The Role of Nutrition in Allergy Management

 INTRODUCTION

Nutritional management is also important for another broad aspect of allergy care, the design of therapeutic diets. When elimination or substitution diets are used to treat food allergy, it is important to identify and replace key nutrients that are omitted. This is most likely to be a problem in growing children, but can also become a problem in zealous adults that very rigidly follow a diet. Nutrient depletion is more likely to occur as the number of omitted foods increases, or whenever a food comprising more than half of the source of a particular nutrient is restricted. For example, a strict yeast avoidance diet excludes so many common foods that it may lead to total calorie deficiency, while milk avoidance may cause calcium and vitamin D deficiencies, since milk often supplies most of those nutrients in a typical American diet. Therefore, the essential nutrients that must always be considered during diet manipulations are also reviewed and discussed in this chapter. Finally, nutritional management can complement other allergy treatments, is usually inexpensive, and, in most cases, has a large margin of safety, with few side effects.

PATHOLOGIC ROLE OF OXIDANTS IN ALLERGY

Total Oxitant Load

PROTECTIVE ANTIOXIDANT MECHANISMS

BENEFITS OF NUTRIENTS IN ALLERGY TREATMENT

There is also good epidemiologic evidence for both the effects of low cellular antioxidant levels and increased oxidant exposures causing a worsening of allergies. For example, dietary surveys have shown that there is a strong statistical probability that asthmatics will have low levels of vitamin C, magnesium, and manganese, and that people with seasonal hay fever will have low zinc levels, when compared with matched, nonallergic peers (16). A recent review of nutritional influences in asthmatics versus normal patients compiled relevant references and rated them for both positive clinical effects of nutritional treatment, and, for the presence of a demonstrated nutritional deficiency (17). Magnesium was positive in three of six quoted references, vitamin C was positive in ten of thirteen articles, selenium was positive in all of six studies, and omega-3 essential fatty acids (EFAs) were positive in six of seven reports, suggesting strongly that these specific nutrients do have a role in mitigating allergic disease.

Vitamin C has been studied more than most nutrients. Recently, it has been shown to have an essential role in normal neutrophil function (18), and thus, is critical in preventing infection-induced asthma flares. Furthermore, vitamin C reduces the inflammatory effects of inhaled or internally generated oxidants, prevents the formation of the allergic mediator, platelet activating factor (19), and enhances the release of cytokines by stimulated lymphocytes (20). Vitamin C also shifts the cyclooxygenase pathway of arachidonic acid metabolism towards anti-inflammatory, bronchodilating prostaglandins, and has been found to prevent exercise-induced asthma attacks in some patients (21). Finally, vitamin C has antihistamine activity. At plasma vitamin C levels achievable by taking oral supplements, histamine levels are decreased by vitamin C mediated histamine oxidation (22).

Other nutrients have also been shown to have beneficial immunologic, respiratory, or antiallergic actions. For example, use of vitamin E supplements improves both cell-mediated immunity and specific antibody responses to vaccination (23), while dietary vitamin E intake is strongly correlated with preservation of lung function during aging (24). And, high vitamin E levels, combined with adequate vitamin C and selenium, appear to protect against allergic exacerbations (8, 10). Isolated selenium deficiency increases both susceptibility to, and severity of, viral infections (25). Increasing the ratio of dietary omega-6 EFAs to omega-3 EFAs causes asthma to worsen, whereas increasing the proportion of omega-3 EFAs substantially improves asthma in about 40% of patients (26). Beta-Carotene supplementation eliminates aging associated declines in natural killer cell function (27), improves cell-mediated immunity (28), and also inhibits release of histamine from stimulated mast cells (29). Compared with nonallergic persons, both asthmatics and rhinitics have lower levels of selenium and of glutathione peroxidase activity (30). Finally, N-acetylcysteine (NAC), which is converted by the body into glutathione, both decreases the symptoms of chronic bronchitis, and slows the decline in lung function in chronic obstructive pulmonary disease (31). Nutrients that are known to have beneficial effects on the severity of allergies are listed in Table 1, with an assessment of how common each deficiency is in the U.S. population (32).

