Overview
The word "vitamin" came from the term vita mines (vital amines), which was introduced by Casimir Funk, who, in 1912, isolated a growth factor from rice polishings that contained an amine (a compound incorporating a nitrogen atom with two hydrogen atoms) and could cure the disease beriberi. Several other growth factors were identified early in the twentieth century as well, and these substances were also called vitamins even though they did not contain an amine. Vitamins are classified into two major groups: fat-soluble and water-soluble. (See the Appendix for a complete chart of vitamins.)
Fat-Soluble Vitamins
Vitamin A. In the early 1900s, Sir Frederick Hopkins demonstrated that animals would not grow if lard was provided as a sole dietary lipid. When a small quantity of milk containing fat was added to the diet, the animals thrived. The fat-soluble factor was isolated and designated as vitamin A, later called retinol or retinal; these and similar compounds are referred to as retinoids. Carotenoids, which are essentially two retinoids joined tail to tail, are inactive forms of vitamin A and are called provitamin A. They are converted to vitamin A in the intestine and liver. Vitamin A and carotenoids are absorbed in the chylomicron (a lipoprotein particle that transports lipids from the intestine) fraction and stored in the liver. Some foods such as milk are fortified with vitamin A. Rich sources of carotenoids include carrots, leafy green vegetables, and pink grapefruit.
Vitamin A is, chemically, a subgroup of retinoids, which are defined as a class of compounds that consist of a six-membered ring and a side chain with four conjugated double bonds (four isoprenoid units). The term vitamin A is used to describe retinoids exhibiting qualitatively the biologic activity of the retinoid, retinol.
Vitamin A binds to a retinol-binding protein that transports the light-sensitive vitamin to various target tissues, including the eyes, skin, and gastrointestinal track. The major functions of vitamin A include vision and regulation of cellular proliferation and differentiation. Vitamin A functions on vision by interacting with the rod and cone cells in the retina. It is responsible for absorbing light. The 11-cis form of vitamin A (retinal) combines with the protein opsin to form rhodopsin in the rod cells and iodopsins in the cone cells. The rhodopsin and iodopsins absorb light at various wavelengths and trigger a nerve impulse to the visual cortex in the brain that is ultimately perceived as black-and-white and color vision, respectively.
Vitamin A's other major physiologic function is to maintain the health of skin and mucous-secreting cells by regulating their cellular activity and maturation. The dietary requirements depend on age.
The major consequence of vitamin A deficiency, which continues to be a serious nutritional problem among millions of schoolchildren in southern and southeastern Asia and parts of Africa and South America, is night blindness. Vitamin A deficiency can lead to complete blindness and severe damage to the outer covering of the eye (the cornea), often causing it to perforate, with loss of the fluid from inside the eye (keratomalacia). Vitamin A deficiency also produces changes in the skin that are related to the inability of the skin cells to mature and produce keratin properly. This leads to follicular hyperkeratosis and phrynoderma (a condition characterized by rough, dry skin). Vitamin A deficiency has also been linked to increased mortality in early childhood.
Acute and chronic ingestion of excessive amounts of vitamin A can cause a multitude of symptoms and consequences. The most serious is that it can cause severe birth defects, spontaneous abortions and learning defects, and skin and epithelial-cell exfoliation. Inexperienced white explorers of the Arctic who ate polar-bear liver in excess developed severe vitamin A intoxication that caused a total sloughing of their skin and mucoussecreting cells in the upper airway and esophagus, bringing on painful death. (This is in contrast to the indigenous Inuit, who specifically avoid eating polar-bear liver.)
Vitamin D. One of the consequences of the industrial revolution was the high incidence of the bone-deforming disease rickets. It was estimated, at the turn of the twentieth century, that more than ninety percent of children living in the industrialized cities of northern Europe and the northeastern United States had rickets. It had been known that cod-liver oil possessed a factor that had antirachitic activity. Originally, it was thought that the antirachitic factor was vitamin A. However, Hopkins heated cod-liver oil to destroy the vitamin A activity and demonstrated that it still possessed antirachitic activity. This new fat-soluble vitamin was labeled vitamin D. It was also recognized that exposure of food, animals, and humans to ultraviolet radiation also prevented and cured rickets.
