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Deficient dietary intake of vitamin E in patients with taste and smell dysfunctions:

Deficient dietary intake of vitamin E in patients with taste and smell dysfunctions:

HYPOTHESIS: FOOD FOR THOUGHT Deficient Dietary Intake of Vitamin E in Patients With Taste and Smell Dysfunctions: Is Vitamin E a Cofactor in Taste Bu...

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HYPOTHESIS: FOOD FOR THOUGHT

Deficient Dietary Intake of Vitamin E in Patients With Taste and Smell Dysfunctions: Is Vitamin E a Cofactor in Taste Bud and Olfactory Epithelium Apoptosis and in Stem Cell Maturation and Development? R. I. Henkin, PhD, MD, and J. D. Hoetker, BS From The Taste and Smell Clinic, Washington, DC, USA OBJECTIVES: We reviewed dietary intake of several nutrients in a large group of patients with taste and smell dysfunction, compared intake of these nutrients with standard values, and recognized that intake of vitamin E was significantly less than that of most other nutrients. Based on this observation we attempted to develop an hypothesis of the possible role vitamin E might play in these sensory disorders. METHODS: Vitamin E intake was measured in 250 patients with taste and smell dysfunctions. RESULTS: Intake of the vitamin was 3.2 ⫾ 0.2 mg/d (mean ⫾ standard error of the mean), or 36 ⫾ 2% of the recommended daily allowance, an intake significantly below that considered adequate. This diminished intake occurred with normal intake of total calories; protein; fat; carbohydrate; several vitamins, including thiamin, niacin, and pyridoxine; and the trace metals zinc, copper, and iron. CONCLUSIONS: Although specific relations between vitamin E intake and smell and taste dysfunctions are unclear, the non-antioxidant roles of vitamin E indicate that it is a factor in apoptosis, cellular signaling, and growth of various cell lines, suggesting that this vitamin may play a role in growth and development of stem cells in taste buds and olfactory epithelium. Nutrition 2003;19:1013–1021. ©Elsevier Inc. 2003 KEY WORDS: vitamin E, taste, smell, sensory dysfunction, stem cells, growth, development, sensory processes, apoptosis, olfactory epithelium, taste buds

INTRODUCTION Taste and smell dysfunctions, loss of acuity, and the presence of distortions occur in patients with a variety of clinical disorders involving neurologic, oncologic, endocrine, metabolic, genetic, and nutritional processes (Table I).1 These processes influence neural and receptor functions through specific neurochemical and biochemical effects.2,3 Human taste and smell dysfunctions reflect pathology dependent on complex systems that control food intake, protect the body from exposure to harmful vapor-phase pollutants, and perform many aspects of protective and pleasurable behaviors. To understand the impact of pathology in these complex systems, it is necessary to understand the basic components of these systems. Each of these systems involve three components that are subject to pathologic processes. These include brain, cranial nerves, and specific sense organs. Clinical disorders that compromise function do so by altering function in one or several components of these systems.2,3 Thus, a stroke or a brain tumor can alter taste or smell function by affecting vascular, oncologic, or other central nervous system (CNS) pathology. Vitamin B12 or thiamin deficiencies can alter function in transmission along nerves subserving olfactory and gustatory functions. However, most clinical disorders causing taste and smell dysfunctions compromise function at the sensory end organ, and in this work attention focuses mainly on

Presented in part at Experimental Biology 2000; San Diego, California; April 2000. Correspondence to: R. I. Henkin, Taste and Smell Clinic, 5125 MacArthur Boulevard, NW, Washington, DC 20016, USA. E-mail: [email protected] earthlink.net Nutrition 19:1013–1021, 2003 ©Elsevier Inc., 2003. Printed in the United States. All rights reserved.

TABLE I. CAUSES OF TASTE AND SMELL DYSFUNCTION System or process Neurologic Genetic Oncologic Infectious Endocrine Metabolic Nutritional

Disease examples Head injury, stroke, Alzeimer’s disease Refsum’s disease, abetalipoproteinemia Cancer of lung, gastrointestinal tract Viral (rhinovirus), bacterial (diphtheria) Hypothyroidism, Cushing’s syndrome Gout, cirrhosis, malabsorbtion syndromes Trace metal deficiencies: zinc, copper; vitamin deficiencies: B12, thiamine, niacin, vitamin E?

this aspect of taste and smell dysfunctions because this may be the major locus of vitamin E effects. Among nutritional processes, trace metal deficiencies involving copper,4 – 6 zinc,7–11 or other trace metals12 have initiated loss and distortion of taste and smell functions. Among vitamin deficiencies, vitamin B12 deficiency induced not only the well-recognized combined system disease13 but also other neurologic abnormalities14 –19 and lingual cheilosis,12,20 the red, beefy appearance of the lingual surface that is anatomically devoid of lingual papillae, with associated perversion of taste12,16; perversion and loss of smell21 and decreased flavor perception reportedly were unrelated to lingual cheilosis, but taste loss was associated with absence of lingual papillae.22 Although the metabolic defect affecting neural function in vitamin B12 deficiency is unclear, it is associated with swelling of neuronal fibers, distention of the neural myelin sheath, defective metabolism of myelin lipid with subse0899-9007/03/$30.00 doi:10.1016/j.nut.2003.08.006

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Vitamin E and Taste and Smell Functions

Nutrition Volume 19, Numbers 11/12, 2003 TABLE II.