GENERAL NUTRITIONAL CONCERNS DURING ALLERGY MANAGEMENT

Allergy patients share similar general nutritional requirements: 1. adequate water for replenishment of losses and removal of liquid wastes, 2. enough fiber for normal intestinal function, 3. adequate dietary total calories for energy, 4. sufficient amounts of quality protein , containing the essential amino acids, to maintain anabolic metabolism, 5. correct ratios and amounts of EFAs and other lipids to maintain cell membranes and provide raw materials for hormone biosynthesis, 6. adequate intake of minerals needed for structural, enzymatic, and electrochemical purposes, and, 7. sufficient amounts of vitamins required by cell metabolism . Although allergy patients have these nutritional requirements in common with the general population, certain aspects of allergic illness and treatments may make it more difficult for any particular patient to obtain their requirements. For example, elimination diets may make it difficult to obtain enough of key nutrients. Secondly, atopics may differ biochemically from the general population, thus requiring increased quantities of nutrients (33). Finally, allergy patients may live in stressful environments, and require greater than usual amounts of nutrients to keep up with their metabolic and detoxification demands. This is most likely for urban patients, who will require increased amounts of anti-oxidant vitamins simply to cope with the pulmonary toxicity of air pollution (34).

SPECIFIC NUTRITIONAL REQUIREMENTS

Water

Fiber

Fiber may also have adverse effects (36). Large amounts reduce the absorption of foods. In a marginal diet, this may cause malnutrition. The increased stool bulk after a fiber-rich meal may trigger sigmoid volvulus in susceptible persons. Presence of phytates in fiber may cause mineral or trace element deficiencies, particularly of zinc. Antinutrients in fiber, such as lectins, tannins, saponins, and enzyme inhibitors, may interfere with digestion, or injure the intestinal mucosa, increasing permeability. Fortunately, cooking inactivates most of these antinutrients. Finally, silica particles entrapped in cereal fiber may be an etiologic agent of esophageal cancer. Specific recommendations for consumption of fiber do not yet exist, but increases in daily fiber as small as 5 - 40 gm/day have shown benefits in some human studies.

Total Calories

Energy needs can be met by any food. Usually, carbohydrates supply the bulk, typically at least 55% of total dietary calories. Carbohydrates may be entirely omitted from the diet, since they can be synthesized from protein or from glycerol found in food. However, regular dietary carbohydrate is important for maintenance of maximum liver and muscle glycogen levels (38). Also, the specific type of carbohydrate eaten influences how any excess energy consumed is stored. Excess simple sugars are converted mainly into fat, while excess starch, which is more slowly absorbed, is converted preferentially into glycogen. In humans, there is no evidence that the quantity of carbohydrate consumed influences hunger, and therefore subsequent eating behavior (39). However, low carbohydrate diets have been used very successfully in weight reduction programs, and, recent evidence shows that high carbohydrate diets are more atherogenic than high fat diets (40, 41).

Most carbohydrates are poor antigens. Allergic problems with carbohydrate foods come primarily from the fact that carbohydrate foods are not pure: they are mixed with allergenic plant proteins. Even highly processed foods such as table sugar and cooking starches contain significant amounts of protein. Furthermore, because of the quantity of carbohydrate foods normally eaten, and the frequency with which these foods are eaten, allergic sensitization often occurs. Consequently, carbohydrate rich foods like cereal grains, sugars, and potatoes frequently require omission. If several of these are omitted, total calorie deprivation could occur.

Essential Amino Acids

Humans are unable to synthesize nine of the amino acids, and one more cannot be made in sufficient quantity for growing infants. These are essential, and must be obtained from the diet. Adults require about 20% of their total protein intake be in the form of essential amino acids, whereas pre-teens and infants require over twice as much (42). During severe illness, adult essential amino acid needs increase to resemble those of infants. Of these ten amino acid requirements, lysine and the sulfur-containing amino acids methionine and cystine are present in significantly lower quantities in plant proteins, compared with animal proteins. Combining different plant foods to more closely approximate the essential amino acid content of animal proteins is commonly practiced, usually by combining cereals (low in lysine) and legumes (low in methionine and cystine).

Essential Fatty Acids

Lipid Autoxidation. All lipids that contain unsaturated bonds have the potential for spontaneous oxidation and the production of toxic metabolites such as hydroperoxides, epoxides, dialdehydes, and free radicals. The oxidation-sensitive site is at the methylene carbon atoms adjacent to each unsaturated bond. Hydrogen atoms at these sites can be abstracted, forming free radicals that then trigger self-propagating chain reactions within cell membranes, leading to production of further unstable oxidation products (43). Some of these molecules, especially aldehydes and peroxides, can diffuse long distances before causing damage. These compounds cause molecular cross-linking, enzyme inhibition, and produce insoluble lipofuscin deposits from proteins, thus destroying macromolecules and interfering with cell functioning. They also directly damage DNA, and so are mutagenic and carcinogenic. Cellular aging, arteriosclerosis, malignant transformation, immune dysfunction, or cell death may be the ultimate result of extensive autoxidation.