There are two principal forms of vitamin D: Vitamin D 2 comes from the precursor ergosterol found in yeast and plants, and vitamin D 3 comes from the cholesterol precursor 7-dehydrocholesterol that is found in the skin of reptiles, birds, mammals, and humans. Vitamin D 2 and vitamin D 3 are essentially equally active in most birds and in most mammals, including humans. Chickens and New World monkeys, however, cannot utilize vitamin D 2. There are very few foods that naturally contain vitamin D. Fatty fish, such as salmon and mackerel, and fish-liver oils, such as cod-liver oil are good sources of vitamin D. Cow's milk and human milk have very little vitamin D. However, in the United States and Canada, milk and some breads and cereals are fortified with vitamin D. In Europe, fortification of foods with vitamin D was outlawed when sporadic cases of vitamin D intoxication were observed in children in the 1950s. Today some margarine and cereals are fortified with vitamin D in Europe, but milk is not.
Vitamin D 3 is made by the action of sunlight on the skin. Provitamin D 3 (7-Dehydrocholesterol) absorbs solar ultraviolet B radiation (wavelengths 290–315 nm) and is transformed into previtamin D 3. Previtamin D 3 is unstable at body temperature and isomerizes (rotates its double bonds) to vitamin D 3. Once formed, vitamin D 3 leaves the skin and enters the circulation, bound to the vitamin D binding protein. It travels to the liver where it is activated to 25-hydroxyvitamin D [25(OH)D]. This form, however, is biologically inert at physiologic concentrations and is the major circulating form of vitamin D. It is, nevertheless, the form that is measured to determine the vitamin D status of an individual, because it represents a summation of dietary and skin sources of vitamin D. 25(OH)D is transported on the vitamin D binding protein to the kidney, where it undergoes its final activation on carbon 1 to form 1,25-dihydroxyvitamin D [1,25(OH) 2D], the biologically active form of vitamin D.
The principal function of vitamin D is to maintain blood calcium and phosphorus in the normal range in order to promote neuromuscular function and to maintain metabolic activities. It accomplishes this by enhancing the efficiency of intestinal calcium transport in the small intestine and by stimulating precursor cells of osteoclasts to become mature osteoclasts. Among the functions of osteoclasts is to remove calcium from bone. Serum calcium and phosphorus are in the form of Ca x(PO 4). When these compounds are in the normal range, they are in a supersaturated state that can thus be deposited in the skeletal matrix as calcium hydroxyapatite.
1,25(OH) 2D interacts with a receptor in the nucleus of cells, known as the VDR (vitamin D receptor). It also complexes with the "retinoic acid x" receptor in that cellular structure. These receptor-activated vitamin D complexes find their way to genes that have responsive elements known as the vitamin D-responsive element. These elements in turn unlock genetic information that is responsible for various biologic functions in intestine and bone. It is recognized that a wide variety of tissues including the brain, parathyroid glands, breast, pro state, stomach, and skin also have VDR. Although the exact physiologic function of 1,25(OH) 2D in these non-calcium-regulating tissues is not well understood, 1,25(OH) 2D inhibits cellular proliferation and induces terminal differentiation of a wide variety of cells, including bone, skin, skeletal muscle, breast, and prostate. The dietary requirement depends on age.
Vitamin D deficiency results in a decrease in the efficiency of intestinal calcium absorption that in turn leads to a decrease in unbound or free calcium concentrations in the circulation. This is recognized by the parathyroid gland and results in an increase in the production and secretion of parathyroid hormone (PTH). PTH enhances calcium reabsorption by the kidney and causes increased output of phosphate in the urine. PTH also stimulates the kidney to produce more 1,25(OH) 2D. The net effect of vitamin D deficiency is a low-normal serum calcium and a low serum phosphorus (due to the PTH-induced phosphate wasting in the kidney). Thus calcium and phosphorus concentrations fall below supersaturating levels, thereby resulting in poorly mineralized bone. In children, this causes rickets and, in adults, osteomalacia. In addition, vitamin D deficiency in adults can precipitate and exacerbate osteoporosis. In winter, little if any vitamin D can be made in the skin of people who live above 40° north or below 40° south of the equator. An increase in the zenith angle of the sun due to latitude, time of day, and season of the year will dramatically reduce the production of vitamin D 3 in the skin. Moreover, aging and sunscreen use can markedly reduce the production of vitamin D by more than 60 percent and 99 percent, respectively. Rickets due to vitamin D deficiency in children may include bowlegs or knock-knees, widening of the ends of the long bones, growth retardation, and muscle weakness. In adults, in addition to osteomalacia and increased risk of osteoporosis, it causes bone pain, muscle weakness, and fractures.
