Book: Nutrition: A Very Short Introduction (Very Short Introductions)

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In addition to sources of energy and protein, there is a need for two further groups of nutrients in the diet, in relatively small amounts: mineral salts and vitamins. Together these are known as micronutrients, because they are required in small amounts.

The vitamins were discovered at the beginning of the 20th century as a group of organic compounds (and hence distinct from essential minerals) that are required in the diet in small amounts (milligrams or micrograms per day), and so distinct from the essential amino acids that are required in gram amounts. They are essential for maintenance of normal health, growth, and metabolic integrity. Deficiency leads to more or less specific clinical signs and symptoms and metabolic disturbances, and replacing the vitamin in the diet will prevent or cure the deficiency disease. Vitamins cannot be made in the body and must be provided in the diet. There are two exceptions here. Vitamin D can be synthesized in the skin if there is adequate sunlight exposure, and niacin can be synthesized from the essential amino acid tryptophan. However, deficiencies of both do occur.

There is another group of compounds found mainly in plants that are not dietary essentials, but may be beneficial. Collectively these are known as phytonutrients. They have a number of different potentially protective actions against cancer and cardiovascular disease.

Essential minerals

Two minerals, iron and calcium, are required in relatively large amounts. The remainder of minerals are required in small amounts and are sometimes called trace elements; some (ultra-trace elements) are required in very small amounts. Deficiency of the ultra-trace minerals is unlikely, but deficiency of other minerals does occur, especially where locally grown foods provide the main intake and the soil is deficient in a mineral. Deficiencies of iron and iodine are major problems of public health worldwide, and iron and iodine, together with vitamin A, are key micronutrient targets of the World Health Organization.

shows the essential minerals classified by their functions in the body. Some minerals appear more than once—for example, calcium is important in the structure of bone, but also has an important role in responses to hormones.

Iron. The greatest need for iron in the body is for synthesis of the protein haemoglobin, which transports oxygen in red blood cells. It is also required for the oxygen transport protein myoglobin in muscle, and in a large number of enzymes. Iron deficiency is seen as anaemia—small, underpigmented red blood cells with a reduced capacity to transport oxygen. This leads to easy fatigue and breathlessness during exercise. It is especially a problem of women of child-bearing age, since losses of iron through menstrual blood loss are frequently greater than can be replaced from the diet. Worldwide, more than two billion people are iron deficient.

There are two sources of iron in the diet: haem from myoglobin in meat, and inorganic iron salts, mainly from plant foods. Iron absorption from the diet is poor, especially for inorganic iron salts; the absorption of iron from haem is higher. However, the absorption of both is controlled, largely in response to the body’s need for iron. There is no mechanism for excretion of excess iron that has been absorbed, and people with genetic defects in the regulation of iron absorption suffer from haemochromatosis—iron overload. This is characterized by bronze colouration of the skin, depletion of vitamin C, and damage to various tissues, including the pancreas, leading to the development of diabetes, as well as inflammation of joints and heart disease. Up to 10 per cent of the population is genetically at risk of iron overload if intake of iron is too high.

Table 6. Minerals classified by their functions in the body

Functions

Mineral name

Structural function

calcium, magnesium, phosphate

Involved in membrane function Function as prosthetic groups in enzymes

sodium, potassium cobalt, copper, iron, molybdenum, selenium, zinc

Have a regulatory role or a role in hormone action

calcium, chromium, iodine, magnesium, manganese, sodium, potassium

Known to be essential, but whose function is unknown

silicon, vanadium, nickel, tin

Have effects in the body but are not considered to be essential

fluoride, lithium

May occur in foods, have no known function in the body and are known to be toxic in excess

aluminium, arsenic, antimony, boron, bromine, cadmium, caesium, germanium, lead, mercury, silver, strontium

Inorganic iron in the diet must be chemically reduced before it can be absorbed into the cells of the small intestine, and it has been known for many years that when iron supplements are given for treatment of anaemia, they should be accompanied by vitamin C as a reducing agent, or taken with orange juice as a source of vitamin C, to improve absorption. Alcohol and meat protein also increase the absorption of inorganic iron. A number of dietary factors decrease the absorption of inorganic iron, including calcium, dietary fibre, tannins, and egg and soya proteins.

