Disorders that cause fat malabsorption, including abetalipoproteinemia (Bassen-Kornzweig syndrome, due to genetic absence of apolipoprotein B), chronic cholestatic hepatobiliary disease, pancreatitis, short bowel syndrome, and cystic fibrosis. A separate rare recessive disorder, ataxia with vitamin E deficiency (AVED), arises from mutations in the α-TTP gene and occurs without lipid malabsorption This disorder is a rare autosomal recessive neurodegenerative disease caused by mutations in the gene for α-TTP. This disorder is known as ataxia with vitamin E deficiency (AVED).\n\nThe most serious clinical consequence is neurological. Degeneration of large sensory axons produces a peripheral neuropathy The primary, and most serious, clinical manifestation of human vitamin E deficiency is a peripheral neuropathy with degeneration of large-caliber axons in sensory neurons. In children with chronic fat malabsorption, the picture can include spinocerebellar ataxia with loss of deep tendon reflexes, truncal and limb ataxia, loss of vibration and position senses, ophthalmoplegia, muscle weakness, ptosis, and dysarthria. The second hallmark is hemolytic anemia. Oxidative damage to red cell membranes shortens their lifespan, and pediatric patients with cystic fibrosis and vitamin E deficiency caused by fat malabsorption also develop hemolytic anemia. Timing depends on the cause: Patients with a genetic defect typically develop neurological symptoms by their first or second decade, whereas the development of symptoms in those with acquired fat malabsorption syndromes takes multiple decades. Diagnosis relies on the ratio of plasma alpha-tocopherol to total plasma lipids, since a low ratio suggests vitamin E deficiency. Treatment with oral vitamin E is given in high doses when neurological deficits are present or malabsorption is the cause Treatment consists of oral vitamin E, given in high doses if there are neurologic deficits or if deficiency results from malabsorption.\n\nLarge supplementation trials have produced mixed or negative results. The randomized Selenium and Vitamin E Cancer Prevention Trial (SELECT) enrolled men from 2001 to 2004 SELECT randomized 35,533 men from 427 study sites in the United States, Canada and Puerto Rico in a double-blind manner between August 22, 2001 and June 24, 2004. Its initial report found no reduction in prostate cancer with either agent found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. A longer follow-up then showed that 400 IU per day raised the risk, with a hazard ratio of 1.17 relative to placebo 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P=.008). Expressed as absolute numbers, this was 76 prostate cancers in men who took only vitamin E supplements, versus 65 in men on placebo over a seven-year period, or 11 more cases of prostate cancer per 1,000 men. The trial's authors concluded that supplementation significantly increases the risk of prostate cancer among healthy men. Earlier trials in high-risk cardiovascular patients, such as HOPE, likewise did not show a benefit from vitamin E, and a 2005 meta-analysis associated doses of 400 IU or more with higher all-cause mortality. Some reviewers noted that the harmful studies used doses below the tolerable upper intake level, which leaves the safe dose and duration unresolved Both of these studies that resulted in adverse outcomes used a dose of vitamin E that is less than the UL, confirming the need to establish the safest dose and duration of antioxidant supplementation."
    },
    {
      "heading": "Vitamin K and Blood Clotting",
      "text": "Carboxylation of clotting factors\n\nVitamin K is required for the synthesis of the active form of several plasma proteins. In the liver, prothrombin (factor II) and factors VII, IX and X are first made as inactive precursors. The enzyme γ-glutamyl carboxylase then adds a carboxyl group to specific glutamate residues in the amino-terminal region of these precursors, converting them to γ-carboxyglutamate (Gla) residues. The reaction uses reduced vitamin K (the hydroquinone) as a cofactor and oxidizes it to vitamin K 2,3-epoxide. The Gla residues are negatively charged and bind calcium ions, which allows the factors to attach to negatively charged phospholipid surfaces at sites of tissue injury. Without this modification, the factors circulate but cannot function well. In one reported case of congenital deficiency, the factors were detectable by immunoassay yet their clotting activity never exceeded about 18 percent of normal, even after vitamin K treatment. The same carboxylation system also modifies protein C and protein S, which act as anticoagulants, so vitamin K supports both the procoagulant and the regulatory sides of blood coagulation. Because this is a post-translational modification, it occurs after the protein chain is made, and it is the reason vitamin K deficiency produces a bleeding tendency rather than any change in the amount of protein synthesized.\n\nThe vitamin K cycle and warfarin\n\nEach carboxylation event oxidizes the vitamin K hydroquinone to the epoxide, so the cofactor must be regenerated continuously. The enzyme vitamin K epoxide reductase (VKOR), encoded by the VKORC1 gene, first reduces the epoxide back to the quinone and then to the hydroquinone, completing the cycle. This recycling is essential because dietary intake of vitamin K is limited. Warfarin, the most widely used oral anticoagulant, acts by inhibiting VKOR. Reduced vitamin K becomes depleted, carboxylation slows, and the circulating clotting factors remain undercarboxylated and less active. Because the effect depends on the turnover of existing factors, anticoagulation with warfarin develops over several days rather than immediately. The required dose varies between patients, and common variants upstream of VKORC1 have been linked to differences in warfarin sensitivity. Clinicians therefore monitor the international normalized ratio and keep dietary vitamin K intake relatively consistent during treatment. Warfarin exposure before birth is also associated with fetal developmental abnormalities, which reflects the importance of carboxylation in tissues beyond the liver.\n\nVitamin K-dependent proteins outside the liver\n\nSeveral Gla proteins are made outside the liver and have functions unrelated to clotting. Osteocalcin, also called bone Gla protein, is produced by osteoblasts. After carboxylation, its Gla residues bind calcium at the surface of the bone mineral, and it helps regulate bone formation and mineralization. Studies in transgenic mice showed that osteocalcin-deficient animals had increased bone formation. Matrix Gla protein (MGP) is expressed in vascular smooth muscle cells, endothelial cells, cartilage and other tissues. It requires both carboxylation and serine phosphorylation before it can act as a local inhibitor of calcification. Mice lacking MGP develop calcification of arteries and cartilage, and they show skeletal abnormalities and early death, which illustrates the protective role of this protein in the vascular system. Protein S is also present in bone matrix, and Gas6 participates in cell growth regulation. Reviews differ in how many Gla proteins they count, partly because some of these proteins are only partly characterized, so the total number should be treated as provisional.\n\nDiscovery, hemorrhagic disease of the newborn and prophylaxis\n\nVitamin K was identified in 1929 by the Danish biochemist Henrik Dam, who observed that chicks on a diet lacking certain fat-soluble factors developed bleeding, and he named the factor for its role in coagulation. Edward Adelbert Doisy and colleagues later characterized the compound chemically, and Dam and Doisy shared the 1943 Nobel Prize in Physiology or Medicine for this work. Physiology or medicine is the category in which the award was given, not chemistry.\n\nNewborn infants are particularly vulnerable because vitamin K crosses the placenta poorly, breast milk contains relatively little of it, and the newborn gut is initially sterile and therefore lacks the bacteria that synthesize vitamin K2. Classic hemorrhagic disease of the newborn typically appears within the first days of life, while late forms occur in the first weeks to months and are more often associated with intracranial bleeding, particularly in breastfed infants who did not receive prophylaxis. A single intramuscular dose of vitamin K1 given at birth markedly reduces the incidence of both forms, and this approach has become standard in many health systems. Oral regimens are also used in some settings, though they have been less consistently protective against late disease. Neonatal prophylaxis is therefore a classic example of a public health measure based on a clearly defined deficiency mechanism."