The safe upper limit for Vitamin D is 2,000 units a day. Although it is difficult to ingest enough to cause vitamin D intoxication, it can occur. Usually, oral ingestion of 10,000 units a day and greater will cause vitamin D intoxication. This intoxication causes an elevation in the blood levels of calcium and phosphorus, which results in the calcification of soft tissues, including the kidney and major blood vessels, and may also cause the formation of kidney stones.
Vitamin E. The discovery of vitamin E (tocopherols—from toc- meaning 'childbirth', phero- meaning 'bringing forth', and -ol representing the alcohol portion of the molecule) was due to the observation that supplementation of the diet with vitamin E prevented fetal death in animals that were fed a diet containing rancid lard. There are eight naturally occurring vitamin E compounds. Four of them are known as tocopherols and four are known as tocotrienols. The most abundant form of vitamin E is alpha-tocopherol. One of the major functions of vitamin E is to act as a biologic antioxidant to protect the sensitive cellular membranes from oxidative destruction. The major sources of vitamin E consumed by Americans are vegetables and seed oils, such as corn oil, soybean oil, and safflower oil. Wheat germ is a rich source of vitamin E. Although butter contains very little vitamin E, American margarine contains a significant amount of this antioxidant vitamin.
Vitamin E, like the other fat-soluble vitamins, is absorbed in the chylomicron fraction into the lymphatic system and is transported into the venous blood. The dietary requirements depend on age.
There have been difficulties in defining a clinical syndrome that correlates with vitamin E deficiency in humans. Vitamin E deficiency is associated with anemia in newborns.
Toxicity from excess vitamin E has been associated with increased bleeding tendency in adults and impaired immune function, decreased levels of vitamin K-dependent clotting factors, and impairment of leukocyte function.
Vitamin K. Vitamin K was discovered by Henrik Dam in Copenhagen in 1929. He observed that chicks fed a fat-free diet developed severe bleeding under the skin and in the muscle and other tissues. He named this new fatsoluble vitamin, vitamin K (for "Koagulation vitamin"). Vitamin K is distributed widely in both animal and vegetable foods as well as in milk. It comes in several forms: vitamin K 1 comes from plants and is known as phylloquinone, and vitamin K 2, first isolated from fish meal and in animal foods, comprises a group of compounds known as menaquinones. In addition, bacterial flora in the intestine synthesize menaquinones that are bioavailable.
Vitamin K, like other fat-soluble vitamins, is absorbed in the chylomicron fraction and then appears in the lymph and subsequently in the venous circulation. The major physiologic function of vitamin K is to activate blood-clotting proteins. This is accomplished by the modification of a substance, glutamate, found in several precoagulant factors, including factors II, VII, VIIII, and X, that are produced in the liver. Vitamin K is also re sponsible for the modification of other proteins, including the major noncollagenous protein in bone. The dietary requirements depend on age.
Vitamin K deficiency is rare because of the widespread distribution of the vitamin in plant and animal foods and because microbiotic flora in the normal gut synthesize menaquinones. However, vitamin K deficiency in breast-fed newborns remains a major worldwide cause of infant morbidity and mortality. Infants have very little stored vitamin K at birth, and the gut is nearly sterile during the first few days of life. As a result, infants can develop a severe bleeding condition known as hemorrhagic disease of the newborn if they do not obtain vitamin K during the first few days of life from an exogenous source, particularly since mother's milk contains little vitamin K and few bacteria other than those it picks up from maternal skin as an infant suckles. Adults who have intestinal malabsorption syndrome and who are taking antibiotics can become severely vitamin K-deficient. This can lead to generalized bleeding from all orifices.
