CONTENTS
General Comments on Vitamin Defi ciencies ... 178
Vitamin A ... 179
Functions ... 179
Defi ciency ... 179
Laboratory Diagnosis of Defi ciency ... 180
Prevention ... 180
Treatment ... 180
Vitamin E ... 181
Functions ... 181
Defi ciency ... 181
Laboratory Diagnosis of Defi ciency ... 181
Prevention ... 182
Vitamin K ... 182
Functions ... 182
Defi ciency ... 182
Laboratory Diagnosis of Defi ciency ... 183
Prevention ... 183
Treatment ... 184
Thiamin (Vitamin B1) ... 184
Functions ... 184
Defi ciency ... 184
Laboratory Diagnosis of Defi ciency ... 184
Prevention ... 185
Treatment ... 185
Ribofl avin (Vitamin B2) ... 185
Functions ... 185
Defi ciency ... 185
Laboratory Diagnosis of Defi ciency ... 186
Prevention ... 186
Treatment ... 186
Niacin (Sometimes Referred to as Vitamin B3) ... 186
Functions ... 186
Defi ciency ... 186
Laboratory Diagnosis and Defi ciency ... 188
Prevention ... 188
Treatment ... 188
Pyridoxine (Vitamin B6) ... 188
Functions ... 188
Defi ciency ... 188
Laboratory Diagnosis of Defi ciency ... 189
Prevention ... 189
Treatment ... 189
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178 Handbook of Nutrition and Food
In this era of increasing obesity and growing portion sizes, with food fortifi cation well established and nutritional supplements widely consumed by the public, it is important to keep in mind those special circumstances in which vitamin defi ciencies still continue to occur. A diet high in calories is not necessarily high in nutrients. In fact, a high-fat diet based to a large degree on
“fast foods” may be low in some of the essential vitamins and minerals.
GENERAL COMMENTS ON VITAMIN DEFICIENCIES
In general, vitamin defi ciencies arise when the diet is inadequate in its content of one or more nutrients or when the body is unable to utilize dietary nutrients adequately. Impaired intestinal absorption or defects in metabolic processes, storage, or excre-tion can each result in vitamin defi ciency. Single-nutrient defi ciencies are rare these days, because a diet that is suboptimal in one vitamin is nearly always suboptimal in others. Thus, a poor diet tends to have multiple inadequacies. Furthermore, some vitamins are involved in the metabolism of other vitamins, and therefore defi ciencies may be interconnected.
A number of exogenous factors may serve to intensify the biological effects of a poor diet. For example, excess alco-hol consumption has specifi c and selective effects on vitamin metabolism, interfering with the absorption of some vitamins (e.g., thiamin and ribofl avin) and accelerating the metabolic degradation of another (B6). In addition, a number of medications may affect vitamin metabolism and at multiple sites. From a practical point of view, laxatives and diuretics, often used for minimal indications and prolonged periods by vulnerable elderly patients, are probably among the most common causes of drug-induced vitamin defi ciencies.
The concept of risk factors, utilized effectively in the evaluation and prevention of heart disease, needs to be applied to the assessment of vitamin defi ciency. Thus, a patient who abuses alcohol, requires several medications chronically, and suffers from malabsorption due to alcohol will have a greatly enhanced risk of becoming grossly vitamin defi cient.
A much greater understanding is needed of the effects of herbal products and the so-called alternative/complementary rem-edies on vitamin metabolism. Many prescription drugs are known to affect vitamin metabolism. With large numbers of people consuming a wide variety of unregulated products about which there is little information, a potential exists for developing signifi cant forms of malnutrition. We urgently need more information on drug–herbal and food–herbal interactions and their implications for vitamin metabolism. Several comments about the patterns of vitamin defi ciencies currently emerging in the United States are summarized in Table 9.1.