CLINICAL DIAGNOSIS OF PATIENTS WITH TASTE AND SMELL DYSFUNCTION IN WHOM VITAMIN E INTAKE WAS EVALUATED Taste loss type (%) Diagnosis Post–influenza Post–concussive syndrome Allergic rhinitis Idiopathic Dysgeusia/dysosmia Cyclic phantosmia Other Total

Patients (n)

Total (%)

Dysgeusia and/or dysosmia present (%)

Total (%)

103 34 36 20 15 5 37 250

41 14 14 8 6 2 15 100

74 20 20 12 15 5 20 166

72 59 56 60 100 100 54 66

quent defective myelin synthesis, and disruption of neural conduction.14,15 Thiamin deficiency is associated with multiple neurologic abnormalities described in the syndrome known as beriberi20,23; thiamin deficiency induces peripheral neuropathy with axonal atrophy. CNS symptoms include Wernicke-Korsakoff syndrome20 with associated taste24 and smell25 dysfunctions. Niacin deficiency is associated with multiple neurologic abnormalities common to the syndrome known as pellagra,20,26 with associated lingual cheilosis,26 loss of lingual papillae,27 and reported distortion of taste and smell28; although reported anecdotally, there also was an associated loss of taste and smell with what was termed subclinical pellagra.28 Vitamin A deficiency reportedly induces night blindness29 and xerophthalmia.30 Vitamin A treatment was reported to return smell function to normal in a group of patients with smell loss, although their vitamin A status was not reported.31 Taste loss in animals was reportedly associated with vitamin A– dependent cellular metaplasia with lingual keratinization and decreased tastant accessibility to taste pores.32,33 Studies in which vitamin A deficiency was induced by vitamin deprivation over a period of 4 to 8 mo resulted in loss of taste and smell functions,22 with pathologic derangement of taste buds similar to that observed in patients after a viral-induced loss of taste34 as observed by transmission electron microscopy. Vitamin E deficiency has been associated with several neurologic abnormalities in humans involving the CNS35,36 and the peripheral nervous system,37,38 with resultant ophthalmoplegia, diminished deep tendon reflexes, decreased vibratory and proprioceptive functions, and ataxia. Vitamin E deficiency also has been reported to cause spinocerebellar degeneration and centrocecal scotomata39 in addition to peripheral neuropathy.38 A variety of mechanisms has been suggested as responsible for these changes40 including diminished antioxidant and non-antioxidant effects dealing mainly with abnormalities in lipid metabolism. Vitamin E deficiency has been reported to inhibit nerve regeneration per se,41 to play an important role in inhibition of glutamate toxicity,42 and to stabilize neural membranes.43 Mechanisms associated with vitamin deficiency–induced changes in taste and smell have not been vigorously pursued. These changes have not been considered clinically important, and after recognition of the deficiency, administration of the missing or deficient vitamin usually has been successful in correcting the associated sensory and other neurologic changes. In our studies of patients with taste and smell dysfunctions, we were interested in the role that diet might play in onset and perpetuation of taste and smell dysfunctions and the role sensory dysfunction might play in diet choice. This complex interplay of sensory function and dietary factors has been evaluated to some extent by several investigators.44 –50 Problems encountered in this complex interplay have generated great interest and confusion due to the multiple and complex factors involved in this interaction.

Smell loss type (%)

I

II

III

None

I

II

III

None

0 0 0 0 0 0 0

90 95 55 80 10 5 75

10 5 5 5 5 0 5

0 0 40 15 85 95 20

20 65 10 40 0 0 30

75 35 85 60 5 20 65

5 0 5 0 5 20 5

0 0 0 0 90 80 0

For some time, we have been investigating dietary intake in patients evaluated and treated at The Taste and Smell Clinic in Washington, DC. Although the amount of data collected is daunting, we have from time to time investigated intake of specific nutritional components in an effort to isolate what might be considered key factors related to their sensory dysfunction. In this study we reviewed dietary intake of several nutrients in a large group of patients with taste and smell dysfunctions, compared intake of these nutrients to standard values, and recognized that intake of vitamin E was significantly less than that of most other nutrients. Based on this observation, we attempted to develop a hypothesis of the possible role vitamin E might play in these sensory disorders.

