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Original Research Communications |
| ABSTRACT |
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Objective: The objective was to test the hypothesis that age-related hearing loss may be associated with poor vitamin B-12 and folate status.
Design: A thorough audiometric assessment was conducted in 55 healthy women aged 6071 y. Hearing function was determined by the average of pure-tone air conduction thresholds at 0.5, 1, 2, and 4 kHz and was categorized into 2 groups for logistic regression analyses: normal hearing (<20 dB hearing level; n = 44) and impaired hearing (
20 dB hearing level; n = 11).
Results: Mean age was the same (65 y) for the normal hearing and impaired hearing groups. Pure-tone averages were inversely correlated with serum vitamin B-12 (r = -0.58, P = 0.0001) and red cell folate (r = -0.37, P = 0.01). Women with impaired hearing had 38% lower serum vitamin B-12 (236 compared with 380 pmol/L, respectively, P = 0.008) and 31% lower red cell folate (425 compared with 619 nmol/L, respectively, P = 0.02) than women with normal hearing. Among participants who did not take supplements containing vitamin B-12 or folate, women with impaired hearing had 48% lower serum vitamin B-12 (156 compared with 302 pmol/L, respectively, P = 0.0007) and 43% lower red cell folate (288 compared with 502 nmol/L, respectively, P = 0.001) than women with normal hearing.
Conclusion: Poor vitamin B-12 and folate status may be associated with age-related auditory dysfunction.
Key Words: Age-related hearing loss impaired hearing hearing impairment presbycusis presbyacusis vitamin B-12 folate atrophic gastritis elderly women humans
| INTRODUCTION |
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24% in those aged 6574 y and
40% among those
75 y of age (3). Along with heart problems, hypertension, and arthritis, hearing impairment is 1 of the 4 leading chronic health conditions experienced by the elderly (1). Despite the high prevalence of hearing impairment, the biological basis of age-related hearing loss is unknown. Hughes (5) suggested that diet may play a role in the pathogenesis of many auditory disorders. Auditory dysfunction has been associated with deficiencies of several micronutrients in humans (69) and young growing animals (1014). However, we found no studies in humans or experimental animals that specifically examined the role of nutrition in age-related hearing loss.
We propose that age-related hearing loss may be associated with poor micronutrient status. Two of the most common vitamin inadequacies in the elderly are vitamin B-12 and folate (15). In addition, atrophic gastritis affects
2030% of those aged
60 y and can lead to the malabsorption of vitamin B-12 (16, 17). Anywhere from 515% of the elderly population may be vitamin B-12 deficient (18), and the prevalence of folate deficiency in the elderly has been estimated at 220% (19). We suspect that the roles of vitamin B-12 and folate in cellular metabolism, the nervous system, and vascular function (9, 2022) are important for the auditory system.
The cochlea of the inner ear is where much of the hearing loss in the elderly is believed to occur (23). The cochlea is highly vascularized and is supported by a single artery. High homocysteine concentrations associated with low vitamin B-12 status, low folate status, or both were shown to be a risk factor for cerebral, coronary, and peripheral vascular disease (24). Perhaps high homocysteine concentrations associated with poor vitamin B-12 or folate status also adversely affect blood flow to the cochlea.
Low vitamin B-12 status may also impair myelination of the neurons in the cochlear nerve. Deficiencies of vitamin B-12 and folate or impaired methionine synthase activity results in decreased S-adenosylmethionine synthesis, the primary source of methyl groups in the nervous system, which may impair methylation reactions in myelin synthesis (25). Alternatively, during vitamin B-12 deficiency, accumulation of methylmalonyl-CoA and propionyl-CoA may result in the synthesis of branched or odd-numbered fatty acids, which may interfere with myelin formation (25).