Once inside the intestinal cell, whether it is absorbed as inorganic iron or released from haem, iron is bound to a storage protein, ferritin. It is then transported into the bloodstream only if there is free transferrin available, without iron bound. Transferrin is the protein that transports iron to tissues that require it. If all the transferrin in the blood has iron bound (indicating that body iron reserves are adequate), iron cannot be transported out of the mucosal cells, and is lost in the faeces when the cells are shed. There is a further control over iron absorption. Transport from the intestinal cell onto transferrin requires the protein ferroportin, and ferroportin synthesis is regulated by a protein, hepcidin, which is synthesized in the liver in response to the state of body iron reserves.

Calcium. The body contains about 1kg of calcium, of which 99 per cent is in bones and teeth. There is thus obviously a need for an adequate intake of calcium for bone formation. Milk and dairy products are the main source of calcium in the diet, but cereals, fruits, and vegetables provide significant amounts. Calcium also has a role in regulating the activity of muscle, and in response to the actions of many hormones. The plasma concentration of calcium is tightly regulated. An excessively high plasma concentration of calcium can lead to calcification and hardening of soft tissues, including blood vessels. If the plasma concentration of calcium falls too low, neuro-muscular coordination is lost, leading to tetany and convulsions.

The absorption of calcium from the gut requires vitamin D, and in vitamin D deficiency there is not enough calcium available for normal formation of bone mineral. In children this leads to the disease of rickets, when bone that is formed as the child grows is soft and the long bones of the body bend. As they gradually become mineralized, so the bone remains deformed. The adult equivalent of rickets is osteomalacia. There is normal turnover of bone, with mobilization of mineral and erosion of bone proteins, followed by replacement bone synthesis. In calcium deficiency due to a lack of vitamin D there is insufficient calcium available to permit mineralization of this newly formed bone.

A normal consequence of ageing is loss of bone matrix proteins and calcium, leading to fragile, porous bones—the condition of osteoporosis. Osteoporotic bones fracture readily, in response to mild trauma, and when the condition affects the vertebrae there is serious curvature of the spine—so-called dowager’s hump. Oestrogens and androgens stimulate the formation of new bone. Osteoporosis affects women more than men, because the loss of oestrogens at the menopause is abrupt while the loss of testosterone occurs more gradually, as men age.

There is some evidence that supplements of calcium and vitamin D in later life slow the progression of osteoporosis. However, the major factor affecting the rate of development of clinically significant osteoporosis is the peak density of the bones in early middle age. The denser the bones are to start with, the longer it will take for there to be enough bone loss to cause problems. This means that it is important to have an adequate intake of calcium (and vitamin D) from childhood through adolescence into middle age.

Iodine. Iodine is required for synthesis of the thyroid hormones, which control metabolic rate and the coordination of growth and development. In response to iodine deficiency, the thyroid gland in the neck enlarges in an attempt to synthesize enough of the hormones. In severe deficiency the enlarged gland may be as large as a football. This condition is iodine deficiency goitre. The thin, free-draining soils in inland upland areas over limestone are deficient in iodine. In many regions of the world, including the Himalayas, the Matto Grosso of Brazil, and large areas of central Africa, the prevalence of iodine deficiency goitre was nearly 100 per cent before the introduction of preventative programmes. It was formerly a common problem in the Alps and in Derbyshire—indeed, at one time goitre was called ‘Derbyshire neck’. Fish and other sea-foods are rich sources of iodine.