Inside the cell, normal fatty acid oxidation for energy production is accomplished in peroxisomes and mitochondria. Both are specialized organelles that are capable of controlling the reactive compounds normally generated by lipid oxidation. Oxidation is also carefully controlled within lysosomes, during generation of reactive oxygen compounds to destroy microbes. All of these organelles contain protective antioxidant enzymes, including catalases, peroxidases, and superoxide dismutases. They also contain molecular antioxidants, including vitamins C and E, carotenoids, reduced glutathione, the essential peroxidase cofactors heme iron and selenium, and the essential superoxide dismutase cofactors copper, zinc, and manganese. Of these protective substances, all must be ingested in adequate amounts in order to have maximal protection from uncontrolled oxidation. The only exceptions are the enzymes and reduced glutathione, all of which can be synthesized, provided adequate essential amino acids are consumed.

Under the stress of a high fat diet or vitamin E deficiency, peroxisomes proliferate in an attempt to compensate for the increased oxidative load (44). However, when large amounts of highly unsaturated fatty acids, cholesterol, or vitamin A are absorbed, uncontrolled autoxidation may occur outside of these organelles. Lipid autoxidation is further increased by exposure to other agents capable of generating free radicals, such as radiation, oxidants in smog, and chemical pollutants that require oxidative detoxification. Essential Fatty Acids. Essential Fatty Acids are unsaturated fatty acids with multiple double bonds, one of which is close to the methyl end of the molecule. Human enzymes are unable to work closer than seven carbon atoms from the methyl (omega) end, so that we are completely dependent upon plants to synthesize these necessary lipids. There are two EFA families, the omega-6, or linoleic acid family, synthesized by all plants, and the omega-3, or linolenic acid family, synthesized by marine phytoplankton. Essential fatty acids may be ingested as linoleic or linolenic acids, and then enzymatically elongated and desaturated to form all of the EFAs humans require. Alternately, preformed polyunsaturated EFAs such as arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, and docosahexaenoic acid (DHA) may be absorbed and utilized directly. In prevention or treatment of EFA deficiency, except for rare individuals with converting enzyme deficiencies, it is sufficient to supply adequate amounts of one member from each of the omega-3 and omega-6 EFA families. People with eczema may also convert omega-6 EFAs poorly, since gamma-linolenic acid supplements cause clinical improvement (45).

EFA supplementation has complex effects on the balance of prostaglandin and leukotriene regulated immune functions. Synthesis of eicosanoid hormones from EFAs amounts to only milligrams per day, compared to a daily dietary consumption of about 10 grams of EFAs, but eicosanoid production falls as soon as the regular dietary supply of EFAs is interrupted. In addition, modifying the relative amounts of omega -3 and omega-6 EFAs consumed influences tissue levels of both proinflammatory and anti-inflammatory hormones, with omega -3 EFAs shifting the balance toward antiinflammation. For these reasons, feeding different absolute amounts of dietary EFA, as well as changing the omega-3 to omega-6 ratio, can have a profound effect on all eicosanoid functions, and can effect the activity of diseases such as asthma, that are affected by leukotrienes and prostaglandins (46).

How much EFAs should be included in a prudent diet? Most authorities recommend limiting total EFA consumption to no more than 10% of total calories, but absolute minimal needs are still unknown (43). Clinical deficiency of EFAs can occur in several situations, including premature and young infants, fat malabsorption, multiple sclerosis, and several other illnesses. Greater amounts of EFAs may be safe, but there are concerns over possible carcinogenesis, and since fats are the most calorie dense foods, control of total calories is difficult when any fat is increased. Experimental studies on prevention of nervous system or retinal injury in growing animals show that omega-6 EFA to omega-3 EFA ratios between 4 to 1 and 10 to 1 are optimal. This range of ratios agrees exactly with analyses of human milk from mothers on a wide variety of diets, where omega-3 EFA are a constant 1.5% - 2.5 % of total fat, and 0.7% - 1.3% of total calories. Based on this data, recommended levels of omega-3 EFA, given current average omega-6 EFA consumption of about 7% of total calories, would be around 1% of total calories, or about 4 grams/day in adults. Childhood needs are not precisely known, but are significant due to nervous system growth requirements. How the omega-3 EFA are ingested is as important as is the correct amount of supplementation. If pure fish liver oils are used, it is possible to ingest toxic overdoses of vitamins A and D. On the other hand, eating a half pound a day of wild-caught fatty fish, such as salmon, tuna, sardines, or mackerel, provides about 4 to 6 grams of omega-3 EFA, but only small amounts of vitamins A and D, and is better tolerated. Omega-6 EFAs are easily supplied by ordinary polyunsaturated vegetable oils. For infants, breast-feeding is strongly recommended, since it is not possible to adequately feed required amounts of long chain EFAs using traditional formulas or solid foods.