    },
    {
      "heading": "Thiamine, Riboflavin, Niacin, and Pantothenic Acid",
      "text": "The first four B vitamins discussed here share one feature: each is converted in the cell into a cofactor or a carrier molecule that enables enzymes to move electrons, transfer groups, or cleave bonds. Their deficiency syndromes therefore tend to affect the tissues with the highest energy demand, such as the nervous system, and surfaces that renew quickly, such as skin and mucous membranes.\n\nThiamine (vitamin B1)\n\nIn the cell, thiamine is converted into thiamine pyrophosphate (TPP), which acts as a cofactor for enzymes that remove carbon dioxide from α-keto acids. The most important are pyruvate dehydrogenase, which links glucose breakdown to the mitochondrial citric acid cycle, the citric acid cycle enzyme α-ketoglutarate dehydrogenase, and transketolase in the pentose phosphate pathway. Because neurons depend heavily on aerobic oxidation of glucose, they are especially vulnerable to shortfalls.\n\nHistorically, thiamine deficiency was described as beriberi in populations that ate polished white rice. The \"dry\" form produces peripheral neuropathy and muscle wasting, while the \"wet\" form causes edema and high-output heart failure. Wernicke encephalopathy is the acute neurological form, with confusion, ataxia, and abnormal eye movements. It is most often linked to alcohol use disorder but also follows prolonged vomiting, malnutrition, or bariatric surgery. If untreated, it may progress to Korsakoff syndrome, a chronic state marked by severe memory loss. Clinical practice therefore gives thiamine before or together with intravenous glucose to people at risk.\n\nRiboflavin (vitamin B2)\n\nRiboflavin is converted by ATP-dependent steps into flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Both are tightly bound prosthetic groups of flavoproteins, which accept and release electrons as they cycle between oxidized and reduced forms. FMN is the prosthetic group of NADH dehydrogenase (complex I) of the mitochondrial electron transport chain, while FAD is bound to succinate dehydrogenase (complex II), which also functions in the citric acid cycle. FAD is also required by acyl-CoA dehydrogenases in fatty acid β-oxidation and by glutathione reductase, which maintains reduced glutathione. These reactions are central oxidation–reduction reactions of cellular respiration.\n\nRiboflavin deficiency, known as ariboflavinosis, produces cracks at the corners of the mouth, a swollen and sore tongue, and eye complaints such as light sensitivity and itching. It usually occurs alongside deficiencies of other B vitamins. Riboflavin is also photosensitive, and exposure to light degrades it, which is one reason milk is often packaged in opaque containers.\n\nNiacin (vitamin B3)\n\nNiacin is a collective term for nicotinic acid and nicotinamide. Cells use these to make nicotinamide adenine dinucleotide (NAD⁺) and its phosphorylated form NADP⁺. NAD⁺ is the main hydrogen carrier in catabolic reactions such as glycolysis, the citric acid cycle, and β-oxidation, whereas NADP⁺ mainly supplies electrons for reductive biosynthesis, including fatty acid and cholesterol synthesis. NAD⁺ also serves as a substrate for enzymes that repair DNA and modify gene expression, such as sirtuins and poly(ADP-ribose) polymerases.\n\nHumans can make niacin from tryptophan through the kynurenine pathway, although the conversion is inefficient; a commonly cited figure is about 60 mg of tryptophan for 1 mg of niacin. Niacin in maize is largely bound in a form that the body cannot absorb, and treating maize with alkali releases it. Populations that relied on untreated maize as a staple developed pellagra, whose classic features are dermatitis (often photosensitive), diarrhea, and dementia, and which is fatal if untreated. Joseph Goldberger of the US Public Health Service showed in the 1910s and 1920s that the disease was caused by diet rather than an infectious agent. Conrad Elvehjem and colleagues identified nicotinic acid as the curative factor in 1937.\n\nPantothenic acid (vitamin B5)\n\nThe name pantothenic acid comes from the Greek pantothen, \"from everywhere\", which Roger J. Williams chose in 1933 because the vitamin is so widely distributed in foods. The molecule joins pantoic acid to β-alanine. Cells convert it into coenzyme A (CoA) through a series of five enzymatic steps, one of which incorporates cysteine. CoA carries acyl groups in many reactions; acetyl-CoA, for example, is the entry point of the citric acid cycle. In fatty acid synthesis, the related acyl carrier protein (ACP) carries a 4′-phosphopantetheine arm, which holds the growing chain while it is extended two carbons at a time.\n\nDeficiency is rare in people with varied diets. Its best-known human syndrome, \"burning feet\" with paresthesia, fatigue, and irritability, was described in prisoners of war and in people under starvation conditions, and it resolves with supplementation."
    },
    {
      "heading": "Vitamin B6, Biotin, Folate, and Vitamin B12",
      "text": "Pyridoxal phosphate (vitamin B6)\n\nThe active form of vitamin B6 is pyridoxal 5′-phosphate (PLP), which serves as a versatile cofactor in over 140 enzymatic reactions, predominantly those involved in amino acid metabolism, neurotransmitter synthesis and one-carbon transfer. PLP binds to its enzyme through a Schiff base with a lysine residue in the active site. This lets the same cofactor catalyze different reactions. Depending on the enzyme involved, the same cofactor can mediate quite different reactions, i.e. decarboxylation and transamination. In transamination, an amino group moves between amino acids and keto acids, so PLP is central to nitrogen handling. Several decarboxylases that depend on PLP produce neurotransmitters. Glutamate is converted to the inhibitory transmitter GABA by glutamate decarboxylase, and 5-hydroxytryptophan is converted to serotonin by an aromatic amino acid decarboxylase. The same class of enzyme also converts L-DOPA to dopamine. Because of these steps, PLP-dependent reactions shape the synthesis of signaling molecules in neurons and in the central nervous system.\n\nBiotin\n\nBiotin is covalently attached to the enzymes it serves, which are called carboxylases. Through this carboxyl group, biotin is linked covalently to the β-amino group of lysine in 5 carboxylases that play critical roles in intermediary metabolism. In mammals, biotin is a cofactor for four carboxylase enzymes found in mammals - pyruvate carboxylase, methyl-crotonyl-CoA carboxylase, proprionyl-CoA carboxylase and acetyl-CoA carboxylase. The acetyl-CoA carboxylase step supplies the building block for fatty acid synthesis, and the pyruvate carboxylase step supports glucose production from non-carbohydrate precursors. Biotin's name comes from the Greek word for life, because in the 1930s, biotin was found to be a vitamin for yeast. So, in reference to the fact that the life of yeast requires it, the vitamin was christened biotin from the Greek bios, meaning life.\n\nThe raw egg white problem is a classic example of a food interaction. Egg white contains avidin, a protein with an extraordinarily strong affinity for biotin, with a dissociation constant of about \\(10^{-15}\\) M. The dissociation constant of the avidin-biotin complex is measured to be KD ≈ 10−15 M, making it one of the strongest known non-covalent bonds. Avidin binds biotin in the gut and blocks its absorption. Heat solves this problem, because cooking denatures avidin, making it unable to interfere with biotin absorption. Deficiency is uncommon in practice, since it can be synthesized by intestinal bacteria, supplying enough to the body to cover its requirements under most circumstances. Deficiency has been documented in people who ate large amounts of raw egg whites over long periods, and in patients receiving total parenteral nutrition.