The iodine deficient goitrous patient has a low metabolic rate, gains weight, and has a dull mental apathy. Children born to iodine deficient mothers are very seriously affected, with deafness and severe mental impairment—the condition of goitrous cretinism.

In developed countries and urban areas of developing countries, the problem is prevented by provision of iodized salt, or the mandatory use of iodized salt for bread making. In less developed areas where this is not possible, medical teams give injections of iodized oil. An undesirable side-effect of improving iodine status in areas of deficiency is that adults whose thyroid glands have enlarged as a result of deficiency now become transiently hyperthyroid, as the enlarged gland synthesizes excessive amounts of thyroid hormones when iodine becomes available. However, this is considered to be an acceptable trade-off for preventing the severe effects of iodine deficiency in unborn and young children.

If iodine status is adequate, there is no evidence that any additional intake will cause hyperthyroidism unless the gland is enlarged as a result of previous deficiency. There is certainly no evidence that additional iodine will increase metabolic rate and aid weight loss.

Selenium. Selenium is required for synthesis of the amino acid selenocysteine, which is important in a number of enzymes, including glutathione peroxidase, which forms part of the antioxidant defences of the body, and the deiodinase enzyme that activates the thyroid hormone. Rich sources of selenium include Brazil nuts, fish and sea-foods, and organ meat (especially kidneys). Selenium deficiency is a problem in several areas of the world where the selenium content of the soil is low, including New Zealand, Finland, and large regions of China. Equally, there are regions of the world where the selenium content of the soil is so high that cattle cannot safely be grazed, and locally grown crops may contain undesirably high levels of selenium. There is concern in the UK that levels of selenium intake have fallen over the past quarter century, to the extent that average intakes are below requirements. This is largely because wheat that was formerly imported from Australia and North America (where soil selenium levels are relatively high) has been replaced by wheat grown in Europe (where soil selenium levels are relatively low).

There is a need to exercise caution with selenium supplements. A desirable level of intake is 55 μg/day, and once the activities of the various selenium-containing enzymes have been optimized, higher levels of intake have no additional effect. However, at intakes above about 400 μg/day, signs of selenium toxicity develop. In addition to loss of hair and nails, selenium poisoning leads to the excretion in the breath and from the skin of foul smelling selenium compounds. People taking inappropriately high selenium supplements are not pleasant companions.

Sodium and potassium. Sodium and potassium ions are important in generating electrical impulses in the nervous system, and both are dietary essentials. Except where salt losses in sweat are excessive, as may occur in the tropics, or during vigorous exercise, sodium deficiency is not a problem. Indeed, the main concern is that average intakes of sodium (mainly in table salt added to foods) are excessively high, and high intakes of sodium are associated with increased blood pressure and increased risk of stroke. While both sodium and potassium are found in most foods, fruits and vegetables are good sources of potassium with little sodium.

Vitamins

Eleven compounds are considered to be vitamins. Four (vitamins A, D, E, and K) are fat-soluble; the remainder are water-soluble and act mainly as coenzymes in various metabolic reactions. In addition, there are a small number of compounds that have clear metabolic functions in the body, but are not considered to be vitamins since they can be made in the body in adequate amounts. Such compounds include carnitine, choline, inositol, taurine, and ubiquinone (which is sometimes misleadingly sold as vitamin Q).

Vitamin A. Vitamin A has two very different functions in the body. It provides the visual pigment in the eye that is sensitive to light and leads to the initiation of a nerve impulse to the visual centres of the brain. It also acts like a hormone, binding to intracellular receptors, regulating the expression of genes, and controlling tissue differentiation during development. Vitamin A receptors with the vitamin bound are also essential for the actions of vitamin D and thyroid hormone.

There are two sources of vitamin A in the diet: preformed vitamin A in meat, and carotenes in red, yellow, and orange fruits and vegetables, as well as green leafy vegetables, which can be converted to vitamin A in the body. The name carotene comes from the fact that β-carotene was first isolated from carrots.