A final concern is that adequate vitamin E is also consumed, so that EFA autoxidation is prevented. Fortunately, most natural plant sources of EFAs contain vitamin E in adequate amounts, (34,35) but, fish oils do not (43). Since vitamin E can also be destroyed by processing, heating, and improper storage, EFA supplements or oils may contain preformed oxidative toxins (37). And, since average vitamin E consumption is below recommended levels, many people will need vitamin E supplements, particularly if they are treated with EFA concentrates.

Major Minerals

Besides inadequate calcium intake, three other common factors tend to further worsen calcium deficiency. First, high phosphate levels that are present in a diet rich in meats or carbonated soft drinks promote increased calcium excretion. Second, inadequate vitamin D levels due to limited sunlight exposure, as well as reduced gut efficiency due to aging, also decrease calcium absorption. These are important factors in the U.S., and consequently, average calcium consumption should be further increased. Complications from excessive calcium intake do not occur in normal individuals at amounts up to 2500 mg/day (47). However, patients with sarcoidosis or patients with calcium-containing renal stones may develop complications from ingesting as little as 800 mg/day, particularly if also given vitamin D supplements. All growing children, and many adults, should receive calcium supplements if taken off of milk products. Even young children will usually chew flavored calcium carbonate antiacid tablets, and adults can take any inexpensive calcium supplement. The third factor that lowers body calcium stores is magnesium deficiency (see below).

Phosphorus. In contrast, phosphorus, which is ordinarily considered together with calcium because of the joint regulation of their metabolism, is present in so many foods and food additives, that deficiency is seldom seen (47). For adults, 800 to 1500 mg/day of phosphorus is required, only a fraction of the average U.S. daily consumption. Phosphate deficiency may be a problem when it's absorption is prevented, for example, by the regular ingestion of large amounts of antiacids, iron salts, or unsaturated fatty acids. Hereditary hypophosphatemia also occurs, and low phosphate levels are also common in hospitalized persons. But the much larger problem is that excess dietary phosphate stimulates excessive parathormone production, causing calcium mobilization and osteoporosis. With the exception of infants, who require more calcium than phosphorus, phosphorus should be ingested at the same level as calcium.

Magnesium. Although widely distributed in foods, magnesium deficiency is common. Because magnesium has multiple roles in energy production, it is important for muscle function, and thus, deficiency can worsen serous otitis and asthma. In addition to enabling parathormone secretion, magnesium has recently been found to control osteoclast activity, so that bone resorption occurs when magnesium levels are low. This is probably an important factor in osteoporosis pathogenesis. Confirmation of suspected magnesium deficiency is by a three-step process. First, a serum magnesium level is done. When a patient has a deficiency risk factor, a normal serum level should be checked by measuring 24-hour urinary excretion (normal is > 24 mg). A low serum level should also be confirmed by measuring 24-hour urinary excretion. If the serum and 24-hour urine results conflict, then a magnesium load test is performed (48).

Low daily intakes in U.S. adults of from 234 - 323 mg/day have been reported, with the adult RDA being set at 320 - 420 mg/day (48). The most frequent medical causes of magnesium deficiency are diabetes mellitus, alcoholism, and intestinal malabsorption syndromes. Since inflammatory bowel disease due to food allergies may cause malabsorption, magnesium deficiency should be considered in every allergy evaluation. Magnesium toxicity is rare, due to the large capacity of normal renal excretion, however, magnesium supplements should not be given in renal impairment. Magnesium oxide is poorly absorbed, but large excesses of any magnesium salt are cathartic. Recommended daily magnesium intakes are listed in Table 5 (48).

Iron. Still the most common nutrient deficiency, both in the U.S., and in the world, anemia due to low iron is a problem, particularly in menstruating women, children, adolescents, and the elderly (49). Average iron intakes in the U.S. are about 10 - 20 mg, with average absorption of about 10%. These levels should be adequate, except during pregnancy. Although iron is common in many foods, it is poorly absorbed, especially from plant sources. Iron deficiency occurs when cereals make up a major portion of the diet, due to both low iron content and interference with absorption due to the presence of phytates. In allergy diets, iron deficiency may arise from exclusion of meats and eggs. Recommended daily iron intake is shown in Table 6 (49).