TABLE 9.1
Some Features of Vitamin Defi ciencies at the Present Time
1. Dietary vitamin defi ciencies tend to be multiple, not single
2. Clinical evidence of vitamin defi ciencies develops gradually, and early symptoms, such as fatigue and weakness, may be vague, ill-defi ned, and nonspecifi c
3. The physical examination cannot be relied upon to make a diagnosis of early vitamin defi ciency; classic features of vitamin defi ciencies, such as the corkscrew hairs of scurvy, are only detectable after a profound defi ciency state has been attained
4. The rate of development of vitamin defi ciencies is highly variable. In general, most water-soluble vitamins may be depleted within several weeks; longer periods are needed for signifi cant depletion of fat-soluble vitamins. Several years are required for clinical manifestations of vitamin B12 defi ciency unless there are complicating factors, such as ileal resection or infl ammatory bowel disease involving the ileum
5. The impact of dietary defi ciencies of vitamins is greatly augmented by the long-term chronic use of certain medications that may affect absorption, utilization, or excretion of vitamins. Chief among these are laxatives and diuretics. These considerations are particularly relevant to older individuals, who use the largest number of drugs and remedies, for the longest duration, and may have marginal diets to begin with
6. The concept of “risk factors” may be helpful in assessing factors, such as drugs and alcohol, that contribute to accelerating the clinical presentation of a given dietary inadequacy
Vitamin C (Ascorbic Acid) ... 189
Functions ... 189
Defi ciency ... 189
Laboratory Diagnosis of Defi ciency ... 191
Prevention ... 191
Treatment ... 191
Vitamin D ... 191
Bibliography ... 192
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While the effects of full-blown vitamin defi ciencies are well known and have been thoroughly described, the effects of lesser or marginal defi ciencies are not as well appreciated by health professionals. In recent years, both scientists and the general public have been paying more attention to marginal vitamin and mineral defi ciencies in attempting to gain maximal benefi ts from diet for health. Recent fi ndings suggest that the concept of so-called “normal” needs to be carefully reconsidered, inasmuch as there may be different risks for disease within the range considered “normal.”
For example, individuals with serum folic acid levels in the lower part of the normal range have been shown to have signifi -cantly elevated serum concentrations of homocysteine compared with those whose folic acid concentrations are in the upper range of normal. With elevated serum homocysteine concentrations emerging as a risk factor for heart disease, these observa-tions suggest that perhaps we should set higher standards and more defi ned expectaobserva-tions for the “normal” range.
In the prevention and treatment of vitamin defi ciencies, one must approach the patient in a logical fashion and proceed in an orderly direction. Medical history is of greatest importance and one needs to know details of food intake, portion size supple-ment use, remedies, and drugs. The physical examination only rarely reveals pathognomonic signs of specifi c vitamin defi cits.
Laboratory tests, appropriately utilized, may be helpful in documenting vitamin defi ciencies. Long-term compliance with an appropriate diet and the use of supplements, if indicated, is the goal, but may be diffi cult to achieve. Some of the points regarding correction of vitamin defi ciencies are summarized in Table 9.2.
VITAMIN A FUNCTIONS
Vitamin A has a wide variety of functions, including specifi c roles in vision, embryogenesis, cellular differentiation, growth, reproduction, immune status, taste sensations, and, increasingly, in disease prevention and treatment.
DEFICIENCY
Defi ciency of vitamin A is of crucial importance as a worldwide nutritional problem. The resultant xerophthalmia is a cause of blindness in at least half a million preschool children each year in the developing countries. In these areas, the diet is composed primarily of such items as rice, wheat, maize, and tubers, which contain far from adequate amounts of vitamin A precursors.
The World Health Organization (WHO) and other groups have made great efforts to plan programs that identify people at risk and to institute appropriate preventive measures on a broad scale. It is now recognized that dietary defi ciency of vitamin A is a clear risk factor for severe cases of measles. Many of the deaths that result from measles in young children could be greatly reduced by large doses of vitamin A given parenterally. The diet prevailing in these areas simply does not contain enough vitamin A precursors or vitamin A itself to prevent a defi cient state from developing.
Clinical defi ciency of vitamin A may be overt or subclinical. One of the earliest signs of vitamin A defi ciency is night blind-ness, observed in both children and adults. The development of xerophthalmia follows a defi ned sequence, leading eventually to keratomalacia, in which perforation of the cornea occurs. A characteristic sign that is observed later in advanced vitamin A defi ciency is Bitot’s spots, collections of degenerated cells in the outer aspects of the conjunctivae that appear white in color.
TABLE 9.2
Some Considerations in Correction of Vitamin Defi ciencies
1. Approach the clinical setting in its entirety; ask yourself, how could a vitamin defi ciency develop in the fi rst place? Ask whether there are complicating conditions, that is, other risk factors, in addition to the poor diet
2 Unless there are specifi c indications of a single-nutrient defi ciency, such as vitamin B12 in pernicious anemia, most malnourished patients will have multiple defi ciencies and require rehabilitation with multiple nutrients. Repletion is best accomplished primarily with diet, and additionally with specifi c supplementation, if necessary
3. Simple steps can often improve a diet signifi cantly, such as discarding old produce, avoiding “fast food” meals on a regular basis, and increasing the intake of fresh fruits and vegetables. In modern nutrition, one speaks of “junk diets” rather than single “junk foods,” and of the necessity of moderation and variety in one’s daily diet
4. Learn how to read a label from a nutritional supplement bottle so that you can properly instruct your patients. The array of choices of nutritional supplements is bewildering, and patients must learn that more is not necessarily better
5. Remember that vitamins may behave like drugs and have a defi ned toxic: therapeutic ratio. Some vitamins, such as vitamins A and D, have a real potential for causing toxicity. B vitamins may also cause problems, as exemplifi ed by the sensory neuropathy resulting from large doses of vitamin B6
6. A multivitamin supplement containing all nutrients at the levels of the RDI is safe to take by nearly everyone and may help to alleviate defi ciencies and prevent them in the future
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180 Handbook of Nutrition and Food
Vitamin-A-defi ciency eye disease in its end stages is irreversible, but if abnormalities are detected earlier and treated vigor-ously, they may be potentially preventable.