Vitamin A deficiency is the largest preventable cause of blindness worldwide. Deficiency is a major problem of public health, with 14 million children deficient and more than 190 million people at risk of deficiency.

Taken in excess, however, vitamin A is toxic. While there is a 12-fold difference between desirable levels of intake and the toxic threshold in adults, for children there is only a 3.5-fold difference. For pregnant women the difference is less than 5-fold; excess vitamin A causes fetal abnormalities, and pregnant women are advised not to eat liver and liver products, which are especially rich sources of the vitamin.

Vitamin D. Vitamin D is essential for the absorption of calcium from the diet, and hence for the maintenance of normal calcium metabolism and bone formation. As we have seen, deficiency leads to rickets in children and osteomalacia in adults. Rickets was a major problem of public health in many Northern countries until the introduction of vitamin D enrichment of infant foods in the 1940s. The vitamin is toxic in excess, and a small number of infants developed signs of vitamin D poisoning. As a result, the level of food enrichment was reduced, and up to 10 per cent of young children now show sub-clinical signs of deficiency.

Like vitamin A, vitamin D acts as a hormone, controlling gene expression. There is increasing evidence that in addition to its functions in calcium absorption and metabolism, it is important in regulating the expression of a large number of genes, and higher intakes of vitamin D than are considered to be adequate for bone health may provide protection against some cancers, type II diabetes, and possibly also obesity.

Apart from fortified foods, there are few dietary sources of vitamin D: oily fish (such as herring, salmon, and trout), eggs, and full-fat dairy produce (butter, cream, and cheese). The vitamin can also be synthesized in the skin when there is adequate sunlight exposure. In Northern countries, this is possible only in summertime, and there is considerable seasonal variation in the blood concentration of vitamin D. By the end of winter, the average blood concentration is only slightly higher than that seen in marginal deficiency.

While increased sunlight exposure provides a way of increasing vitamin D status without the problems of toxicity that might be seen if there was widespread excessive enrichment of foods, it also increases the risk of developing skin cancer. Because of the paucity of dietary sources, and the risks of excessive sunlight exposure, it is accepted that supplements are required for pregnant and lactating women, and people over the age of 65, to meet the recommended intake of 10 μg/day. There is evidence that higher intakes, 10–20 μg/day, have health benefits for all adults.

Vitamin E. Vitamin E functions as an antioxidant in cell membranes and plasma lipoproteins. Requirements vary depending on the intake of polyunsaturated fats, but dietary deficiency is extremely rare, since most oils that are rich sources of polyunsaturates are also rich sources of vitamin E. The antioxidant actions of vitamins E and C are related; oxidized vitamin E in cell membranes and plasma lipoproteins is reduced back to the active vitamin by reacting with vitamin C in the blood plasma and cytosol of the cell. Oxidized vitamin C can be reduced back to the active vitamin enzymically.

There is a considerable body of epidemiological evidence that high vitamin E status is associated with a lower risk of atherosclerosis and coronary heart disease. However, intervention trials have shown increased mortality among people taking high-dose supplements of vitamin E.

Vitamin K. Vitamin K is required for the synthesis of blood clotting proteins and proteins involved in the mineralization of bone. Dietary deficiency is rare, because vitamin K is present in plant oils and green leafy vegetables. Intestinal bacteria synthesize it, although it is not clear how much of this bacterial vitamin K is absorbed.

Deficiency of vitamin K leads to impaired blood clotting, and prolonged bleeding. The widely used anticoagulant drugs used to treat people at risk of blood clots, such as Warfarin, act as antagonists of vitamin K. The vitamin also acts to antagonize the actions of the anticoagulant drugs, and problems may arise when people taking anticoagulants either start to take vitamin K supplements, or stop taking them when their dose of anticoagulant has been increased to overcome the effect of high intakes of the vitamin.