Iron toxicity. Toxic accumulation can occur with prolonged administration of iron supplements to normal, non-menstruating adults. For this reason, iron supplements should not be prescribed without prior evaluation. Furthermore, approximately one in 250 people is homozygous for hereditary hemochromatosis (HHC), and is at particular risk of iron overload. Since symptoms of iron overload occur late in the illness, many of these persons have no knowledge of their disease, and do not know that they should never take iron supplements. Prior to prescribing iron, hematocrit and serum iron should be checked. If iron binding capacity, transferrin saturation, and serum ferritin have not been previously determined within the past 10 years, these should also be done (49). However, even if all tests are normal or low, follow-up is still required, since no available test, except liver biopsy, is absolutely diagnostic and able to identify all cases of HHC in the early stages (50). High levels of ionized iron are strongly pro-oxidant, potentially causing toxic free radical production. However, because of the strong protein binding of iron, significant radical production may not be a common clinical problem (49).

Iodine. Worldwide, iodine deficiency is probably nearly as common as iron deficiency, but for a different reason: iodine is a rare element, is not uniformly distributed in soils, and is not concentrated in any common foods (51). Large areas of the world are depleted in iodine due to loss of topsoil or leaching by water, and crops grown in such areas are poor iodine sources. The best sources of iodine are in foods not widely consumed (seaweeds, marine fish, and shellfish), so the major source for most people is staple foods to which iodine supplements have been added. Average U.S. diets are adequate, containing between 400 and 800 micrograms/day, compared to an estimated minimum daily requirement of 50 micrograms. Intake of from 100 - 200 micrograms/day is probably sufficient, even when goitrogens, plant components that interfere with iodine absorption, are present in the diet (51). Exclusion of seafood and iodized salt from the diet may lead to iodine deficiency. Iodine toxicity can occur from frequent consumption of water that has been disinfected with iodine. Iodine status can be easily determined by measurement in a random urine sample (normal: 100 - 200 microgm / liter), and abnormals are confirmed by measuring blood thyroid stimulating hormone levels. Recommended iodine intakes are shown in Table 7 (51).

Zinc. Present in the adult to the extent of only 2 - 3 grams, this small amount of zinc has many crucial roles in the body as an enzyme cofactor and membrane stabilizer. Since zinc acts as a cofactor in DNA, RNA, and protein synthesis, as well as in detoxification enzymes and immune cell functioning, zinc deficiency may be both insidious and serious. Zinc deficiency is common in hospitalized patients, and in outpatients with cancer or chronic illnesses, especially those affecting the intestinal tract, skin, or immune system. The major limiting factor in zinc metabolism is usually poor absorption due to inhibitory substances that are widely distributed in the diet. In addition to cereal phytates, tea and coffee, cow's milk products, soy protein, iron, calcium, and alcohol all impair zinc absorption. Human breast milk, zinfandel wine, and some organic acids, including citric, enhance zinc absorption. Meats, especially beef, lamb, mollusks, and crustaceans, are good zinc sources that are essentially free of inhibitory substances. Estimated guidelines for zinc intake are shown in Table 8 (52). Zinc status is difficult to assess, since serum levels and urinary excretion of zinc may not decrease until deficiency is severe, and hair zinc may be falsely high in severe deficiency.

Zinc toxicity can be a significant problem, either accidental, or through overzealous use of supplements (52). Acid foods stored in galvanized containers can leach enough zinc to produce acute toxicity, with cramps, vomiting, headache, and seizures. Chronic overdose results in impaired copper absorption and copper deficiency anemia, although this competition can be used clinically to assist in control of Wilson's disease. Gastric ulcers may occur from slowly dissolving tablets. Daily zinc doses of only 150 mg may cause toxicity, and maximum daily doses of 40 mg, or less, are prudent.

Copper. A critical enzymatic cofactor in multiple oxidation reactions, copper is vital both for energy production and for detoxification. There is only about 70 to 100 mg of copper in the average adult, so deficiency can easily occur, most commonly causing iron-resistant microcytic anemia, neutropenia, and impaired glucose tolerance (53). Since superoxide dismutase is a copper-zinc enzyme, deficiency of either metal will seriously disrupt leucocyte oxidative killing, and possibly triggers neutrophils to autolyse by oxidative damage. Similar oxidative damage may also occur in hepatocytes, since copper deficiency also decreases the detoxifying selenium enzyme, glutathione peroxidase. Even in the absence of Wilson's disease, high copper levels are implicated in free radical production and neurodegenerative diseases (53). Copper deficiency, like zinc deficiency, also impairs lymphocyte functions. Copper deficiency is most likely to occur in infants fed mainly cow's milk or rice, since both foods are extremely low in copper content. It may also occur due to regular use of antiacids, excess zinc supplementation (see above), or from high levels of dietary phosphate. Malabsorption syndromes and chronic intestinal diseases may also cause copper depletion.