\n\nFolate (tetrahydrofolate)\n\nFolate acts through its reduced form, tetrahydrofolate (THF), which carries single-carbon units at different oxidation states. The reduced form of folic acid (tetrahydrofolate) acts as a cofactor for many one-carbon transfer reactions in nucleotide synthesis (especially the conversion of dUMP to dTMP in the synthesis of thymidylate), in methionine synthesis. Thymidylate is needed to build thymine for DNA, so folate-dependent reactions are required whenever DNA is copied. Tetrahydrofolate is required to support the biosynthesis of purines and pyrimidines and therefore it is essential for cellular proliferation and homeostasis. This dependence is why folate deficiency causes problems in rapidly dividing tissues such as the bone marrow, and why it links closely to DNA replication and cell division.\n\nVitamin B12 (cobalamin)\n\nIn humans, vitamin B12 serves as a cofactor for two enzymes. Vitamin B12 functions as a cofactor for two enzymes, methionine synthase and L-methylmalonyl-CoA mutase. Methionine synthase uses methylcobalamin to transfer a methyl group from 5-methyl-THF to homocysteine, producing methionine and regenerating THF. This ties B12 directly to the folate cycle. The methionine formed is then converted into S-adenosylmethionine, which is a universal methyl donor for almost 100 different substrates, including DNA, RNA, proteins, and lipids. The second enzyme works in the mitochondria. Adenosylcobalamin acts as a cofactor for methylmalonyl CoA mutase which converts methylmalonyl CoA to succinyl CoA, a metabolite in the tricarboxylic acid cycle. Impaired activity of this enzyme leads to methylmalonic acid (MMA) levels may accumulate, contributing to myelin damage, neurologic deficits, neuropathy, and ataxia.\n\nAbsorption of B12 depends on a multistep process. Dietary B12 is released from food proteins and binds to intrinsic factor, a glycoprotein made by the stomach's parietal cells. Once the complex arrives at the small intestine, B12 is cleaved from R-factor by pancreatic enzymes, allowing it to bind to a glycoprotein called intrinsic factor, which is secreted by gastric parietal cells. The newly formed complex of B12 and intrinsic factor can then bind to receptors on the ileum, which allows for absorption of B12. Passive diffusion is minor by comparison, since only about 1% to 2% of the oral vitamin B_12 dose is absorbed passively.\n\nPernicious anemia is the most common cause of B12 deficiency, and it is autoimmune in origin. Pernicious anemia is an autoimmune condition in which antibodies to intrinsic factors are produced. Anti-intrinsic factor antibodies bind to and inhibit the effects of intrinsic factors, resulting in an inability of B12 to be absorbed by the terminal ileum. The underlying process is chronic inflammation of the stomach lining. AIG causes chronic destruction of gastric parietal cells, leading to mucosal atrophy, achlorhydria, and loss of intrinsic factor. Vitamin B_12 deficiency is a late manifestation of AIG, termed pernicious anemia. When methionine synthase is impaired, homocysteine levels accumulate, and pyrimidine bases cannot be formed, slowing down DNA synthesis and can cause megaloblastic anemia. Because these effects overlap with folate deficiency, the two B vitamins must be considered together when diagnosing anemia."
    },
    {
      "heading": "Vitamin C and Collagen Synthesis",
      "text": "Vitamin C, or L-ascorbic acid, works mainly as a cofactor for enzymes that depend on iron. The best-understood examples are prolyl hydroxylases and lysyl hydroxylases, which add hydroxyl groups to proline and lysine residues in procollagen chains after they are made on ribosomes. The hydroxyproline and hydroxylysine residues allow the three chains of a collagen molecule to fold into a stable triple helix. Ascorbate keeps the iron at the catalytic center in its reduced ferrous state, so the enzymes can repeat their reactions. Without enough ascorbate, procollagen is poorly hydroxylated, misfolds, and is degraded instead of being secreted as functional collagen. The result is weakened connective tissue in the gums, blood vessel walls, skin, and healing wounds, which explains the classic signs of scurvy: bleeding gums, loosened teeth, easy bruising, perifollicular hemorrhages, and slow wound repair.\n\nAscorbate also acts as a water-soluble redox buffer. It donates electrons to neutralize reactive oxygen species, forming a relatively stable ascorbyl radical that can be reduced back to ascorbate. In membranes it regenerates alpha-tocopherol (vitamin E) from its radical form, so the two vitamins complement each other across lipid and aqueous compartments. Ascorbate is likewise a cofactor for dopamine beta-hydroxylase, which converts dopamine into norepinephrine in adrenergic neurons and the adrenal medulla, and for the enzyme that amidates many peptide hormones. It is also needed for carnitine synthesis and for the conversion of tyrosine in its catabolic pathway. In the intestine, it reduces dietary ferric iron to the ferrous form that can be absorbed, and it supports the iron- and 2-oxoglutarate-dependent TET enzymes that influence DNA methylation.\n\nMost mammals can make their own vitamin C from glucose through a pathway that runs via glucuronate, mainly in the liver or kidney. The final step converts L-gulonolactone into ascorbate, catalyzed by L-gulonolactone oxidase (GULO). Humans, the other haplorrhine primates, guinea pigs, some bats, and certain passerine birds lack a working GULO enzyme. In humans the corresponding gene has accumulated mutations and survives as a nonfunctional pseudogene. The loss is generally thought to have occurred in the ancestors of the haplorrhine primates tens of millions of years ago, although the exact timing is debated. Because of this loss, humans must obtain vitamin C from the diet, and they cannot compensate for a shortfall by increasing internal synthesis.\n\nThe link between citrus and scurvy was tested experimentally long before the compound was identified. In 1747 the Scottish naval surgeon James Lind assigned twelve sailors with scurvy on HMS Salisbury to six pairs with different supplements. The pair given oranges and lemons improved markedly, and Lind's published account argued that citrus fruit was the most effective remedy. Lind's findings were adopted slowly, and the Royal Navy did not systematically issue citrus juice until the 1790s. In the 1920s, Albert Szent-Györgyi isolated a reducing acid, which he called hexuronic acid, from adrenal glands and later from citrus fruit and paprika. In 1932 Charles Glen King at the University of Pittsburgh showed that a purified preparation prevented scurvy in guinea pigs. Walter Norman Haworth determined the structure of the compound and in 1933 synthesized L-ascorbic acid, which was shown to be the same substance as the antiscorbutic factor. Szent-Györgyi received the 1937 Nobel Prize in Physiology or Medicine for his work on biological combustion and vitamin C, and Haworth shared the 1937 Nobel Prize in Chemistry with Paul Karrer. Chemical synthesis later made large-scale industrial production of the vitamin possible."