Vitamin B1. Vitamin B1 (thiamin) acts as a coenzyme in a number of key reactions in carbohydrate and general energy-yielding metabolism, as well as having a role in nerve transmission. Deficiency of thiamin, leading to the disease of beriberi, was formerly common in the Far East after the introduction of steam-powered rice mills and the widespread use of polished rice—the vitamin is in the bran that is discarded when rice is milled. Potatoes, cereals, and meat are rich sources of thiamin; pork is an especially rich source.

Nowadays, deficiency occurs mainly in alcoholics with a poor food intake, because alcohol inhibits the absorption of the vitamin. In this case, deficiency causes brain damage, leading to the Wernicke-Korsakoff syndrome—loss of recent memory (although distant memory may be unimpaired) and neurological signs. Deficiency also occurs when people who have been starved for a period of time are given intravenous glucose without added thiamin. In this case (and sometimes in alcoholics) there are disturbances of carbohydrate metabolism leading to potentially life-threatening acidosis.

Vitamin B2. Vitamin B2 (riboflavin) acts as a coenzyme in a number of energy-yielding metabolic pathways. Deficiency is relatively common in some countries, but is rarely fatal. This is because as the intake of riboflavin falls, so the vitamin that is released when enzymes turn over is very efficiently salvaged and re-used.

Milk and dairy produce are important sources of riboflavin (as well as of calcium and protein), and riboflavin status reflects dairy consumption in many countries.

Niacin. Two compounds have the activity of the vitamin niacin: nicotinic acid and nicotinamide. They are interconvertible in the body, and the function of niacin is to provide the coenzyme nicotinamide adenine dinucleotide (NAD), which is involved in a very large number of oxidation and reduction reactions in the body. Meat, eggs, and fish provide significant amounts of preformed niacin, as does coffee; cereals are a poor source.

In addition to using the vitamin, NAD can be synthesized in the body from the essential amino acid tryptophan, and under normal conditions this probably meets requirements for niacin without the need for a dietary source of the preformed vitamin. Most foods, apart from maize and sorghum, contain significant amounts of tryptophan, and if protein needs are met, then so is the need for niacin.

Pellagra, the niacin deficiency disease, was a major public health problem in the southern USA until the middle of the 20th century, and in other areas of the world (especially Southern Africa) where maize provided the dietary staple, with little meat or other sources of tryptophan. The proteins of maize contain very little tryptophan, and, as in other cereals, most of the niacin in maize is chemically bound to carbohydrates and is not available for absorption. Pellagra was never a problem in Mexico, the original home of maize, because of the traditional method of preparing the grain. It was not ground into flour, but was soaked in (alkaline) lime water. This treatment liberates niacin from the otherwise unavailable complexes with carbohydrates.

Vitamin B6. Vitamin B6 is required for the action of a large number of enzymes involved in the metabolism of amino acids and in mobilization of the storage carbohydrate glycogen in liver and muscles. It has a separate function in regulating the activity of steroid hormones. Meat, fish, and legumes are good sources of vitamin B6.

Deficiency of this vitamin leads to abnormalities of amino acid metabolism, and a number of studies suggest that although clinical deficiency disease is uncommon, marginal deficiency may occur in 10 per cent of the population in developed countries.

Studies in the 1960s suggested that high-dose oral contraceptive drugs led to vitamin B6 deficiency. However, this was an artefact, and was in fact the result of oestrogen metabolites inhibiting an enzyme in tryptophan metabolism, leading to biochemical changes that falsely suggested B6 deficiency. There are no such problems with modern low-dose oral contraceptives.

Some studies have suggested that relatively high doses of vitamin B6 (50 to 100 mg/day) relieve the symptoms of premenstrual syndrome. There is little evidence of efficacy from controlled trials, but the vitamin is still prescribed and self-prescribed for premenstrual syndrome. There is some evidence that doses between 25 to 100 mg/day may lead to nerve damage; certainly this occurs with intakes above 200 g/day.