Important dietary sources of copper are copper water pipes and copper cooking utensils, mollusks, crustaceans, and legumes. Unlike cow's milk, human breast milk enhances copper absorption. Estimated copper needs are shown in Table 9 (53). Copper supplementation must be carefully approached, since excess copper is significantly toxic. Doses of as little as 5 - 10 mg may produce nausea, 250 mg produces vomiting, and as little as 3.5 gm may be fatal. Chronic daily doses of 10 mg may be tolerated. The ratio of copper to zinc is important: about ten times more zinc than copper is required. Copper status is assessed by measuring serum copper and ceruloplasmin levels, however, neither is sensitive to marginal deficiency, and, as acute phase reactants, they may be artificially elevated in numerous illnesses. Erythrocyte superoxide dismutase activity is an alternative measure.

Trace Elements

Chromium. Needed for carbohydrate, lipid, and nucleic acid metabolism, overt chromium deficiency has been seen only in patients who are severely malnourished or on prolonged total parenteral nutrition. However, improvements in glucose tolerance and cholesterol metabolism have been shown to occur in a significant fraction of persons given chromium supplements. Since average U.S. dietary chromium intakes are near or below the lower end of the recommended range, many apparently normal persons may be subclinically deficient. Foods with high chromium content include mushrooms, brewer's yeast, prunes, nuts, asparagus, wines, and beer. Significant chromium also leaches into acidic foods from stainless steel cookware. The recommended intake of dietary chromium is shown in Table 10 (55). Chromium toxicity occurs with industrial exposure to hexavalent chromates, which damage DNA and increase the risk of lung cancer. Oral use of trivalent chromium compounds has not yet been shown to cause toxicity, however, high doses of chromium picolinate, but not chromium chloride or nicotinate, cause chromosome damage in tissue culture, and chromium may accumulate during clinical supplementation (55, 56). For these reasons, prolonged supplementation without laboratory monitoring is probably unwise. Both hexavalent, and also trivalent, chromium may cause chronic dermatitis due to allergic sensitivity (57).

Manganese. Required in small amounts for normal growth and reproduction, symptomatic manganese deficiency has not been shown in humans, except for long-term parenteral nutrition patients. In some patients, low manganese levels were correlated with asthma (16). Manganese is an essential cofactor for several enzymes, including manganese superoxide dismutase, the enzyme that protects mitochondria from oxidative damage. The average adult contains about 12 to 20 mg of manganese, and tissue levels remain very constant throughout life, despite poor absorption. Normal diets are believed to contain manganese levels significantly exceeding requirements. Good manganese sources include most plants, including tea. Recommended dietary levels are shown in Table 10 (58, 59). Manganese has low toxicity, with no known toxicity due to dietary intake. High levels of dietary manganese, however, impair iron absorption. Miners exposed to manganese dust or fumes do develop ecentricity, and a central nervous system dysfunction similar to Parkinsonism (58).

Cobalt. The only known role for cobalt in human nutrition is as the active cofactor of vitamin B 12. Consequently, it is discussed under the heading of water-soluble vitamins. Cobalt is a significant allergic sensitizer (57).

Ultratrace Elements

Molybdenum is an enzyme cofactor for important detoxifying enzymes, including aldehyde oxidase, sulfate oxidase, and others. Since it may be required at levels close to average dietary intakes, persons with extra needs, such as chemically exposed individuals, may need supplements. Arsenic is believed to be required for taurine and sulfate production from methionine, and may be involved in other methyl transfer reactions. Boron is known to be essential in both plants and animals, but it's specific role is not yet clear, although it may be a regulator of membrane transport. Nickel has no known definite role in mammals, but may play a role in methionine synthesis. Nickel is a significant allergic sensitizer (57). Silicon is required for connective tissue and bone structure to form properly, probably by influencing calcium deposition. Vanadium has no known definite role in mammals, but may affect iodine transfer in the thyroid, and it has insulin-like properties. It is also very toxic. Germanium has been felt by some researchers to also be essential, but the evidence to date is not convincing, and germanium is a significant nephrotoxin. Deaths from germanium supplementation have been reported (59). Estimated U.S. average dietary intakes and possible requirements for the ultratrace elements are shown in Table 11 (59). All of the ultratrace elements, except molybdenum, are normally present in the diet at levels that exceed their estimated requirements.