MATERIALS AND METHODS Patients Subjects in this study were 250 consecutive patients who presented to The Taste and Smell Clinic in Washington, DC from 1995 to 1999 for evaluation of taste and smell dysfunctions. These patients were those with these disorders who presented to The Clinic during this period in whom dietary data were obtained. Patients were ages 14 to 89 y (54 ⫾ 1 y, mean ⫾ standard error of the mean [SEM]); 97 were men (age range ⫽ 14 – 89 y, 53 ⫾ 2 y) and 153 were women (age range ⫽ 16 – 83 y, 54 ⫾ 1 y). They had a variety of disorders of taste and smell similar to those previously reported1 (Tables I and II). Patients exhibited a loss of taste or smell acuity (235 patients), a distortion of taste or smell function without accompanying acuity loss (15 patients), or a loss of acuity and the presence of distortions (166 patients). Loss of acuity for taste and smell was defined by a four-step classification based on degree of loss (Table III). Distortions were defined by classification based on the presence or absence of exogenous stimuli (Table III). Among patients in this study, 30% exhibited type I hyposmia, 59% had type II hyposmia, 4% had type III hyposmia, none had anosmia, and 7% had no measurable smell loss (Table II). Seventy seven percent had type II hypogeusia, 7% exhibited type III hypogeusia, 16% had no taste abnormality, and no patient had ageusia or type I hypogeusia (Table II). For distortions, 65% of patients exhibited aliageusia or aliosmia, 40% exhibited phantosmia or phantogeusia, and 55% exhibited aliageusia/aliosmia and phantosmia/ phantogeusia. The proportion of patients in the present series with post-influenza loss of taste and smell acuity was greater than in prior series,1 as was the number of patients with distortions of taste and smell (i.e., dysgeusia or dysosmia; Table III). All studies were performed consistent with a protocol previously approved by the Institutional Review Board of the Georgetown University Medical

Nutrition Volume 19, Numbers 11/12, 2003

Henkin and Hoetker

1015

TABLE III. CLASSIFICATION OF LOSS AND DISTORTION OF TASTE AND SMELL FUNCTION IN RELATION TO ANATOMY, PHYSIOLOGY, AND PATHOLOGY OF TASTE AND SMELL Dysfunction Loss

Distortion

Taste Ageusia Hypogeusia Type I Type II Type III Aliageusia Cacogeusia Torquegeusia Mixed Parageusia Phantogeusia Cacogeusia Torquegeusia Mixed

Smell

Definition

Anosmia Hyposmia Type I Type II Type III Aliosmia Cacosmia Torquosmia Mixed Parosmia Phantosmia Cacosmia Torquosmia Mixed

Center; all patients gave their informed consent to participate in this clinical study.

Dietary Evaluation Each patient was studied by use of a consecutive 3-d diet record collected (2 weekdays and the following weekend day or a weekend day and the following 2 weekdays) before their first visit to The Taste and Smell Clinic. Each patient was given an extensively illustrated packet of written instructions about reporting dietary intake before use of the actual diet record and specific verbal instructions on the telephone before their first clinic visit, which detailed each aspect of diet record collection. Each patient acceded to understanding these instructions before acquisition of the written instructions, which they received in the mail. Each day of the diet record was recorded on each of three separate printed sheets that accompanied the written instructions. The diet record documented 3 d of typical dietary intake. Each time any food or drink was taken, it was noted in the record as the type of food and fluid item taken, the amount of each item taken, if a prepared food, in what manner, with what ingredients, and how the item was prepared. At the patient’s first clinic visit, each item noted on each diet record was reviewed with a trained nutritionist. Any omission or error with respect to any aspect of any item was corrected at this time. Food models were used to ensure correct food or fluid item size. Diet records were entered by the nutritionist, as previously described,51,52 into a modified Nutritionist IV computer program53 to which an additional list of diet items related to zinc content of foods was included. Because of the diversity of food intake among patients, on occasion, equivalent food or fluid items were used; however, each item was discussed with the patient to ensure that equivalency was achieved. All major nutrient intakes were obtained by this method. For vitamin E, only dietary intake of ␣-tocopherol was calculated. Records of each patient for each item and each nutrient were computed. Intake of each nutrient was expressed in dietary units appropriate for each nutrient, and mean ⫾ SEM for daily intake of each nutrient were obtained. Dietary nutrient intake was compared with the recommended daily allowance (RDA) for each nutrient for each patient related to age, weight, height, and sex. For vitamin E the conservative intake standards of 10 mg of the vitamin for men and 8 mg of the vitamin for women were considered adequate

Inability to detect or recognize any stimuli Decreased ability to detect or recognize any stimuli Absent stimulus recognition Decreased ability to detect or recognize stimuli Decreased ability to judge stimulus intensity From environmental, exogenous stimuli Rotten, decayed, fecal Chemical, metallic, bitter, burned Caco- and torqueSkewed but normal (onions smell like roses) From endogenous stimuli Rotten, decayed, fecal Chemical, metallic, bitter, burned Caco- and torque-

(100% of the RDA) as opposed to the recent increase of the RDA for this vitamin to 15 mg for men and for women. Intake of dietary supplements was also recorded, and the supplement contents were verified with review of the supplement nutritional labeling when possible. Means and SEMs were obtained for all nutrients, and significance of differences was determined by Student’s t test.