There are no reported cases of intoxication due to excessive ingestion of phylloquinone. Ingestion of excessive amounts of menadione, a vitamin K precursor, can cause anemia secondary to the destruction of red blood cells, and an alteration in bilirubin metabolism causing hyperbilirubinemia in infants (kernicterus).
Water-Soluble Vitamins
Thiamine (vitamin B1). Beriberi is a disease with a constellation of systems affecting the nervous and cardiovascular systems. It was first described by the Chinese in 2697 B.C.E. In 1926, B. C. P. Jansen and W. F. Donath identified a factor from rice-bran extracts that prevented beriberi. The antiberiberi factor was identified chemically and called thiamine (vitamin B1). Thiamine is found in yeast, lean pork, and legumes. It serves as a receptor for high-energy pyrophosphate. It is this form of the vitamin that provides its chemical function. Pyrophosphate is extremely important for the generation of energy in the cell. However, it cannot enter the cell unless it is attached to thiamine. Thiamine is absorbed by the small intestine and transported to the liver. The major biochemical function of thiamine is to act as a coenzyme (that is, to provide a transfer site) in the alpha-keto acid carboxylation pathway. The dietary requirements depend on age.
Thiamine deficiency causes beriberi. Anorexia, neuritis, gastrointestinal dysfunction, cardiac irregularities, and muscle atrophy are present. There are three types of this disorder: wet, dry, and infantile. Wet beriberi is associated with body fluid retention (edema). Dry beriberi is related to neurologic abnormalities. It is recognized that alcoholics who have poor nutrition and thiamine deficiency, when receiving intravenous fluids, for example in the emergency room of a hospital, can develop severe altered mental states known Wernicke's and Korsakoff's syndromes. Wet beriberi is associated with heart abnormalities; dry beriberi is associated with neurological abnormalities that can cause permanent confusion if not treated in a timely manner.
Excessive ingestion of thiamine is cleared by the kidneys. There is no evidence that ingesting excessive amounts causes toxicity.
Riboflavin. In the 1920s, another water-soluble vitamin was discovered; it exhibited antipellagra activity and was termed vitamin B2. The substance was found to be yellow in color and was identified as a coenzyme, riboflavin 5'-phosphate (flavin mononucleotide or FMN).
The more abundant form of this vitamin is a complex flavin-adenine dinucleotide (FAD) that also participates as a coenzyme. Usually, the FMN and FAD are associated loosely with proteins and are released in the acidic gastrointestinal juices. The vitamin is absorbed by the proximal small intestine. Sources of riboflavin include eggs, lean meats, milk, broccoli, and enriched breads and cereals.
The physiologic function of riboflavin is to participate in oxidation-reduction reactions in numerous metabolic pathways and in energy production via the respiratory chain in the mitochondria. The dietary requirements depend on age.
Riboflavin is distributed widely in foodstuffs, and therefore deficiency is not common. However, there are reported cases of deficiency that are characterized by sore throat, hyperemia and edema of the pharyngeal and oral mucosal membranes, cheilosis (abnormal scaling and fissuring of the lips), angular stomatitis (surface inflammation of the mouth), glossitis (inflammation of the tongue), seborrheic dermatitis (an inflammation of the skin involving oversecretion by the oil-producing cutaneous glands), and anemia. Severe riboflavin deficiency can affect the conversion of vitamin B6 to its coenzyme and reduce the conversion of tryptophan, an amino acid found in proteins of animal and plant origin, to niacin (see next section). Deficiency is principally due to abnormal digestion, abnormal absorption, or both. People who are lactose-intolerant—a condition that is most common among blacks and Asians—often limit consumption of milk (as noted above, an excellent source of riboflavin); they may therefore be at increased risk for riboflavin deficiency. Intestinal malabsorption syndromes, including tropical sprue celiac disease, small bowel resection, and gastrointestinal and biliary obstruction can lead to riboflavin deficiency.
There is no evidence that toxicity can occur as a result of excessive ingestion of riboflavin. The most likely reason for this is that riboflavin is cleared rapidly by the kidney and is not stored in the body.