Vitamins

Fat-Soluble Vitamins

Vitamin D. Provitamins D2 and D3 are related steroid compounds that cannot be synthesized by humans, but are absorbed from fatty fish or fish liver oil meals, and transported to the skin, where ultraviolet light opens the ring structure to form vitamin D. Vitamin D is then hydroxylated in the liver to form active 1, 25 dihydroxy-D. Active vitamin D is essential for absorption of calcium and phosphorus, and maintenance of stable levels of these minerals . Excessive vitamin D intake, of 1000 IU or greater, can lead to irreversible damage to heart, aorta, and kidneys from ectopic calcification (62). If high vitamin D doses are given, serum and urine calcium levels must be monitored. Vitamin D deficiency is thought to be common, and can occur with milk exclusion, in the elderly, and from sun avoidance and sunscreen use. Vitamin D doses of 400 IU daily, or 50,000 IU weekly for 8 weeks, are adequate for repletion in deficient adults. Vitamin D levels in serum vary rapidly with dietary and solar exposure, and cannot be used as a guide to therapy. Instead, vitamin D status is determined by measuring the serum level of the previtamin, 25-hydroxy-D (62).

Vitamin E. The group of eight chemically similar natural tocopherols and tocotrienols that are produced by plants is termed vitamin E. Vitamin E is a free radical chain reaction-breaking antioxidant. It also has immune stimulatory properties that may be biologically important (63). Alpha tocopherol is the most potent of the natural vitamin E components (64). Synthetic vitamin E contains eight sterioisomers of alpha tocopherol, and the isomer mixture is less active than the natural isomer. There may be distinct roles for each different molecular type of natural vitamin E. For example, gamma-tocopherol has been found to be the primary vitamin E component to neutralize reactive nitrogen oxides (65). Because vitamin E is the major antioxidant capable of stabilizing membranes, it is required in greater amounts when intake of unsaturated lipids such as vitamin A or EFAs increases (see above). Vitamin E deficiency can easily occur when consumption of any polyunsaturated oil is high, especially fish and fish oils, which do not contain significant amounts of vitamin E. Premature infants often require vitamin E supplements. Vitamin E is not readily mobilized, so that rapid depletion of membrane levels occurs when dietary supplies are low. Supplements of 400 IU daily have been shown to decrease oxidation of serum low-density lipoproteins (64).

Adult doses of vitamin E up to 3200 IU/day appear to be free of side effects, but the actual dose at which side effects may occur is unknown (37, 54). Vitamin E can act as a prooxidant during in vitro experiments, although it has never been observed in this role in life (64). Consequently, there is some doubt about the safety of very large supplemental doses. Large doses may also cause flatulence, malabsorption of vitamins A and K, and interference with the procoagulant activity of vitamin K (66). Vitamin E overdose is suspected of depressing lymphocyte functions, and daily doses over 10,000 IU may be teratogenic (56). Short-term vitamin E status can be determined by measuring plasma levels, while levels in adipose tissue reflect long-term, average levels (63)

Vitamin K. As with vitamin E, Vitamin K is not a single chemical entity, but rather, a group of chemically similar napthoquinones with an unsaturated side chain composed of repeating isoprene units. Produced by plants, bacteria, and by some animals, about half of the daily human requirement for vitamin K is supplied by bacterial synthesis from the normal small intestinal flora (67). Prolonged or repeated antibiotic therapy, as is often seen in allergic patients with otitis or sinusitis, may produce vitamin K deficiency. Breast fed babies also have low levels, and should receive vitamin K at birth. Vitamin K supplements have never been reported to have toxic effects, however, vitamin K precursors, such as menadione, can cause hemolytic anemia and hyperbilirubinemia in infants (67).

Recommended daily doses, average dietary intakes, and toxic doses for the fat-soluble vitamins are shown in Table 12 and Table 13 (61, 62, 64, 67).

Water-Soluble Vitamins

Vitamin C. Vitamin C is the most effective water-soluble antioxidant because it readily donates electrons to quench many oxidants, and can also be easily recycled (68). Only 5 - 10 mg of daily ascorbic acid is needed to prevent scurvy, but larger doses may have significant benefits, particularly in allergy and asthma (see above), and should always be strongly considered for supplementation (68, 69). In smokers, vitamin C is depleted at about twice the usual rate, and their RDA is set 40 mg higher, at 100 mg daily. It is likely that the vitamin C RDA will be raised to 120 mg (70). There is a large body of evidence that suggests even higher doses of vitamin C may reduce the risk of developing chronic diseases such as cancer, circulatory disorders, eye diseases of aging, and neurodegenerative diseases (68).