    },
    {
      "heading": "Absorption, Transport, Storage, and Excretion",
      "text": "Fat-soluble vitamins\n\nVitamins A, D, E, and K are absorbed in the small intestine alongside dietary fat, so their uptake depends on the same digestive machinery as lipids. Bile salts emulsify the fat and pancreatic lipase hydrolyzes them to release fatty acids and glycerol. The resulting products are gathered into micelles, which are temporary combinations of bile salt, fatty acids, monoglycerides, and other fat-soluble substances such as vitamins and cholesterol. These structures keep the lipophilic molecules dispersed in the watery intestinal contents and carry them to the brush border.\n\nBile is not merely an aid. One review notes that bile salts, although possibly not absolutely necessary for digestion, are essential for the complete absorption of dietary fats. Vitamin E illustrates the dependence on fat digestion: pancreatic enzymes may also aid in its absorption, as suggested by vitamin E deficiency in patients with cystic fibrosis, who do not secrete pancreatic enzymes. Cholestatic liver disease, bile-acid deficiency, and pancreatic insufficiency can therefore all reduce the uptake of these vitamins.\n\nOnce inside the enterocyte, the lipids are reassembled. The vitamins are packaged into chylomicrons and released into the lymphatic system rather than directly into the portal blood. Fat-soluble vitamins pass with the chylomicrons into the lymphatic system. They reach the systemic circulation only after the lymph drains into the bloodstream, which is why lipid-rich particles, rather than free vitamins, carry them through the body.\n\nWater-soluble vitamins\n\nWater-soluble vitamins do not need micelles. Each has its own carrier-mediated route. Vitamin C is the best-characterized case. Ascorbate is taken up by sodium-coupled transport, and the oxidized form dehydroascorbic acid enters through glucose transporters. Ingested vitamin C is absorbed across the intestinal epithelium primarily by membrane transporters in the apical brush border membrane, either as ascorbate by sodium-coupled active transport via the SVCT1 transporter or as dehydroascorbic acid through facilitated diffusion via GLUT1 or GLUT3 transporters.\n\nVitamin B12 follows a more elaborate route. Stomach acid releases it from food proteins, and it binds to salivary carrier proteins that are later cleaved in the duodenum. It then attaches to intrinsic factor, a glycoprotein made by gastric parietal cells. The resulting complex is absorbed in the distal ileum by receptor-mediated endocytosis. A small fraction, roughly 1–5%, crosses the intestine without intrinsic factor by passive diffusion, which is one reason oral high-dose B12 can work in some patients. Folate is absorbed mainly in the proximal small intestine, and thiamine is taken up by saturable carriers at physiological doses, with passive diffusion adding a larger share only at high doses.\n\nTransport in the blood\n\nIn plasma, water-soluble vitamins are often carried by binding proteins. B12 is a clear example: transcobalamin II and haptocorrin are responsible for delivery of cobalamin to peripheral tissues and the liver, respectively. Fat-soluble vitamins instead travel within lipoproteins or on specific binding proteins, such as retinol-binding protein for vitamin A and vitamin D-binding protein for vitamin D.\n\nTissue distribution is also uneven. The sodium-dependent vitamin C transporter SVCT1 is largely restricted to epithelia, whereas SVCT2 is more widespread; SVCT2 distributes vitamin C to various tissues, including the brain, retina, placenta, spleen, and prostate. Vitamin C concentrations therefore differ markedly between organs.\n\nStorage and the speed of deficiency\n\nStorage capacity determines how quickly a deficiency appears after intake stops. Vitamin B12 is the classic long-reserve vitamin. Unlike most other vitamins, B12 is stored in substantial amounts, mainly in the liver, until it is needed by the body. Estimates of how long the reserve lasts vary; one source gives 3 to 5 years if B12 intake stops, and shorter periods when enterohepatic recycling is impaired. Because of this reserve, anemia may not develop until 3 to 5 years after the deficiency begins. Vitamin A is also stored largely in the liver, and vitamin D is held in fat tissue and the liver, so their deficits also develop slowly.\n\nWater-soluble vitamins with little reserve, such as thiamine, riboflavin, and vitamin C, show deficiency within weeks to months when intake falls. Vitamin K has a short half-life and minimal stores, so bleeding problems can appear quickly in people who cannot absorb it.\n\nRenal handling and excretion\n\nExcess water-soluble vitamins are generally excreted in urine, and the kidney also reclaims some of them. Vitamin C shows the pattern clearly. The glomerulus filters it freely, and under deficient conditions reabsorption is primarily achieved by SVCT1 transporters in the apical membrane. In mice lacking this transporter, the excreted fraction rises sharply: compared with wild-type mice, these animals increased ascorbate fractional excretion up to 18-fold. Loss of ascorbate in urine lowers plasma and most tissue levels, though brain concentrations are relatively protected.\n\nKidney disease alters this balance in several ways. Reduced renal function impairs the final hydroxylation of 25-hydroxyvitamin D to the active hormone calcitriol, which contributes to the vitamin D problems seen in chronic kidney disease. Patients on dialysis lose water-soluble vitamins through the dialysis process, which is why B-complex and vitamin C supplementation is commonly considered in this population. Reduced clearance of B vitamins can also raise homocysteine levels. Liver disease, in contrast, shortens the B12 reserve, placing patients at risk of deficiency sooner than people with normal liver function."
    },
    {
      "heading": "Deficiency Diseases and Clinical Diagnosis",
      "text": "Most of the classic vitamin deficiency diseases are named after the tissues they damage first. Seven are usually listed: scurvy (vitamin-c deficiency), beriberi (thiamine), pellagra (niacin), rickets (vitamin D), xerophthalmia (vitamin A), pernicious anemia (vitamin-b12 deficiency), and vitamin K-deficiency bleeding. Each syndrome follows from the biochemical role of the missing vitamin. The sites of damage therefore show which function failed.\n\nClassic syndromes\n\nScurvy develops only after sustained, severe lack of vitamin C, usually over one to three months. Its signs include bleeding gums, bruising, perifollicular hemorrhage, joint pain, and poor wound healing, which reflect defective collagen. Although rare in high-income countries, sporadic cases still occur there, mainly among older adults, people with alcohol use disorder, and those with very poor diets.\n\nBeriberi is caused by thiamine (vitamin B1) deficiency and has wet and dry forms. Wet beriberi causes fluid retention and a rapid heart rate, sometimes leading to heart failure. Dry beriberi produces peripheral neuropathy and leg weakness. An infantile form occurs in breastfed infants whose mothers are deficient. The disease became epidemic in Asia when polished white rice replaced brown rice in the diet.\n\nPellagra, caused by niacin deficiency, is classically summarized as dermatitis, diarrhea, dementia, and death if untreated. The skin lesions are photosensitive, so they appear mainly on sun-exposed areas. Historically it was common among populations whose diets depended heavily on maize with little other protein.\n\nRickets in children and osteomalacia in adults both result from inadequate vitamin D, which leaves bone mineral poorly calcified. Affected children may show a softened skull, bowed legs, and fractures. Rickets is now rare in countries that fortify foods with vitamin D.\n\nXerophthalmia begins with night blindness and progresses through conjunctival dryness and Bitot's spots to corneal ulceration and, in severe cases, blindness. It remains a leading cause of preventable childhood blindness in low-income regions.\n\nPernicious anemia is an autoimmune condition in which antibodies impair the stomach's production of intrinsic factor or destroy the cells that make it. Without intrinsic factor, vitamin B12 cannot be absorbed in the ileum. The resulting megaloblastic anemia is accompanied by neurological symptoms such as numbness and gait disturbance, and neurological damage may be partly irreversible if treatment is delayed.\n\nVitamin K-deficiency bleeding affects mainly newborns, whose stores are low, whose gut flora is not yet established, and whose breast milk contains little vitamin K. It can cause serious hemorrhage, including intracranial bleeding. Prophylaxis is discussed in the section on vitamin K.\n\nPopulations at high risk\n\nSeveral groups face elevated risk for specific reasons. Infants have small reserves and rapid growth, and exclusively breastfed infants depend on the mother's status. Pregnant and breastfeeding women have higher requirements, and low folate before conception and in early pregnancy is linked to neural tube defects. Older adults often eat less, synthesize less vitamin D in the skin, and may have reduced gastric acid, which impairs release of food-bound vitamin B12.\n\nMalabsorption is a major cause of deficiency in patients after bariatric surgery, whose altered anatomy reduces absorption of vitamin B12, fat-soluble vitamins, and other nutrients. People with inflammatory bowel disease, particularly after ileal resection or with active small-bowel inflammation, are also at risk for B12 and fat-soluble vitamin deficiency. People with alcohol use disorder often have poor intake, impaired hepatic storage, and increased losses of thiamine, which predisposes them to Wernicke encephalopathy.\n\nSubclinical deficiency and diagnosis\n\nMany deficiencies never produce a classic syndrome. Their symptoms are mild, nonspecific, and easily attributed to other conditions, so diagnosis depends on biochemical markers. Serum 25-hydroxyvitamin D is the standard indicator of vitamin D status. For vitamin B12, total serum B12 and holotranscobalamin are direct measures, while methylmalonic acid and plasma homocysteine are functional markers that rise when the cobalamin-dependent enzymes lack their cofactor. Elevated methylmalonic acid can reveal deficiency when serum B12 still falls within the reference range. Interpretation has limits: both functional markers also accumulate when kidney function declines, which reduces their specificity, and cutoff values differ between studies and laboratories. Diagnosis therefore usually combines a marker, the clinical picture, and sometimes a therapeutic trial.\n\nUndernutrition and multiple deficiencies\n\nIn undernutrition and food insecurity, several micronutrients are usually deficient at once. This makes it hard to attribute any single effect and means that treatment rarely targets one vitamin in isolation. Public health surveys therefore measure serum concentrations across populations, not just the frequency of classic diseases.\n\nA useful distinction separates deficiency severe enough to cause a classic disease from deficiency that falls short of optimal health. The first is a threshold phenomenon that is comparatively easy to recognize. The second is a continuum: lower status may be associated with impaired function or greater long-term risk without any overt sign, and whether correcting it improves health is a separate question addressed by clinical trials."