Vitamin A defi ciency also causes skin disorders in the form of follicular hyperkeratosis. Although characteristic skin changes occur in response to a defi ciency of vitamin A, in practical terms one should remember that skin lesions of some kind may be caused by other nutrient defi ciencies such as zinc, biotin, niacin, and ribofl avin.
Children signifi cantly defi cient in vitamin A manifest increased incidence of serious and life-threatening infections and elevated mortality rates. It has been recognized that defi cient vitamin A status is a risk factor for the maternal-to-fetal transmis-sion of human immunodefi ciency virus; the relative risk of transmistransmis-sion of the virus is fourfold greater in vitamin-A-defi cient than in vitamin-A-suffi cient mothers.
Vitamin A defi ciency in the United States is identifi ed largely with certain risk groups: the urban poor, elderly persons (par-ticularly those living alone), abusers of alcohol, patients with malabsorption disorders, and persons with poor diets. Vitamin A defi ciency is generally found in a setting in which there are multiple vitamin and mineral defi cits. Special attention must be paid to defi ciency of zinc, a frequent fi nding in alcoholism, as depletion of zinc interferes with the mobilization of vitamin A from its storage sites in liver. This effect is achieved by blocking the release of holo-retinol-binding protein from the liver. Even in Western countries, severe cases of measles have been found in children with borderline vitamin A stores, suggesting that perhaps parenteral vitamin A should be administered in this setting as well.
Health professionals must keep in mind that defi ciency of vitamin A in the United States may develop after the long-term use of several medications. Drug-induced nutritional defi ciencies, in general, particularly those involving vitamin A, occur most frequently among elderly persons, because they use medications in the largest number for the most prolonged duration, and they may have borderline nutritional status to begin with. Among the drugs most relevant to compromising vitamin A status are mineral oil, which dissolves this nutrient; other laxatives, which accelerate intestinal transit and may diminish the magnitude of vitamin A absorption; cholestyramine and colestipol, which bind vitamin A; and, under certain conditions, neomycin and colchicines. Olestra may possibly interfere with absorption of a number of vitamins, including A: patients using this agent have been advised to take a multivitamin supplement regularly.
LABORATORY DIAGNOSISOF DEFICIENCY
The laboratory diagnosis of vitamin A defi ciency is based on the fi nding of a low plasma retinal; levels below 10 μg/dl signify severe or advanced defi ciency. Interpretation of plasma retinal concentrations may be confounded, however, by a number of other factors, such as generalized malnutrition and weight loss. Some authorities have preferred to utilize a form of retinal toler-ance test, measuring the increment in serum vitamin A levels over 5 h following an oral load of vitamin A.
PREVENTION
Defi ciency of vitamin A can be prevented by a diet high in carotenes, which serve as precursors to vitamin A. The carotenes, particularly β-carotene, are derived exclusively from plant sources, the richest of which are palm oil, carrots, sweet potatoes, dark green, leafy vegetables, cantaloupe, oranges, and papaya. Preformed vitamin A is derived only from animal sources, such as dairy products, meat, and fi sh. The commercial preparations of fi sh oils are rich, sometimes too rich, as sources of preformed vitamin A.
The nutritional value of dietary sources of vitamin A may be compromised when food items are subject to oxidation, par-ticularly in the presence of light and heat. Antioxidants, such as vitamin E, may prevent the loss of vitamin A activity under these conditions.
TREATMENT
Vitamin A defi ciency has been treated worldwide with single intramuscular injections of massive amounts (100,000 to 200,000 IU) of vitamin A, repeated at intervals of approximately 6 months to 1 year. WHO has recommended that doses of 200,000 IU of vitamin A be given initially and at 2 days to children admitted to hospitals in areas of the world where the case fatality rate is very high. Such doses have been effective and are associated with remarkably little toxicity, perhaps because body stores are markedly depleted at the time of therapy. These doses, however, may produce some acute toxic symptoms in well-nourished persons.