RESULTS Mean dietary intake of vitamin E in all patients with taste and smell dysfunctions is shown in Table IV. Intake ranged from 0.08 to 33.1 mg/d, with a mean daily intake of 3.2 mg for the total group. This intake reflected a mean intake of 35% of the RDA (Table IV). Women took in a mean of 2.8 mg, a significantly (P ⬍ 0.001) lower amount of vitamin E than did men who had a mean intake of 3.8 mg; however, severity of taste or smell dysfunction did not differ between men and women. Based on an RDA of 15 mg, intake of women was 19% of the RDA and that of men was 25% of the RDA, with an overall mean of 21%. To understand in more detail about this dietary lack, daily intakes of other nutrients were investigated. Intakes of calories, protein, fat, and carbohydrate were at levels considered adequate for each nutrient, and intake was no lower than 78% of the

TABLE IV. DIETARY VITAMIN E INTAKE IN PATIENTS WITH TASTE AND SMELL DYSFUNCTIONS Vitamin E Patients (n) Total (250) Men (97) Women (153)

Age (y)*

mg*

%RDA

Range

54 ⫾ 1 53 ⫾ 2 54 ⫾ 1

3.2 ⫾ 0.2 3.8 ⫾ 0.3 2.8 ⫾ 0.1†

36 ⫾ 2 38 ⫾ 4 35 ⫾ 1

0.08–33.1 0.08–26.6 0.21–33.1

* Mean ⫾ standard error of the mean. † P ⬍ 0.001 versus men. RDA, recommended daily allowance

1016

Vitamin E and Taste and Smell Functions

Nutrition Volume 19, Numbers 11/12, 2003 TABLE V.

CALORIE AND NUTRIENT INTAKE IN PATIENTS WITH TASTE AND SMELL DYSFUNCTION* Calories Patients (n) Total (250) Men (97) Women (153)

Protein

Fat

CHO

Vitamin E

Total

% RDA

g

% RDA

g

% DRI

g

% DRI

mg

% RDA

1824 ⫾ 58 2155 ⫾ 69 1610 ⫾ 34

81 ⫾ 2 85 ⫾ 3 79 ⫾ 2

76.2 ⫾ 1.7 89.6 ⫾ 3.0 67.5 ⫾ 1.8

138 ⫾ 3 144 ⫾ 5 134 ⫾ 3

61.4 ⫾ 1.8 74.3 ⫾ 3.5 53.1 ⫾ 1.8

82 ⫾ 2 88 ⫾ 4 78 ⫾ 3

234 ⫾ 5 269 ⫾ 10 212 ⫾ 5

84 ⫾ 2 84 ⫾ 3 83 ⫾ 2

3.2 ⫾ 0.2 3.8 ⫾ 0.1 2.8 ⫾ 0.2

36 ⫾ 2 38 ⫾ 4 35 ⫾ 2

* Mean ⫾ standard error of the mean. CHO, carbohydrate; DRI, dietary reference intake (see Recommended dietary allowance, 16th ed. Washington, DC: National Research Council, 1989); RDA, recommended daily allowance

respective RDA for each nutrient in which such a standard was available (Table V). Intake of fat was significantly lower in women than in men but still within the range considered nutritionally adequate. Daily intake of other nutrients was investigated (Table VI). Intake of several vitamins was at adequate levels with respect to the RDA. However, mean intake of pantothenic acid was at the lower limit of the acceptable RDA, with mean intake by women significantly lower than that by men (P ⬍ 0.001). Mean intakes of biotin and vitamin D for men and women were less than 66% of the RDA for each vitamin, a level generally considered to reflect inadequate intake. Daily intakes of zinc, copper, and iron were at adequate levels with respect to their RDA values (Table VI). Of the entire group, 75 patients took a supplemental multivitamin preparation that usually contained 400 IU of vitamin E in some form and an additional 25 took a preparation of vitamin E containing 200 to 800 IU. Most vitamin E supplements contained ␣-tocopherol. Twenty-seven of these patients took a multivitamin preparation plus a vitamin E supplement. The remainder (125 patients) did not take any vitamin preparation. There was no significant difference in taste or smell dysfunction between the patients taking or not taking vitamin E supplements.

DISCUSSION These results indicate that dietary intake of vitamin E is deficient in patients with taste and smell dysfunctions. In men and women, this deficient dietary intake was observed in the face of adequate intake of calories, protein, fat, carbohydrate, several other vitamins and several trace metals. Mean vitamin E intake for all patients was 3.2 mg/d, or 36% of the old RDA. Using 66% of the RDA as the standard for deficiency, mean intake of these patients constituted approximately one half the RDA for vitamin adequacy and about one third the amount for optimal RDA. These results indicate that these patients were taking in an inadequate amount of this essential nutrient. Compared with the more recently established RDA of 15 mg, mean intake reflected intake of about one fifth the optimal RDA or about one third the RDA considered necessary for adequate intake. Even when intake of dietary supplements of vitamin E are considered, about 60% of the total group was taking nutritionally inadequate amounts of vitamin E. Despite this low intake of vitamin E, neurologic symptoms reportedly related to vitamin E deficiency were not present in these patients. It is well known that severe and longstanding vitamin E deficiency induces several neurologic symptoms, but the deficiency was not low or longstanding enough to induce reported symptoms of vitamin E deficiency. Vitamin E concentrations in blood were not measured in this study. This limits specificity of these findings. However, assessment of vitamin E status is reportedly difficult to make because