Niacin. In the mid-1700s, a Spanish physician, Gaspar Casal, recognized a disease known as pellagra that caused diarrhea, dementia, and dermatitis in maize-eating (corneating) populations throughout the world. In 1937, Conrad Elvehjem and his colleagues observed that nicotinic acid was an effective treatment for pellagra. Nicotinic acid is synonymous with both niacin and nicotinamide. It is associated with ribose lyphosphate to form nicotinamide adenine dinucleotide (NAD) and NAD phosphate. Most niacin in food is present as a component of NAD or NADP and is relatively stable to cooking and storage. Good sources of niacin include meats (especially liver), fish, legumes such as peanuts, some nuts, and some cereals. Both coffee and tea also contain reasonable amounts of this vitamin. Niacin is unique among the B vitamins because its precursor amino acid, tryptophan, can help meet the daily niacin requirement.
Niacin has a multitude of physiologic functions in a wide variety of metabolic pathways that are related to energy production and biosynthetic processes. At least two hundred enzymes are dependent on NAD and NADP. Both of these substances act as electron acceptors or hydrogen donors. Most NAD-dependent enzymes are involved in catabolic reactions, whereas NADP is used more commonly for reductive biosyntheses of fatty acids and steroids, for example. The dietary requirements depend on age.
Niacin deficiency causes pellagra. This condition is associated with diarrhea, dementia, and dermatitis. It is endemic in India and in parts of China and Africa. The classic appearance of pellagra is a pigmented rash that develops symmetrically in areas of the skin exposed to sunlight. The tongue can become bright red and there is often vomiting and diarrhea. Patients can also exhibit anxiety or sleeplessness, and can become disoriented and delusional.
Nicotinic acid is now used to treat hypercholesterolemia. Side effects of large amounts of nicotinic acid include flushing of the skin, abnormalities in liver function, and hyperglycemia. At extremely high ingestion levels, nicotinamide causes death in rats.
Pyridoxine (vitamin B6 ). Vitamin B6 was identified in the 1930s. Like many of the water-soluble B vitamins, vitamin B6 includes a group of compounds that act as a coenzyme phosphate donor. These include pyridoxal 5>-phosphate (PLP), and pyridoxamine 5>-phosphate (PMP). Plants foods contain predominantly pyridoxine, whereas animal products contain primarily pyridoxal and pyridoxamine. Vitamin B6 is absorbed mainly by the lower small intestine (jejunum).
Like many of the other coenzyme B vitamins, vitamin B6 has numerous biologic functions that are related to metabolism. B6 is critically important for the production of glucose. PLP is also necessary for the conversion of tryptophan to niacin, which is why the two are often associated. The dietary requirements depend on age.
As with many of the other B vitamins, there are a wide variety of clinical symptoms associated with vitamin B6 deficiency including an abnormal electroencephalogram, convulsions, stomatitis, cheilosis, glossitis, irritability, depression, and confusion.
High doses of pyridoxine have been used to treat premenstrual syndrome and other neurological diseases. Such uses have resulted in neurotoxicity and photosensitivity.
Pantothenic acid. Pantothenic acid was one of the more difficult vitamins to isolate and separate from the other water-soluble B vitamins. Finally in the 1940s, it was synthesized and was found to be associated with coenzyme A (CoA). CoA is an essential cofactor for biologic acetylation reactions and participates in the respiratory tricarboxcylic acid cycle, fatty-acid synthesis and degradation, and a wide variety of other metabolic and regulatory processes. The dietary requirements depend on age.
Pantothenic acid deficiency affects the adrenal gland, nervous system, skin, and hair adversely. Pantothenic acid deficiency in humans is rare, but has been associated with fatigue and depression.
High doses of calcium pantothenate have not been found to be toxic in humans.
Folic acid and cobalamin (vitamin B12 ). In the mid-1800s, several physicians recognized that a severe form of anemia was associated with disorders of the digestive system. In 1934, William Castle and his associates observed that normal human gastric juice contained an intrinsic factor (IF) that combines with an extrinsic factor in animalprotein food, resulting in the absorption of a vitamin that prevents anemia. Vitamin B12 was isolated in 1948 and was shown to be the extrinsic antianemia factor.