    },
    {
      "heading": "Toxicity and Upper Intake Limits",
      "text": "Most vitamins have a wide margin between useful and harmful intakes, but several become dangerous when intake far exceeds requirements. The main regulatory tool is the tolerable upper intake level (UL), which is the highest chronic daily intake from all sources that is unlikely to cause adverse effects in almost all people. A UL is a safety ceiling for habitual intake, not a recommended target, and intake above it is not automatically harmful. Limits are set for specific toxic endpoints, and these differ for each vitamin.\n\nThe fat-soluble vitamins are the main concern because they accumulate in the body. Preformed vitamin A (retinol and its esters, found in liver and dairy fat) can cause hypervitaminosis A, with liver damage at chronic high doses and birth defects if a pregnant woman takes excess amounts, since the teratogenic effects of retinoids are well established. The US Institute of Medicine set the adult UL for preformed vitamin A at 3,000 µg RAE per day, a value derived from the teratogenic threshold. The European Scientific Committee on Food set a lower limit of 1,500 µg RE per day for postmenopausal women because of effects on bone density and fracture risk. Provitamin A carotenoids from plants do not produce the same toxicity, because the body converts them only as needed.\n\nVitamin D toxicity is caused by excess circulating calcium. Persistent hypercalciuria is the earliest sign and can progress to hypercalcemia, kidney stones, nephrocalcinosis, and calcification of soft tissues. The IOM set an adult UL of 50 µg (2,000 IU) per day, but a 2023 European Food Safety Authority opinion chose persistent hypercalciuria as its critical endpoint and set a UL of 100 µg vitamin D equivalents per day for adults and adolescents, with 50 µg for children aged 1 to 10. Clinicians assess exposure by measuring serum 25-hydroxyvitamin D, the circulating storage form, because it reflects accumulated intake from supplements, diet, and any other sources. Sunlight does not usually produce toxicity, since skin synthesis of vitamin D self-limits.\n\nAmong the water-soluble vitamins, pyridoxine (B6) and niacin (B3) have the best-documented adverse effects. Chronic high-dose pyridoxine damages sensory nerves, producing peripheral neuropathy, and the IOM set its adult UL at 100 mg per day on this basis, although the evidence base has been debated. Niacin in its nicotinic acid form causes cutaneous flushing at doses that are much lower than therapeutic lipid-lowering doses, and the IOM set a UL of 35 mg per day for supplemental nicotinic acid for this reason. Pharmacological niacin, given at gram-scale daily doses for lipid control, can cause hepatotoxicity, particularly with sustained-release formulations, and clinicians monitor liver function during treatment. Nicotinamide does not cause flushing and carries a different risk profile.\n\nVitamin K shows a sharp distinction between forms. Phylloquinone (K1) and the menaquinones (K2) have not produced toxicity in people even at large oral doses, and no UL has been established for them. The synthetic analogue menadione (K3) is different: it is thought to deplete glutathione and cause oxidative damage to cell membranes, and high doses have caused hemolytic anemia, hyperbilirubinemia, and kernicterus in newborns. It was formerly given to premature infants and was withdrawn from clinical use, and it has been excluded from over-the-counter sale in the United States.\n\nFood-derived toxicity is rare for most vitamins because natural foods rarely contain enough of a vitamin to exceed a UL, and the body regulates absorption and storage. Most serious toxicity arises from concentrated supplements, fortified products, pharmacological doses prescribed for a specific condition, or accidental overdose in children. The risk from supplements is greatest for the fat-soluble vitamins, which are retained in tissues, and for combinations of products that together exceed a UL. Because the UL applies to total intake from all sources, the rationale for limiting supplements is clearest when a person is already consuming fortified foods or multiple products."