serum concentrations depend not only on nutrient concentration but also on concentrations of circulating lipoproteins,54 with ␣-tocopherol increasing with degree of hyperlipidemia.55 Other serum substances may influence serum tocopherol. In addition, there is difficulty in assessing bioavailability of vitamin E when using only plasma concentrations of the vitamin are used.56 Blood levels of vitamin E also may not reflect tissue levels of the vitamin, the determining factor in inducing taste and smell dysfunctions in these patients. Intakes of biotin and vitamin D were nutritionally inadequate in these patients, although only biotin intake was deficient in a range comparable to that measured for vitamin E. No clinical symptoms associated with any aspect of decreased biotin or vitamin D intake were observed in these patients. Intakes of zinc, copper, and iron were adequate in these patients. It is well established that zinc2,3 and copper4,5 deficiencies are associated with taste and smell dysfunctions, and iron deficiency has been implicated in pica57 and other aspects of impaired dietary intake.58 With intake of these nutrients at adequate levels, the low levels of vitamin E intake in these patients emphasize the putative relevance of its low intake in the observed taste and smell dysfunctions. A major question raised by these results is the role that vitamin E intake might play in etiology of taste and smell dysfunctions. ␣-Tocopherol plays multiple roles in CNS function. In animals, ␣-tocopherol was found in brain with no detectable tocotrienol59; this distribution is distinctly different from the composition in all other tissues,59 especially because, with vitamin E deficiency, the brain is affected more sensitively than any other tissue.60 Although the roles of vitamin E in neurologic function,35,36,39 as an antioxidant,61 as an anti-nitrating factor,62 and as a factor in retinal function63,64 including macular function65 have received a great deal of attention, this is the first time that any putative interaction between vitamin E and taste or smell has been suggested. Vitamin E deficiency could alter function of any or all components of taste or smell. The brain appears to be the most susceptible of neural tissues to functional changes after vitamin E deficiency.66 Cerebral spinal fluid ␣-tocopherol and ␣-tocopherol quinone levels were significantly lower in patients with amyotrophic lateral sclerosis than in normal subjects.67 Vitamin E deficiency has been conjectured to cause pathology in nigrostriatal pathways in Parkinson’s disease,68 and cerebrospinal fluid ␣-tocopherol was significantly reduced in patients with Parkinson’s disease but increased after L-dopa treatment.69 Brain cell membranes were protected from hypoxic damage after ␣-tocopherol administration.70 Spinal cord changes were observed with spinocerebellar tract degeneration,71 axonal dystrophy with degeneration in the nucleus gracilis and posterior spinal columns and associated ataxia of trunk and limbs, loss of deep tendon reflexes, loss of vibration and position senses, impaired sensory nerve condition velocity,

Nutrition Volume 19, Numbers 11/12, 2003 muscle weakness, and myopathy. Familial isolated vitamin E deficiency is an uncommon autosomal recessive neurodegenerative disease whose clinical presentation is similar to that of Friedreich’s ataxia and is caused by mutations in the gene for ␣-tocopherol transfer protein72; cerebellar atrophy also has been associated with this disease.73 With respect to cranial nerves, lesions in the third (oculomotor) and fourth (trochlear) cranial nerves have been observed with associated ophthalmoplegia and ptosis. Peripheral neuropathy was observed in vitamin E– deficient patients.72 With respect to sense organs, impaired retinal function has been observed with vitamin E deficiency.63,73–75 However, no prior data about vitamin E in the function of taste buds or olfactory epithelium has been published. To entertain a possible interaction between vitamin E deficiency and taste or smell dysfunction, a discussion of the function of taste buds and olfactory epithelia may be helpful. At the level of the sensory organ, several complementary functions are involved. Sensory transduction involves several specific steps: 1) binding of a tastant or odorant to a specific receptor (in cilia-like projections from type III cells of taste buds76 and in cilia of olfactory mitral cells,77 respectively), 2) transduction of the chemical binding process via trimeric G protein processes in both systems with subsequent activation of cyclic guanosine monophosphate or cyclic adenosine monophosphate,78 – 81 and 3) subsequent activation of appropriate channels82– 84 with 4) ultimate membrane depolarization85 and initiation of the electrical discharge,2,86 which is carried through the appropriate sensory nerves to the brain. Taste or smell pathology can occur at each step of this process. However, sensory end organ function dealing with growth, development, and maturation of taste buds and olfactory epithelial cells may be more directly related to putative vitamin E effects. Taste buds and olfactory epithelial cells are unique tissues in that their functioning sensory cells do not contain blood vessels or lymphatic channels, with only stem cells of these systems exhibiting mitosis; i.e., the receptors and supporting cells of these systems do not exhibit mitoses.11,34 Receptor and supporting cells of both tissues depend on stem cells (perigemmal cells for taste buds11 and basal cells for olfactory epithelium11) to induce the elegant repertoire of cells that serve as active components of taste buds or olfactory epithelium. These stem cells transmit a specific program to each cell type of taste buds and olfactory epithelium, such that rapid apoptosis occurs in taste bud cells (total turnover in 24 to 48 h) and a variety of apoptotic time factors occur in olfactory epithelial cells (total turnover in 12 h to 30 d). For taste, stem cell maturation and development depend mainly on growth factors produced in and secreted from the parotid gland and transmitted via saliva in a paracrine-type system to taste buds11; similarly for smell, growth factors are produced in and secreted from nasal serous glands and transmitted via nasal mucus in a paracrine-type system similar to olfactory epithelium.11,87,88 This paracrine aspect is part of the unique character of these two sensory systems in which cellular function is maintained in the face of multiple physiologic, environmental, and local factors that act to inhibit function of these two systems. Because these systems are so important to the survival of the organism, there should be no surprise that there are multiple growth factors that control these critical sensory organs. The physiologic relevance of these systems is clearly apparent. Taste buds act as guardians of the gastrointestinal tract by protecting the body from poisoning and directing the body organism, with minimal energy expenditure, to sweet or carbohydrate-rich foods and liquids to supply appropriate nourishment.89 Olfactory epithelial cells, acting as a distance sense, direct the body, with minimal energy expenditure, to nourishing sweet or carbohydrate-rich foods to obtain maximal nutrient sources; they also interact with endocrine and neuroendocrine systems to ferret out specific sexrelated responses to maximize several activities at ovulation, provide signal protection for the female of the species from predatory