Folic acid (folate). Folic acid acts in a variety of reactions involving the transfer of one-carbon units from one compound onto another, including DNA synthesis and vitamin B12 metabolism. Deficiency is relatively common, leading to megaloblastic anaemia—the release into the bloodstream of immature red blood cell precursors. Legumes, fruits and vegetables, meat, and fish are all good sources of folate.

Supplements of folic acid of the order of 400 μg/day (in addition to the normal dietary intake) reduce the incidence of spina bifida and neural tube defect very considerably. The neural tube closes, and therefore the damage is done, before day 21 of pregnancy, which is before a woman knows she is pregnant. Therefore, in the UK and many other countries, women who are planning pregnancy are advised to start taking folic acid supplements before conception. The problem is, of course, that many pregnancies are unplanned. A number of countries (including the USA and Canada) have therefore introduced mandatory fortification of flour with folic acid, and this has led to a significant decrease in the number of infants born with neural tube defects.

A relatively common genetic abnormality, affecting 10 per cent of the population, leads to a high blood concentration of the metabolic intermediate homocysteine, which is a factor in the development of atherosclerosis. The abnormal gene occurs in 17 per cent of people with atherosclerosis, but only 5 per cent of those without. High intakes of folic acid overcome the gene abnormality, and lead to reduction in the blood concentration of homocysteine. There is also some evidence that poor folic acid status is a factor in colorectal cancer.

There are a number of potential problems with widespread enrichment of foods with folic acid, which explain why many countries have not introduced mandatory enrichment of flour. As people age, their secretion of gastric acid decreases, and they are unable to release vitamin B12 from proteins in foods, leading to possible deficiency. Like folic acid deficiency, vitamin B12 deficiency causes megaloblastic anaemia, but it also causes irreversible nerve damage. A high intake of folic acid prevents the development of the anaemia, and elderly people with vitamin B12 deficiency will first present with the irreversible nerve damage rather than the reversible anaemia. High blood concentrations of folic acid also antagonize the actions of some of the anticonvulsant drugs used to treat epilepsy. Although poor folic acid status is associated with increased incidence of colorectal cancer, there is some evidence that high intakes of the vitamin by people who have benign precancerous polyps may accelerate the transition to cancer.

If the enrichment of flour with folic acid is to be made mandatory, there needs to be a careful balancing act between providing intakes that will have a significant effect on reducing the incidence of neural tube defects and intakes that will put the elderly at risk. The UK Food Standards Agency has advised that if mandatory enrichment were to be introduced, all voluntary enrichment of other foods would have to cease.

Vitamin B12. Vitamin B12 is required for only two metabolic reactions, the most important of which is the folic acid dependent conversion of homocysteine to the amino acid methionine. As noted above, deficiency leads to megaloblastic anaemia, which is the result of trapping folic acid as a derivative that cannot be used without vitamin B12, and irreversible nerve damage, which is the result of a deficiency of methionine in the nervous system. Because of this nerve damage, the condition is known as pernicious anaemia.

There are no plant sources of vitamin B12, and strict vegetarians (Vegans) are at risk of dietary deficiency unless they take supplements made by bacterial fermentation (which are ethically acceptable to them). The richest sources are meat and fish, but eggs and milk provide significant amounts. From time to time there are suggestions that algae and fermented soya products contain vitamin B12, but this is misleading. The legally required method of measuring vitamin B12 is by its ability to act as a growth factor for a specific strain of bacteria, but this also measures analogues of the vitamin that are growth factors for the bacteria, but do not have vitamin activity in human beings.