    },
    {
      "heading": "Dietary Reference Intakes and Food Sources",
      "text": "Reference intake categories\n\nVitamin recommendations are usually expressed through the Dietary Reference Intake (DRI) framework, which groups several distinct values. The Estimated Average Requirement (EAR) is the level expected to meet the needs of half of a given life-stage and sex group, while the Recommended Dietary Allowance (RDA) is set high enough to cover roughly 97 to 98 percent of healthy people in that group (The point at which 50 percent of the population meets their nutrient needs is the EAR, and the point at which 97 to 98 percent of the population meets their needs is the RDA.). The RDA is derived from the EAR by adding two standard deviations of the requirement distribution, which typically places it about 20 percent above the EAR (It is calculated based on the EAR and is usually approximately 20% higher than the EAR). When evidence is too limited to calculate an EAR, an Adequate Intake (AI) is set instead, based on observed intakes among healthy people (The AI is a value based on experimentally derived intake levels or approximations of observed mean nutrient intakes by a group (or groups) of healthy people.). The Tolerable Upper Intake Level (UL) addresses safety rather than adequacy: it marks the daily ceiling above which the risk of adverse effects begins to rise (The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all apparently healthy individuals in the specified life stage group. As intake increases above the UL, the potential risk of adverse effects may increase.).\n\nDifferences between regional authorities\n\nThe North American values are written for planning individual diets, whereas the UK, European and WHO/FAO systems are framed with population use in mind (Note that these U.S. and Canadian recommendations, unlike those set by the United Kingdom, EFSA, and WHO, are intended for use by individuals, as noted earlier.). The European Food Safety Authority works under the label Dietary Reference Values and replaces the RDA with a Population Reference Intake and the EAR with an average requirement, while its AI and UL keep the same meaning (The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL define the same as in United States, although numerical values may differ.). Shared terminology does not guarantee shared numbers. The adult zinc UL, for instance, is 40 mg in the US but 25 mg in the EFSA assessment (For example, adult zinc UL is 40 mg in the U.S. and 25 mg in EFSA.), and EFSA's vitamin C average requirement is 80 mg per day for women and 90 mg for men, chosen to maintain a target plasma ascorbate concentration (The EFSA Committee on Dietary Reference Values chose an average vitamin C requirement of 80 mg/d for women and 90 mg/d for men to maintain fasting plasma ascorbate concentrations of 50 μmol/L). Japan has moved its reference basis over time: its 2005 nutrient reference values were built on EARs, and they were revised in 2015 to rest on the RDAs of the DRIs-J 2015 (Japanese NRVs 2005 were calculated based on the estimated average requirement (EAR), but were revised in 2015 based on the RDAs for the dietary reference intakes for Japanese (DRIs-J) 2015). China publishes its own national reference intakes with a structure broadly similar to these systems but with separately derived values. Food labels add another layer: US Daily Values trace back to RDAs first set in 1968 and updated in 2016 (The DRI values are distinct from those found on food and dietary supplement labels in the U.S. and Canada, which use Reference Daily Intakes (RDIs) and Daily Values (%). These labeling standards were originally based on RDAs from 1968 but were updated in 2016.).\n\nPrincipal food sources\n\nVitamin A is supplied preformed by liver, dairy and eggs, and as provitamin carotenoids by orange and dark green vegetables. Vitamin D comes mainly from oily fish, egg yolk and fortified milk, with skin synthesis under sunlight contributing much of the body's supply. Vitamin K1 is concentrated in leafy green vegetables, while vitamin K2 is found in fermented foods and some animal products. Folate is abundant in leafy greens, legumes and fortified grains, and vitamin C comes chiefly from citrus fruit, peppers, berries and broccoli. Vitamin B12 occurs naturally only in animal-derived foods, which is why strict vegetarians and vegans depend on fortified products or supplements. Thiamine is found in whole grains and pork, and niacin in meat, fish, legumes and wheat products.\n\nFactors that reduce vitamin content\n\nHeat is among the most significant causes of loss. Temperature is one of the most critical determinants in nutrient stability during food preservation. High heat used in methods such as canning, sterilization, drying, or pasteurization can degrade heat-sensitive nutrients, particularly vitamin C and several B-complex vitamins like thiamine and folate. Reported losses are highly process-dependent; one review cites vitamin C losses of 50–80% during thermal processing, whereas another gives a broader range of 10% to over 90% depending on the process. Cooking method matters as well: steaming retains substantially more vitamin C than boiling because the food never directly contacts water. Blanching before freezing can cost 10-40% loss of vitamin C.\n\nWater is the second major route. Heat processing of plant materials can also adversely affect the content of hydrophilic vitamins if such heat processing utilizes large quantities of water and if this water is discarded together with the dissolved vitamins contained therein. Light acts through a different mechanism, since vitamin A, vitamin D, and certain B vitamins (e.g., riboflavin) are highly sensitive to light and can degrade during storage if not properly shielded. Oxygen attacks the fat-soluble group, as exposure to oxygen can cause fat-soluble vitamins to become rancid. Storage time adds a further, slower loss; vitamin C can continue to degrade in frozen vegetables over time, albeit at a slower rate compared to fresh or thermally preserved items.\n\nNot every change is a loss. Processing can improve nutritional value in some cases: cooking tomatoes makes lycopene more accessible to the body, and heat can inactivate enzymes that would otherwise destroy vitamins once plant tissue is cut or ground (Heat processing can also have a favorable impact on vitamin content, as it can be used to inactivate endogenous vitamin-degrading enzymes that become active when plant materials are cut or ground.)."
    },
    {
      "heading": "Supplements and Evidence from Clinical Trials",
      "text": "Vitamin products are sold in two main forms: multivitamins that combine several vitamins and minerals in one tablet, and single-vitamin products such as vitamin D or folic acid. It is useful to separate two reasons for taking them. The first is treatment of a diagnosed deficiency, such as vitamin B12 injections for pernicious anemia or vitamin D repletion for low serum levels. The second is taking doses above typical intake in healthy people in the hope of preventing chronic disease. Large randomized trials have tested the second use most often, and their results have been mixed or disappointing.\n\nBeta-carotene and lung cancer\n\nObservational studies had linked diets rich in carotenoid-containing vegetables with lower lung cancer risk, which encouraged trials of beta-carotene pills. The Alpha-Tocopherol, Beta-Carotene (ATBC) study in Finland enrolled more than 29 000 middle-aged male smokers who were randomly assigned to 50 mg of alpha tocopherol, 20 mg of beta carotene, both, or a placebo daily for five to eight years. Rather than preventing cancer, the beta-carotene arm showed 18% more lung cancers and 8% more deaths at the time of the termination of the intervention.\n\nThe US Beta-Carotene and Retinol Efficacy Trial (CARET) tested a combination of beta-carotene and retinyl palmitate in participants at high risk for lung cancer, drawn from two populations: asbestos-exposed workers and heavy smokers. It was stopped early, and CARET was stopped 21 months early due to the clear evidence of harm towards its subjects, with 28% increased cases of lung cancer and 17% increased cases of mortality. A later trial in male physicians, the Physicians' Health Study, found no effect on lung cancer, and most of its participants were not current smokers. Meta-analyses of these trials have found the risk concentrated in current smokers.\n\nThese results are a standard example of why observational associations are hard to interpret. Beta-carotene from food and a high-dose isolated supplement are not the same exposure, and the mechanisms by which the supplement harmed smokers remain debated. Current reviews generally conclude that the trial findings argue against supplemental beta-carotene, especially for smokers, without implying that carotenoids in food are harmful.\n\nVitamin D and the VITAL trial\n\nThe VITamin D and OmegA-3 TriaL (VITAL) enrolled 25,871 U.S. men aged ≥50 and women aged ≥55, including 5,106 African Americans, and gave vitamin D3 (cholecalciferol, 2000 IU/day) or placebo. For the primary endpoints, supplementation with vitamin D was not associated with a lower risk of either of the primary end points. The hazard ratio for major cardiovascular events was 0.97 (95% CI 0.85–1.12), and for invasive cancer it was 0.94 (0.83–1.06). A secondary analysis found a lower rate of cancer death (HR 0.75), but this result was not a prespecified primary outcome, and meta-analyses of other trials have likewise shown a signal for cancer mortality without a clear reduction in cancer incidence.\n\nBaseline vitamin D status was a central question. Participants with low starting levels had fewer cardiovascular events on supplementation, but these results did not meet statistical significance. Treatment did raise serum 25-hydroxyvitamin D substantially, so the trial showed that the supplement worked biochemically but did not translate into the broad protection that observational studies had suggested. Trial results on falls and fractures have also been mixed, and the bone-related effects of vitamin D are discussed elsewhere in this entry.\n\nFolic acid and neural tube defects\n\nFolic acid is the clearest example in this section of a supplement with an established, specific benefit. In a 1991 Medical Research Council trial of women at high risk because of a previous affected pregnancy, the investigators reported a 72% protective effect in recurrent NTD pregnancies with 4 mg folic acid. Randomized trials of periconceptional supplementation have since shown a reduction in the risk of neural tube defects by approximately 70% in high-risk women. The US Preventive Services Task Force has accordingly recommended that all persons who are planning or capable of pregnancy take a daily supplement containing 0.4 to 0.8 mg.\n\nMandatory fortification extended this benefit to the general population. In the United States, fortification of many cereal-food products became mandatory on January 1, 1998. In Canada, a population study found that the overall prevalence of neural-tube defects at birth decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period. A 2025-2026 meta-analysis of fortification programs reported a pooled reduction of about 44% in NTD risk. Not all analyses agree, however. Some ecological studies argue that falling NTD rates reflect socioeconomic change as well as fortification, and they question how much of the decline can be attributed to the policy. The evidence for supplementation in women who are planning pregnancy is therefore stronger than the evidence for mandatory fortification alone."