Henkin and Hoetker

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males of the same or other species after copulation and fertilization, and minimization of energy expenditure to perform these critical acts of species propagation. In addition, this latter sensory organ serves as the guardian of the respiratory tract so that distant noxious vapors can be avoided and the body organism is spared from exposure and contact with noxious and harmful substances.88,89 Thus, these sensory organs require careful protection because without them life itself would be in constant danger. Thus, phylogenetically, growth factors were synthesized to protect, grow, and develop these sensory organs by direct action on stem cells of each sensory end organ to maintain these systems in the face of the myriad of factors that mitigates against their survival. Taste buds and olfactory epithelial cells are also unique among sense organ receptors in that they are directly exposed to the external environment and are subject to the exigencies of the local environment. Thus, there are a myriad of putative agents that can negatively impinge on taste bud and olfactory epithelial cell anatomy, physiology, and biochemistry and negatively alter function. Thus, if pathology of any type were to affect growth or development of either sense organ, function would be impaired because its basic structural integrity would be compromised. This aspect of sensory end organ function itself has several components. Growth factors are synthesized in specialized glandular cells; for taste these factors are found primarily in the parotid glands but also submandibular glands; for smell, these substances are found primarily in nasal serous glands.88 Multiple genes, gene products, substrates, and cofactors are required for appropriate synthesis and control of these growth factors.90 Nutritional intake is critical for effective control of growth factor synthesis affecting the rate and availability of substrates and cofactors of growth factor function. Impairment of nutritional intake, which might compromise availability of gene function, gene product secretion, substrate or cofactor availability or secretion, could be devastating to sensory end organ survival. Due to unique paracrine effects of synthesis and delivery systems of these growth factors, cells of parotid glands and nasal serous glands communicate via their secretions to stem cells in taste buds and olfactory epithelium to initiate and effect growth and development of the entire cellular repertoire of these sensory end organs. This system is analogous in some manner to the endocrine system in which hormones synthesized in a specific glandular structure are secreted into blood to initiate a physiologic effect at a distant end organ. Pathology that inhibits salivary flow uniformly initiates taste loss and that which inhibits nasal mucus secretion initiates smell loss. This effect was observed after irradiation of the oral cavity91,92 and subsequently in patients with Sjo¨ gren syndrome who exhibit xerostomia and xerorhinia.93 This effect was demonstrated in animal studies in which salivary glands had been surgically extirpated.94 Examination of the sensory end organ under these conditions demonstrated a characteristic anatomic appearance consistent with apoptosis,95,96 as first observed in humans.34 Re-initiation of salivary flow or nasal mucus secretion was associated with reinstitution of taste and smell functions105 and with normalization of sensory end organ anatomy as observed with other treatment modalities.11,34 Inhibition of local neural function supplying taste buds induced loss of taste; peripheral anesthesia of the seventh and ninth cranial nerves induced a relative loss of taste for salt and sweet tastants,97 whereas anesthesia of the dorsal ninth and tenth cranial nerves induced a relative loss of taste for sour and bitter tastants.97 These changes in acuity did not interfere with salivary flow and did not alter taste bud anatomy because normal taste function was restored immediately after remission of the anesthetic effect. Total extirpation of the olfactory epithelium, as occurs after surgical treatment of cancer of the sinuses, uniformly induced type I hyposmia; i.e., removal of the entire olfactory epithelium destroyed the ability to recognize vapors, although detection was preserved at the so-called accessory olfactory regions1,98 (Table

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Vitamin E and Taste and Smell Functions

Nutrition Volume 19, Numbers 11/12, 2003 TABLE VI.