The absorption of vitamin B12 from foods requires the action of gastric acid to release the vitamin from proteins it is bound to. The vitamin then binds to a small protein (intrinsic factor) that is secreted in the stomach, and the intrinsic factor–vitamin complex is then absorbed in the small intestine. Failure of gastric acid and intrinsic factor secretion (achlorhydria), or the production of auto-immune antibodies against either intrinsic factor or the cells in the stomach that secrete it, leads to failure to absorb the vitamin, and the development of pernicious anaemia. It is treated by injection of the vitamin, or, in cases where the problem is failure to secrete intrinsic factor, oral doses of intrinsic factor. The reduction in gastric acid secretion without loss of intrinsic factor secretion that is seen with increasing age impairs the absorption of dietary vitamin B12 bound to proteins, but not the absorption of crystalline vitamin B12 from supplements.

Biotin. Biotin acts in a small number of metabolic reactions, and also has a role in controlling cell division and proliferation. The vitamin is widespread in foods, and deficiency has only been reported in a small number of people who consumed abnormally large amounts of uncooked egg white (typically a dozen or more raw eggs a day for several years). The protein avidin in egg white binds biotin so that it is not available for absorption. However, when the egg is cooked, avidin is denatured and can no longer bind biotin.

Pantothenic acid. Pantothenic acid (sometimes called vitamin B5) acts as the coenzyme for synthesis and metabolism of fatty acids, and a number of other reactions. The vitamin is widely distributed in foods and deficiency is unknown except in specific depletion studies.

Experimental studies of animals that are deprived of pantothenic acid have found that they lose their fur pigmentation, and so the vitamin was at one time known as the ‘anti-grey hair factor’. There is no evidence that supplements of pantothenic acid prevent the normal greying of hair with ageing, and there is certainly no evidence that adding it to shampoo has any beneficial effect.

Prisoners of war in the Far East in the Second World War developed a painful condition known as the burning foot syndrome, which was tentatively attributed to pantothenic acid deficiency. However, for obvious reasons, they were not subject to experiments in order to determine if pantothenic acid was the problem. Levels were replenished with yeast extract, this being a rich source of all B vitamins.

Vitamin C. Vitamin C acts as a water-soluble antioxidant, both in its own right and by reducing oxidized vitamin E back to the active vitamin. It also acts in a small number of enzymes, including those involved in the synthesis of the connective tissue proteins collagen and elastin and the neurotransmitters and hormones noradrenaline and adrenaline. The main sources are fruits and vegetables.

Deficiency leads to the disease scurvy, which is characterized by poor healing of wounds, loosening of the teeth and inflammation of the gums, small haemorrhages under the skin, and intense bone pain. All of these can be attributed to impaired synthesis of connective tissue proteins. In addition there are psychological changes (‘scurvy’ means ‘ill-tempered’), which can be attributed to impaired synthesis of noradrenaline and adrenaline.

Vitamin C is generally considered to have very low toxicity, and relatively large doses (up to several grams per day) can be tolerated, although very large doses may cause gastro-intestinal upset due to bacterial fermentation of unabsorbed vitamin. At intakes over about 100 mg/day, the vitamin is excreted in the urine. It is an acid, and acidifies the urine. This may have the beneficial effect of increasing the solubility of phosphates in the urine, and so reducing the formation of phosphate kidney stones. However, cysteine, oxalic acid, uric acid, and xanthine are less soluble in acidic urine, and high doses of vitamin C will increase the formation of kidney stones containing these compounds.

Phytochemicals and nutraceuticals

A wide variety of compounds in fruits and vegetables may have beneficial effects in the body, although they are not considered to be dietary essentials, and therefore are not classified as vitamins. Collectively they are known as phytochemicals or nutraceuticals.

The carotenes (the pigments of yellow, orange, and red fruits and vegetables), the anthocyanins (the pigments of red, purple, and blue fruits and vegetables) and the polyphenols or bioflavonoids, found in a wide variety of fruits and vegetables, and also in tea and red wine, are all potential antioxidants, and may have other beneficial effects.