Pharmacokinetic studies show that steady state saturation of ascorbate plasma levels can be achieved by daily doses of 200 mg, with renal losses preventing sustained higher levels. Based on metabolic turnover and absorption studies, intestinal absorption of vitamin C is saturated by single doses above 3 grams (71). Single doses greater than this are cathartic, and some individuals only tolerate lower doses without cramping. Primate comparative diet studies suggest normal human consumption should be about 2.3 -10 grams per day (69), consumed in frequent, small doses. Megadoses of vitamin C appear to be safe for most people (56), although persons with glucose-6-phosphate dehydrogenase deficiency may develop hemolysis, and interference with the anticoagulant effects of heparin and coumadin have been reported (68). Vitamin C does enhance iron absorption (68), but this has not been shown to cause iron accumulation, and prior suggestions that ascorbate causes oxalate kidney stones and uricosuria have been disproven (56). However, vitamin C does increase aluminum absorption, and so it should not be taken with aluminum, including some common antiacids. Vitamin C status can be assessed by it's measurement in plasma or leucocytes.

Other water-soluble vitamins are of critical importance in energy production and detoxification pathways and should always be supplemented in chemical toxicity. B vitamins also play a significant role in prevention of arteriosclerosis and of birth defects, and may slow aging changes in the central nervous system.

Because of the biochemical variability of individuals, actual requirements for specific water-soluble vitamins may vary significantly from the average. Also, these vitamins can have pharmacologic actions when used in megadose amounts. Therefore, functional assays, such as serum amino acid analysis or specific enzyme activity determinations, rather than simple measurement of vitamin levels, may be needed in order to assess whether or not a particular vitamin needs to be supplemented, in a specific individual, at higher than usual levels. Recommended average daily doses of water-soluble vitamins are shown in Table 12 (68, 72).

CONCLUSIONS

In lieu of specific knowledge, physicians should recommend that patients consume a varied diet that includes a wide variety of vegetables, fruits, nuts, and other foods known to contain natural antioxidants (4), vitamin C, B vitamins, minerals, and EFAs, as well as enough high quality protein to enable optimal antioxidant enzyme synthesis. Despite a varied diet, some patients, especially growing children, and anyone with increased metabolic needs, may be nutrient deficient (74,75), particularly when their foods may have low vitamin and mineral content from poor farming practices, food processing, or prolonged storage. In the elderly, where both intestinal absorption and diet quality are often poor, deficiencies are very common, and should be expected. Also, allergy patients who are either following strict avoidance diets, or who have significant malabsorption as a consequence of food allergies, may develop important deficiencies. For these reasons, most patients should use vitamin and mineral supplements as insurance that at least minimal quantities of critical vitamin and mineral cofactors are ingested. Third, use of pharmacologic amounts of individual nutrients, especially vitamins C and E, should be recommended for more severely symptomatic allergy patients (76) and in other situations where the oxidant load is known to be either high or sustained. This is particularly likely to be helpful when treating severe asthma, chronic eczema or urticaria, chronic fatigue syndrome, or, in conjunction with other therapies, for treatment of chemical sensitivity patients (77). Pharmacologic supplements of major minerals, particularly calcium, copper, magnesium, zinc, and organic forms of sulfur (essential amino acids) also will be useful in many patients. Trace mineral deficiencies may contribute to many different ailments, but because of nonspecific symptoms, will rarely be identified without specific laboratory testing. Finally, iron supplements should not be used unless there is documented iron deficiency.

Because chronic use of pharmacologic doses of some vitamin and mineral supplements can be toxic (13), and because some people may absorb nutrients poorly or have significantly higher nutrient needs than average, periodic determinations of serum or cellular nutrient levels (60) will be necessary, in order to practice safe and effective nutritional therapy. Laboratory assessment of many nutrients is difficult because serum levels do not always reflect either adequate tissue levels or effective enzyme saturation (77), and many concentrations are at such low levels that they are technically challenging to quantitate. Furthermore, the presence of many interdependent metabolic pathways means that a single deficiency can have multiple manifestations, making clinical diagnosis of deficiencies also very difficult. For these reasons, while serum nutrient levels can be used as a guide to severe deficiency or toxic levels, analysis of blood cell nutrient levels, nutrient loading tests, amino acid determinations, and assay of specific enzyme activities (78) may be required to determine the true nutritional status of some patients.

Because nutrition is a rapidly changing specialty, recommendations in this chapter should be considered as tentative. Other sources should be consulted, and, where appropriate, nutritional consultation should be obtained. It must be stressed that each patient should be systematically evaluated for nutritional risk factors, specific nutritional deficiencies should be identified by laboratory testing, and appropriate prescriptions made for dietary modifications and supplemental nutrients. Careful follow-up is also required to avoid either inadequate treatment, or toxicity due to nutritional supplement overdose or conflicts. In addition, the biochemical variability of humans should be kept in mind, since what is an adequate dose of a nutrient for one person may be toxic for some, and insufficient for still others. If attention is paid to these precepts, nutritional therapy will become a valuable addition to each physician's armamentarium, with significant health benefits for allergy patients.

ACKNOWLEDGMENTS

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