NUTRIENT INTAKE IN PATIENTS WITH TASTE AND SMELL DYSFUNCTION* Vitamin A Patients (n) Total (250) Men (97) Women (153)

Thiamin

Niacin

Riboflavin

Pyridoxine

Folate

Vitamin C

RE

%RDA

mg

%RDA

mg

%RDA

mg

%RDA

mg

%RDA

␮g

%RDA

mg

%RDA

1835 ⫾ 267 2213 ⫾ 486 1590 ⫾ 308

138 ⫾ 8 142 ⫾ 14 135 ⫾ 9

1.5 ⫾ 0.04 1.7 ⫾ 0.06 1.3 ⫾ 0.05

125 ⫾ 5 131 ⫾ 5 120 ⫾ 5

21.2 ⫾ 0.6 25.3 ⫾ 1.1 18.5 ⫾ 0.6

141 ⫾ 4 152 ⫾ 7 134 ⫾ 5

1.6 ⫾ 0.04 1.8 ⫾ 0.07 1.4 ⫾ 0.04

116 ⫾ 3 121 ⫾ 5 116 ⫾ 4

1.7 ⫾ 0.06 1.9 ⫾ 0.09 1.5 ⫾ 0.08

93 ⫾ 3 97 ⫾ 4 90 ⫾ 3

234 ⫾ 8 275 ⫾ 14 208 ⫾ 8

124 ⫾ 4 139 ⫾ 7 114 ⫾ 4

129 ⫾ 5 140 ⫾ 9 122 ⫾ 6

213 ⫾ 8 234 ⫾ 15 200 ⫾ 10

* Mean ⫾ standard error of the mean. RDA, recommended daily allowance; RE, retinol equivalent

III). Installation of cocaine at the olfactory epithelium initiated temporary loss of smell function.99 These results emphasize pathology in these systems related to their structure–function relationships and emphasize the direct relation between sensory end organ growth and development and specific sensory function of these end organs. Identity of these growth factors have only recently been discovered.9,10,100 They include carbonic anhydrase (CA) VI9,10,100 and adenylyl cyclase.101 Decreased secretion of these enzymes is associated with loss of taste10,11 and smell101; re-initiation of secretion of each enzyme is associated with return of taste10,11 and smell101 functions to normal. For example, zinc deficiency of any etiology inhibits availability of zinc cofactor to the zinc metalloenzyme CA-VI and induces taste loss.10 Administration of CA inhibitors sulfonamides,102 acetazolamide,103 sulfasalazine,104 topiramate,105 or dorzolamide106 initiated loss of taste, which returned to normal after stopping the drug. Zinc administration to patients with CA-VI deficiency disease initiated stimulation of gene function (located on the short arm of chromosome 1107) with enhanced secretion of the gene product, the enzyme CA-VI, with subsequent return of taste and smell functions to normal.11 Various hormones affect taste and smell functions. Lack of thyroid hormone is associated with taste and smell dysfunctions in humans108 and animals109; replacement of this hormone returns taste and smell functions to normal.110 Although the role of thyroid hormone on stem cell function in taste buds or olfactory epithelium is unknown, thyroid hormone111 and testosterone112 play roles similar to that of nerve growth factor (NGF) in several systems; CA-VI has activity similar to that of NGF in isolated, purified taste bud membranes113–115; and thyroid hormone also may influence CA-VI.115 Cyclic adenosine monophosphate analogs exhibit NGFlike activity in that they promote neural outgrowth independent of NGF.116 These results indicate that substances such as minerals, hormones, and secondary messengers play roles as cofactors or growth factors in taste bud and olfactory epithelial cell stem cell maturation and development. Vitamins such as vitamin E may play similar roles. Growth factors, in addition to their direct effects on stem cell growth and maturation, play roles in apoptosis in the control of normal and pathologic growth in stem cell maturation and development. Several of the interventions that induce taste loss and anatomic change in taste buds are consistent with well-known apoptotic effects. Zinc deficiency117 and irradiation118,119 are involved in apoptosis in several cell lines and tissues. Zinc may play a dual role in the sense that deficiency and excess trace metal may induce apoptosis. Indeed, apoptosis is a necessary component of normal cellular turnover in taste bud and olfactory epithelial cells, with pathology occurring only after induction of excessive cellular turnover with subsequent massive cell death. This may be analogous to the antiapoptotic and neuroprotective character of some members of the Bcl-2 family (e.g., Bcl-2 itself)120 and to the