Vitamin B12 absorption is unique among the B vitamins, in requiring an IF to help its absorption. Folate, on the other hand, is absorbed directly by the upper (proximal) small intestine.
Whereas vitamin B12 is found only in animal protein, folates are common in nature and present in nearly all natural foods. The dietary requirements depend on age.
Vitamin B12 deficiency can occur either because of inadequate vitamin B12 ingestion or because of the loss or inadequacy of production of intrinsic factor in the stomach. The two most notable clinical signs of vitamin B12 deficiency include megaloblastic anemia and neurological deficits. Vitamin B12 deficiency can cause paresthesia (especially numbness and tingling in the hands and feet); the diminution of vibration and position sense; unsteadiness; poor muscular coordination with ataxia (loss of muscular coordination); moodiness; mental slowness; poor memory; confusion; agitation; depression; and central visual loss. Delusions, overt psychosis, and paranoid ideas may occur in severe deficiency.
Folate deficiency also causes megaloblastic anemia and can cause neurological abnormalities as well, including irritability, forgetfulness, and hostile and paranoid behavior. For adults, ingestion of ten thousand times the minimum requirement for B12 and several hundred times that for folic acid has not been associated with toxicity.
Biotin. Biotin was identified in the 1940s. It, like many of the other B vitamins, acts as a coenzyme. Biotin is plentiful in foods such as liver, egg yolk, soybeans, yeast, cereals, legumes, and nuts. With the exception of cauliflower and mushrooms, vegetables, fruits, and meats, however, are poor sources of biotin. Biotin is also present in human and cow's milk. The major physiologic functions of biotin are related to carbohydrate and lipid metabolism. The dietary requirements depend on age.
Biotin deficiency causes mental-status changes, myalgia (muscle pain), hyperesthesia (abnormal sensitivity to pain, touch, cold, etc.), localized paresthesia, and anorexia with nausea. Dermatitis can also be associated with deficiency. The immune system is impaired in biotin-deficient animals. Neurological disorders including seizures and developmental delays have been reported in children. There have been no reports of intoxication due to excessive biotin ingestion.
Vitamin C. Scurvy is recognized as a deficiency disease that has taken a high toll in human suffering and death. The disease, which is caused by vitamin C deficiency, was recognized in ancient times by the Egyptians, Greeks, and Romans. It was especially prevalent among sea explorers of the sixteenth to eighteenth centuries. Typically, sailors developed bleeding and rotting gums, swollen and inflamed joints, dark blotches on the skin, and muscle weakness that occurred within months when at sea. It was the loss of 1,051 sailors in 1774 that prompted the British Admiralty to seek a cure for this devastating disease. They found that lemon or lime juice could prevent the disease. In the late 1920s, Albert Szent-Györgyi and Glenn King isolated vitamin C and identified it as hexuronic acid. Vitamin C is water-soluble and is absorbed efficiently by the small intestine. Its major physiologic function is to provide reducing activity for a wide variety of metabolic steps. It is important for the modification of lysine and proline—two amino acids that are common components of collagen. These modifications result in the cross-linking of collagen strands providing structural support for this essential component of bone and fibrous tissues. The dietary requirements depend on age.
As noted, vitamin C deficiency causes scurvy, which is associated with a wide variety of abnormalities, including hemorrhages under the skin, black-and-blue marks, hyperkeratosis, joint discomfort, edema, weakness, fatigue, lassitude, depression, and hysteria.
It was suggested by the Nobel Prize Laureate Linus Pauling that extremely high doses of vitamin C could prevent cancer. With the exception of excessive amounts of vitamin C causing bowel impaction via a large number of vitamin C tablets ingested, there are very few serious consequences from an overingestion of vitamin C, though it can increase the risk of kidney stones and other renal diseases.
Other nutrients. Other nutrients that are essential could be considered vitamins. These include choline, carnitine, inositol, and taurine.
Bibliography
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Institute of Medicine. "Vitamin D." In Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride, pp. 250–287. Washington, D.C.: National Academy Press, 1997.
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—Michael Holick