Clinical vitamin A defi ciency in the United States can be treated with either β-carotene if there is normal body conversion to vitamin A or vitamin A itself. Daily doses in the range of 25,000 IU of β-carotene are being consumed by many healthy individuals. The yellowish discoloration of the skin associated with prolonged use of β-carotene is not believed to be harmful.
Vitamin A, in contrast, is quite toxic when ingested in amounts considerably higher than the RDI, especially for prolonged periods. It is probably advisable not to exceed two to three times the RDI for vitamin A when planning a domestic treatment program involving vitamin A administration.
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Congenital malformations, a particularly disturbing consequence of vitamin A overdosage, have been reported in women consuming 25,000 to 50,000 IU daily during pregnancy. The lowest dose of vitamin A that would be completely safe as a supplement for pregnant women is not known defi nitely. Therefore, it is not a good idea for pregnant women to take supplemen-tary vitamin A unless there are specifi c indications, such as malabsorption, or proven diesupplemen-tary defi ciency. Many advisory groups caution that the maximal intake of preformed vitamin A consumed during pregnancy should not exceed 10,000 IU/day.
At present, there is widespread interest in newer therapeutic applications of vitamin A and its derivatives. Certain forms of leukemia have been found to respond to derivatives of vitamin A. The therapeutic potential of this vitamin is being expanded greatly in studies of chemoprevention and treatment of cancer. The toxicity of large doses of vitamin A places important limits on its feasibility in cancer prevention. Attention has turned to β-carotene and related agents, which, in addition to their role as precursors of vitamin A, have strong antioxidant activity and other effects as well. β-Carotene, however, may possibly pose a risk in heavy smokers — two studies in this population have shown an actual increase in prevalence of lung cancer when β-carotene was administered for several years.
Diminished prevalence of certain cancers has been found among people whose intake of fruits and vegetables is high; this fi nding has been attributable at least in part to the high content of carotenoids in the diet. However, many phytochemicals in addition to carotenoids have been found in fruits and vegetables with potential health benefi ts. Some data show that a combina-tion of antioxidants (i.e., vitamin E, vitamin C, and β-carotene) may be more effective than any of these single agents, providing more evidence in favor of moderation and variety in the diet.
VITAMIN E FUNCTIONS
A generally accepted role for vitamin E is as a scavenger of free radicals, and in this capacity it protects cell membranes from damage. The role of vitamin E as an antioxidant in health and disease has attracted wide interest. It has many other properties as well. Vitamin E is essential for the immune system, particularly T-lymphocytes, and has a role in DNA repair. Interest is growing in the effect of vitamin E on inhibiting oxidation of low-density lipoprotein (LDL); oxidized LDL becomes more atherogenic.
The neuromuscular system and the retina also require vitamin E for optimal function.
Vitamin E may have additional cellular protective effects. There is evidence that this vitamin may protect sulfhydryl groups in enzymes and other proteins. Similarly, stores of vitamin E may be conserved by the glutathione-S-transferase system, which utilizes reduce glutathione and serves similar antioxidant functions.
DEFICIENCY
Dietary vitamin E defi ciency is relatively unusual in the United States under ordinary circumstances, as sources of vitamin E are widely available from the food supply. The recognizable cases of vitamin E defi ciency tend to arise in debilitated patients who have had severe and prolonged periods of fat malabsorption. Vitamin E is incorporated into chylomicrons with other products of fat digestion during the process of intestinal absorption. Any illness that interferes with fat digestion, absorption, or metabolism may also impair absorption of vitamin E. Disorders in which symptomatic vitamin E defi ciency develops include cystic fi brosis, celiac disease, cholestatic liver disease, and short-bowel syndrome from any cause.
Major abnormalities of neurologic function are observed in a severe and prolonged vitamin E defi ciency state. Patients display arefl exia, ophthalmoplegia, and disturbances of gait, proprioception, and vibration. In premature infants, vitamin E defi ciency results in hemolytic anemia, thrombocytosis, edema, and intraventricular hemorrhage. There is increased risk of retrolental fi broplasia and bronchopulmonary dysplasia under these circumstances.
In hemolytic anemia, such as that caused by glucose-6-phosphate dehydrogenase defi ciency and sickle cell anemia, vitamin E levels in blood tend to be decreased. Inborn errors of vitamin metabolism have been identifi ed, but are rare. There are severe neurologic abnormalities in this category. In abetalipoproteinemia, there is a defect in the serum transport of vitamin E. A
In hemolytic anemia, such as that caused by glucose-6-phosphate dehydrogenase defi ciency and sickle cell anemia, vitamin E levels in blood tend to be decreased. Inborn errors of vitamin metabolism have been identifi ed, but are rare. There are severe neurologic abnormalities in this category. In abetalipoproteinemia, there is a defect in the serum transport of vitamin E. A