(continued)

proapoptotic and neurodegenerative character of other members of the family (e.g., BAX).121 This complex interaction of pro- and antiapoptotic properties of growth factors acting on cells of these sensory end organs emphasizes the fundamental complexity of these processes. How might vitamin E fit into this complex scheme, and how might vitamin E deficiency contribute to taste and smell dysfunction? Although the antioxidant effects of vitamin E are well known, there are obviously other non-antioxidant roles of this vitamin on physiology and metabolism.122 Indeed, vitamin E effects on function of spinal cord, cranial nerves, and retina may not relate to antioxidant mechanisms at all.122 Recent studies have identified a vitamin E–responsive protein in olfactory epithelium whose function has not yet been identified.123 Other studies using immunohistochemical techniques with an antibody to human ␣-tocopherol transfer protein described a protein in Purkinje cells of cerebellum in patients with vitamin E deficiency with ataxia and other CNS symptoms.124 Specific molecular effects of ␣-tocopherol have been demonstrated on protein kinase C,122,125 on growth of a variety of cell lines40,122,125–127 including smooth muscle cells,127 on transcription of some genes,122,128 and on signaling processes in specific cell types.129 Specific molecular activation events also have been ascribed to vitamin E including activation of protein phosphatase PP2A through dephosphorylation of protein kinase C-␣.128 Non-antioxidant molecular mechanisms also have been described for ␣-tocopherol, ␥-tocopherol, and tocotrienols, including unique signal transduction processes,129 although these effects may be less profound than those of ␣-tocopherol.122 If vitamin E deficiency affects the function of a protein growth factor, then specific changes in olfactory epithelial cells could be identified associated with loss of smell acuity. Vitamin E recently has been shown to play a role in apoptosis in several cell lines,130,131 in Purkinje cells of the cerebellum,124 and in cortical neurons of several types.132,133 Like zinc, vitamin E has proapoptotic and anti-apoptotic properties, and its relative absence could inhibit taste bud and olfactory epithelial cell growth and maturation through these complex effects. In this sense, dietary deficiency of this vitamin could be a factor in these complex effects. Although not implicated in any specific pathologic process, vitamin E deficiency has been suggested as an etiologic factor in Alzheimer’s disease,134,135 a disorder in which smell loss is an early pathologic marker,136,137 in tardive dyskinesia138,139 and in Parkinson’s disease,140,141 also a disorder in which smell loss is an early marker.142 Treatment with vitamin E has been considered clinically useful by some investigators in various neurologic disorders143 including patients with Alzheimer’s disease144,145 and tardive dyskinesia146 but not in Parkinson’s disease.147 No effects of this vitamin on smell function in any of these disorders have been reported. However, positive treatment effects of vitamin E in Alzheimer’s disease were recognized only after prolonged treat-

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TABLE VI. (continued) Biotin Patients (n)

␮g

%RDA

Pantothenic acid mg

% RDA

Vitamin D

␮g

%RDA

Vitamin K

␮g

Vitamin B12

%RDA

␮g

%RDA

Zinc mg

Copper %RDA

mg

%RDA

Iron mg

%RDA

Total (250) 18.0 ⫾ 0.8 27 ⫾ 1 3.6 ⫾ 0.1 66 ⫾ 2 11.2 ⫾ 3.4 51 ⫾ 4 148 ⫾ 13 185 ⫾ 11 2.5 ⫾ 0.3 125 ⫾ 9 8.8 ⫾ 0.6 73 ⫾ 3 1.6 ⫾ 0.1 73 ⫾ 1 13.7 ⫾ 0.9 137 ⫾ 5 Men (97) 21.1 ⫾ 1.1 32 ⫾ 2 4.3 ⫾ 0.2 78 ⫾ 2 18.9 ⫾ 8.2 59 ⫾ 6 175 ⫾ 30 182 ⫾ 18 2.4 ⫾ 0.3 120 ⫾ 9 10.6 ⫾ 0.9 88 ⫾ 6 1.8 ⫾ 0.1 82 ⫾ 2 15.6 ⫾ 1.3 156 ⫾ 9 Women 16.0 ⫾ 0.6 24 ⫾ 1 3.2 ⫾ 0.1 58 ⫾ 2 6.2 ⫾ 1.9 47 ⫾ 4 131 ⫾ 10 188 ⫾ 14 2.6 ⫾ 0.3 130 ⫾ 8 8.1 ⫾ 0.5 68 ⫾ 5 1.5 ⫾ 0.1 68 ⫾ 2 12.4 ⫾ 0.6 124 ⫾ 4 (153)

ment with the vitamin (⬎2 y) and with large daily doses (ⱖ2000 IU daily). We treated a group of seven patients with severe taste and smell dysfunctions resistant to all other known methods of successful therapy with exogenous vitamin E, 2000 IU/d. Early results after 6 to 8 mo of treatment resulted in no change in their taste or smell dysfunction; their serum levels of ␣-tocopherol ranged from 18.1 to 64.1 ␮g/mL (35.4 ⫾ 7.0, mean ⫾ SEM), with serum ␤- and ␥-tocopherol values ranging from 0.2 to 1.0 ␮g/mL (0.6 ⫾ 0.1). The putative role of vitamin E as a growth factor in stem cell function in taste buds and olfactory epithelial cells and in initiation of proapoptotic and antiapoptotic effects offers an attractive concept of pathology and a potential mode of treatment for the symptoms of these patients. Future studies will produce data about the putative role of vitamin E in correction of taste and smell dysfunctions and about its role as a cofactor in cellular growth and development and in cellular apoptosis.

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