    },
    {
      "heading": "Fortification and Public Health Programs",
      "text": "Folic acid fortification of cereal grains has the most extensive outcome data in this group. Roughly 80 to 90 countries now add the vitamin to staples, although sources differ on the exact figure. Currently about 80 countries have adopted folic acid fortification. Another review puts the number at about 90 countries, with the goal to prevent NTDs during pregnancy. The best-known national example is Canada. After mandatory fortification began, the prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction. The fall was steepest for spina bifida, and the size of the drop was proportional to the prefortification baseline rate in each province. A systematic review of 27 studies found that there was a drop in the prevalence of NTD in fifteen of them in response to fortification, with Costa Rica and Chile among the largest reported reductions. The effect was not uniform: the smallest reduction in spina bifida was reported in the United States, at about 3.4%. A 2023 Oxford analysis found that the number of neural tube defects in countries with mandatory folic acid fortification were 50% lower than in countries without any policy, while countries with voluntary programs showed a smaller difference. Critics note that the observational data are confounded by trends that predate fortification, and that evidence in favor of mandatory food fortification to prevent NTDs is limited compared with supplementation trials.\n\nVitamin A programs in low-income countries rely mainly on periodic high-dose capsules given to preschool children. Vitamin A supplementation (VAS) is the mass distribution of vitamin A capsules to preschool-age children to reduce child mortality. Early evidence was strong: a 1993 meta-analysis of community-based trials found that supplementation was also protective against overall mortality in community-based studies. A 2017 Cochrane update pooled 19 trials covering about 1.2 million children and reported a 12% observed reduction in the risk of all-cause mortality for VAS compared with control. The estimate is smaller than the 24% figure from an earlier analysis, mainly because a very large trial conducted in India in 2013 found no significant effect. Program benefit also depends on coverage, which can be low; a review of Ethiopian children reported that despite national supplementation programs, coverage is low and regionally varied.\n\nVitamin D fortification follows a different logic, because there are only a few natural vitamin D-rich foods, such as fish, egg yolk, and some wild mushrooms. Policies vary considerably. In contrast, some countries, like Canada, mandate vitamin D fortification in fluid milk. In the United States, the fortification is not mandate at the federal level, but most states mandate fortification. In Europe the picture is more fragmented. Mandatory fortification is limited to a few countries and specific foods: Finland (homogenized skim milk), Sweden (low-fat milk, fermented dairy, plant-based alternatives, and fat spreads), Belgium (margarine and selected fats), and Poland (margarine and fat spreads). In most other European countries, vitamin D fortification is voluntary under EU legislation or equivalent national legislation, depending on market uptake. The effects are measurable. In Finland, a 2003 program reportedly reduced the prevalence of 25(OH)D below 50 nmol/L from 56 to 9% by 2011 in non-consumers of vitamin D-containing supplements. Where policies cover milk, milk products contributed 28–63% to vitamin D intake. Because intake depends on eating habits, a Swedish cohort found that participants of Asian and African origin exhibited a lower consumption of fortified foods and a smaller simulated change in vitamin D intake than Northern European participants after a policy expansion.\n\nBiofortification, the breeding or genetic modification of staple crops to contain more micronutrients, is an additional strategy. Provitamin A rice, commonly known as Golden Rice, was engineered to produce beta-carotene in the endosperm and has been developed since the late 1990s. Its deployment has been slowed by the need for regulatory approval in each country and by public concern about genetically modified foods, while conventionally bred crops such as orange-fleshed sweet potato have been adopted more readily. (This paragraph is not supported by the search results gathered for this section and should be checked against primary sources before publication.)"
    },
    {
      "heading": "Therapeutic Uses of Vitamins and Analogues",
      "text": "Active vitamin D analogues\n\nIn chronic kidney disease, the failing kidney can no longer make enough active vitamin D, and the resulting rise in parathyroid hormone is a major cause of secondary hyperparathyroidism. Calcitriol, the active hormone, lowers parathyroid hormone, but it tends to raise serum calcium and phosphate, which increases the risk of ectopic calcification. Paricalcitol is a vitamin D analog designed to treat SHPT without raising serum calcium and phosphorus levels. The intravenous preparation is used routinely in hemodialysis patients and has demonstrated a survival benefit over calcitriol. An oral capsule was later tested for earlier-stage disease: three randomized, placebo-controlled, phase-3 trials were conducted in patients with stages 3 and 4 CKD with SHPT.\n\nTopical analogues such as calcipotriol are applied to plaque psoriasis, where they slow the excessive proliferation of keratinocytes and promote their normal differentiation. This use relies on the same receptor-mediated mechanism as the systemic hormone, but at the skin rather than the parathyroid gland.\n\nVitamin B12 injections and oral routes\n\nPernicious anemia results from autoimmune destruction of gastric parietal cells, which makes intrinsic factor production permanently insufficient and blocks absorption of cobalamin from the gut. Management therefore requires lifelong B12 supplementation. The standard regimen is intramuscular cyanocobalamin, 1 mg weekly for four weeks and then monthly for life, to prevent recurrence of hematologic and neurological problems. Injections are also the usual route when neurological deficits are present, because they produce a faster response than oral dosing.\n\nOral therapy works through passive diffusion, which accounts for only a small fraction of intake, about 1% of total absorption, and this route is unaffected in patients with pernicious anemia. In a 2024 prospective cohort, within just 1 mo of oral supplementation, 88.5% of patients with PA were no longer deficient in vitamin B12. A randomized trial from the 1990s found that 2 mg of cyanocobalamin administered orally daily was as effective as 1 mg administered intramuscularly on a monthly basis and may be superior. Oral treatment is still debated for pernicious anemia, and some protocols reserve it for maintenance after an initial intramuscular course.\n\nVitamin K and warfarin reversal\n\nWarfarin lowers clotting by inhibiting vitamin K epoxide reductase, which prevents the recycling of vitamin K needed for the gamma-carboxylation of clotting factors II, VII, IX and X. Because this block is pharmacological, the clinical response to bleeding or an excessively high INR is to give phytonadione (vitamin K1). Oral dosing acts slowly and gives a gentler correction, while intravenous dosing is faster but carries a risk of severe hypersensitivity reactions. In life-threatening bleeding, clinicians combine vitamin K with a prothrombin complex concentrate, since the vitamin itself takes hours to restore clotting factor synthesis. The management of vitamin K antagonists therefore centres on balancing anticoagulant protection against bleeding and reversing excessive effect when it arises.\n\nHigh-dose niacin\n\nPharmacological doses of nicotinic acid, measured in grams rather than milligrams, were once a standard means of lowering LDL cholesterol and raising HDL cholesterol. Earlier trials suggested benefit: allocation to niacin 3 g daily reduced total cholesterol by about 0.7 mmol/L and was associated with a 19% reduction in non-fatal MI or coronary death. The later HPS2-THRIVE trial tested extended-release niacin combined with laropiprant, an agent added to reduce flushing, in 25,673 patients already receiving statins. The composite of major vascular events occurred in 13.2 percent of the combination group and 13.7 percent of the statin-only group, a non-significant difference with a risk ratio of 0.96. The trial also documented harms: the hazard ratio for new-onset diabetes was 1.32. Because the design tested the combination rather than niacin alone, it was not designed to assess directly the separate effects of either extended-release niacin or laropiprant. Following these results, Merck announced steps to suspend the availability of the combination in countries where it had been approved. Niacin's use as a lipid-lowering agent has since declined."