Glucosinolates, glycosides, and sulphur-containing compounds from a variety of foods, especially brassicas (cabbages, cauliflower, sprouts, broccoli, etc.) modify the synthesis and activity of enzymes that metabolize a variety of foreign compounds. Many of these foreign compounds in foods are potential carcinogens, and increasing the activity of the enzymes that metabolize them may reduce the risk of cancer. These compounds are also capable of modifying the metabolism of prescription medication, and reducing its efficacy. The only potentially serious such interaction is with compounds found in grapefruit, and many prescription medicines carry a warning not to consume grapefruit or grapefruit juice while taking the medicine.

Terpenes in citrus oil, ginger, and other spices inhibit the synthesis of cholesterol, and may be useful in the treatment of elevated blood cholesterol. Squalene is an intermediate in cholesterol synthesis. It occurs in relatively large amounts in olive oil, and again acts to inhibit the synthesis of cholesterol. While this may be beneficial, it is also possible that it will be metabolized onwards to cholesterol, so negating some of the potential benefit.

A number of compounds in soya beans have anti-oestrogenic activity, and may be beneficial in prevention of hormone-dependent cancer of the breast, uterus, and prostate. They act by binding to the oestrogen receptor in competition with oestrogens, but they only activate the receptor weakly. Some studies show that habitual consumption of soya products reduces the risk of breast cancer, but others have shown no significant effect.

How much is enough—and can we have too much?

Estimating requirements for vitamins and establishing desirable levels of intake depends on experiments in which volunteers are maintained on a diet that is otherwise adequate, but lacking the vitamin under study, until there is a detectable metabolic abnormality that is a sign of early vitamin deficiency. Levels are then replenished by gradually increasing doses of the deficient vitamin until the metabolic abnormality is just normalized.

Figure 4 shows the results of such an experiment. There is a range of individual requirements around the average, and in most cases there is a statistically normal distribution. This means that a range of ± 2 x standard deviation around the average will include 95 per cent of the population. An intake of average requirement +2 x standard deviations will therefore be greater than the requirement of 97.5 per cent of the population. This is selected as a reference intake to be used in food labelling, in planning meals for institutions, and in assessing the adequacy or otherwise of populations. The reference intake is greater than the requirements of 97.5 per cent of the population, so if an individual has an intake below the reference intake, this does not mean that he or she is deficient.

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4. The derivation of reference intakes for nutrients

This reference intake is known by a variety of names in different countries:

RDA—recommended daily (or dietary) amount (or allowance);

RNI—reference nutrient intake;

PRI—population reference intake;

DV—daily value (used in USA for food labelling, based on a notional 2,000 kcal diet).

The term ‘reference nutrient intake’ (RNI) was coined in the 1991 report on nutrient requirements of the UK Department of Health, by parallel with clinical chemistry, where this 95 per cent range around the average value of a metabolite is known as the ‘reference range’ for a given group of the population. It was considered inappropriate to call this a ‘recommendation’, since the intake figures do not apply to an individual, or to call it ‘an allowance’. A further reason for this choice of terminology is that this is the amount per day on average, and not a precise daily amount. The 1993 report of the EU Scientific Committee on Food coined the term ‘population reference intake’ to emphasize that the figures refer to populations, not to individuals. However, the term ‘recommended daily (or dietary) amount (or allowance)’ (RDA) is still used in food labelling in the EU.

Tables of reference intakes published by different national and international authorities include separate values for men and women, for different ages and for pregnancy and lactation. The values in different tables vary. Sometimes this is because a later expert group has access to more recent experimental data, and sometimes because different expert groups interpret the same experimental evidence differently. shows the values that are used in food labelling in the USA and the EU.

It was noted above that some vitamins and minerals are toxic if taken in excess. also shows the ‘tolerable upper levels’ of habitual consumption that have been set by the US Institute of Medicine and the European Food Safety Authority, on the basis of the highest level of intake that is not known to cause any adverse effects, modified by a safety factor where appropriate.

Table 7. Labelling reference intakes and tolerable upper levels of habitual intake of vitamins and minerals for adults

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