    },
    {
      "heading": "Open Questions and Ongoing Research",
      "text": "The most visible disagreement concerns the target level of serum 25-hydroxyvitamin D, the circulating marker of vitamin D status. One review of the literature places the most favourable range for bone, lower-limb function, dental health, falls, fractures and colorectal cancer at or above 75 nmol/L, with the best outcomes between 90 and 100 nmol/L. The same review argues that the intakes currently recommended for younger and older adults would not lift most people to those levels. For all endpoints, the most advantageous serum concentrations of 25(OH)D begin at 75 nmol/L (30 ng/mL), and the best are between 90 and 100 nmol/L (36–40 ng/mL). In most persons, these concentrations could not be reached with the currently recommended intakes.\n\nPart of the problem lies in how the threshold is defined. The most common criterion is the concentration at which parathyroid hormone is maximally suppressed, but estimates of optimal 25(OH)D concentrations reached by using the PTH suppression criterion vary widely, from 20 to 110 nmol/L (9–38 ng/mL), and a consensus has not been reached. Regional bodies also diverge: European experts favor 50 nmol/L and US experts favor 75 nmol/L. Some guidance sets lower bars than others; the Institute of Medicine's 20 ng/mL figure rests on bone requirements, whereas the Endocrine Society's >30 ng/mL is based on a reinterpretation of bone mineralization data. All of these concentrations are higher than the 20 ng/mL recommended by the Institute of Medicine based on its interpretation of requirements for bone health. They are in general agreement with the Endocrine Society's recommendation of >30 ng/mL.\n\nA related question is whether the evidence for benefits beyond bone is strong enough to justify higher targets. Its proponents often rely on observational, mechanistic and Mendelian randomization studies, because they regard many earlier randomized trials as poorly designed for this purpose. Critics note that those trials have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Whether a fixed dose or the resulting serum level drives any outcome therefore remains unresolved, and this is one reason the threshold debate is still open.\n\nThe gut microbiota is another unresolved area. Bacteria in the colon synthesize menaquinones, the K2 forms, but their contribution to human vitamin K status is not established. Bacteria residing in the human gut produce menaquinones, but the relevance of gut-derived menaquinones to the vitamin K function and health of the host is still speculative. The forms made in the colon differ from those in the diet. Anaerobic bacteria in the colon create longer-chain menaquinones (MK-10 to MK-13), but they are poorly absorbed and have minimal physiological impact at this level. The bacterial supply also varies between people: the concentrations of different MK forms within the intestine show considerable intraindividual and interindividual variations related to heterogeneity in the intestinal microbiome composition. The same microbial link appears in pharmacology, since VKA reactions are significantly correlated with gut microbiota, which suggests that antibiotics or dietary change could alter both vitamin K supply and anticoagulant response. The broader effects of antibiotics and diet on B-vitamin production by microbes, which are also produced de novo by various bacterial species within the gut, are still poorly quantified in humans.\n\nGenetic variation is the third line of inquiry. Several genes shape vitamin D handling, including CYP2R1 and CYP27B1, which influence Vit.D synthesis, CYP24A1, which regulates its inactivation, and the Vit.D receptor (VDR), which mediates Vit.D signaling. Because inter-individual variation in circulating 25-hydroxyVit.D (25-OH Vit.D) levels exceeds a 30-fold range, a single-gene approach may be insufficient. Gene–nutrient interactions for folate are similarly complex. In a nested case-control study within the Nurses' Health Study, the MTHFR C677T variant interacted with folate intake on squamous cell carcinoma risk, with the highest risk was observed among women with TT genotype and low folate intake. The authors cautioned that due to a large number of comparisons and tests, the possible associations should be interpreted with caution and confirmed by other studies. Such findings are not yet sufficient to define individualized dosing, and the case for personalized requirements remains largely prospective.\n\nFinally, requirements are not fixed across the life course. Cutaneous vitamin D synthesis declines with age, pregnancy raises demands for several nutrients, and chronic disease can alter absorption and metabolism. Designing studies that isolate a single vitamin's effect is difficult, because vitamin intake is closely tied to overall diet, body composition and lifestyle, and these factors can confound observational comparisons and complicate trial interpretation."
    }
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  "sources": [
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    },
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    },
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      "url": "https://pubmed.ncbi.nlm.nih.gov/9279066/"
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      "url": "https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.119.12412"
    },
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      "url": "https://www.sciencedirect.com/science/article/abs/pii/S0003986114002719"
    },
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      "url": "https://pubmed.ncbi.nlm.nih.gov/25068814/"
    },
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      "url": "https://www.sciencedirect.com/topics/medicine-and-dentistry/vitamin-k-dependent-carboxylase"
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    {
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    },
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      "url": "https://www.sciencedirect.com/topics/food-science/pyridoxal-phosphate"
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      "url": "https://med.libretexts.org/Bookshelves/Nutrition/Realities_of_Nutrition_(Morrill)/07:_The_Micronutrients/14:_Water-Soluble_Vitamins/14.09:_Biotin"
    },
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      "url": "https://en.wikipedia.org/wiki/Avidin"
    },
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      "title": "Biotin - Health Professional Fact Sheet",
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    },
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      "title": "Vitamin B12 - Health Professional Fact Sheet",
      "url": "https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/"
    },
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      "url": "https://www.sciencedirect.com/topics/nursing-and-health-professions/methylmalonyl-coenzyme-a-mutase"
    },
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      "title": "Neurological Symptoms of B12 Deficiency",
      "url": "https://omegaquant.com/neurological-symptoms-of-b12-deficiency/"
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      "url": "https://www.ncbi.nlm.nih.gov/sites/books/NBK441923/"
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      "url": "https://lpi.oregonstate.edu/mic/vitamins/vitamin-B12"
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      "url": "https://med.libretexts.org/Bookshelves/Nutrition/Intermediate_Nutrition_(Lindshield)/10:_Macronutrient_Metabolism_Micronutrients/10.08:_Biotin"
    },
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      "title": "Biotin",
      "url": "https://lpi.oregonstate.edu/mic/vitamins/biotin"
    },
    {
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    },
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    },
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    },
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      "url": "https://www.sciencedirect.com/science/article/pii/S1470211824019808"
    },
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    {
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    },
    {
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      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8838864/"
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    },
    {
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    },
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    },
    {
      "title": "*Toxoplasma gondii* disrupts vitamin B and K2 biosynthetic pathways in feline gut microbiota: microbial adaptation",
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    },
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    }
  ],
  "license": "https://creativecommons.org/licenses/by/4.0/"
}