Only a few investigators have examined the possible associations between poor vitamin B-12 (8, 9, 14, 2628) or folate (8) status and auditory dysfunction, and little attention has been given to the possible role of these nutrients in age-related hearing loss. Therefore, the objective of this study was to determine whether age-related hearing loss is associated with poor vitamin B-12 status, poor folate status, or both.
| SUBJECTS AND METHODS |
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Methods
Blood was collected between 0730 and 1000 after an overnight fast. Complete blood counts and hematologic measures of whole blood, and serum analyses to evaluate liver, kidney, and thyroid function were conducted by a local clinical laboratory (SmithKline-Beecham Clinical Laboratories, Atlanta). Blood samples (n = 48) for the vitamin analyses were frozen at -70°C in cryogenic vials with minimal air space (Nalgene Brand Products, Rochester, NY) until analyzed. Red cells were frozen in 1% ascorbic acid. Serum vitamin B-12, red cell folate, and serum folate were analyzed at the Centers for Disease Control and Prevention in Atlanta (30) with the Quantaphase II B-12/Folate Radioassay (Bio-Rad, Richmond, CA). Seven participants did not provide a sufficient amount of blood to allow measurements of serum vitamin B-12, red cell folate, and serum folate. Serum pepsinogen I was assessed as an indirect index of atrophic gastritis by radioimmunoassay (INCSTAR Corporation, Stillwater, MN).
The participants' histories of chronic health problems and current medications were obtained. While participants were seated, blood pressure was measured 3 times in the right arm during an 810-min period with an automated instrument (Critikon Inc, Tampa, FL). Three days of dietary records, including one 24-h recall and 2 d of participant diet records (from 2 weekdays and 1 weekend day), were collected and analyzed using the FOODPROCESSOR software (version 6.08; ESHA, Salem, OR). Average daily dietary intakes of vitamin B-12 and folate were determined. The types of vitamin and mineral supplements and the duration and frequency of their use were obtained, and average daily intakes of vitamin B-12 and folate from supplements were calculated. Total average daily intakes of vitamin B-12 and folate were determined by combining the dietary and supplemental intakes.
Auditory exams were conducted at the University of Georgia Speech and Hearing Clinic. Otoscopic examinations of the outer ear and ear canal were conducted to detect excessive ear wax, foreign bodies, or other obvious disorders of the ear canal or ear drum that would prevent a safe and reliable evaluation and to identify obvious disorders that might require a medical referral. Air conduction thresholds at octave intervals from 250 to 8000 Hz and bone conduction thresholds at octave intervals from 500 to 4000 Hz were obtained by using a diagnostic audiometer meeting specifications according to Standard S3.6 of the American National Standards Institute (31) and following standard clinical audiometric procedures. Acoustic immittance, otoacoustic emissions, and speech audiometry tests were also conducted. To categorize hearing function, we used criteria similar to those of the National Health and Nutrition Examination Survey (NHANES; 32) and the Framingham Heart Study (33). Hearing function was assessed as the pure-tone average of the 0.5-, 1-, 2-, and 4-kHz pure-tone air conduction thresholds for the better ear as follows: normal hearing, <20 dB hearing level (n = 3844) and impaired hearing,
20 dB hearing level (n = 1011). Pure-tone averages were also categorized into 3 groups as follows for some analyses: excellent hearing, <10 dB hearing level (n = 18); good hearing,
10 and <20 dB hearing level (n = 20); and impaired hearing,
20 dB hearing level (n = 10).
Statistical analysis
In the analyses, P
0.05 was considered statistically significant. Because hearing function was not normally distributed, nonparametric statistical analyses were conducted (SAS version 6.10; SAS Institute Inc, Cary, NC; 34). Spearman correlation coefficients were used to assess the relation between pure-tone averages and concentrations of vitamin B-12 and folate in the blood. Wilcoxon scores were used for univariate analyses of the continuous variables (age, blood concentrations, and dietary indexes) and chi-square tests were used to determine the percentage of participants who took a supplement containing vitamin B-12 or folate (multivitamin, multivitamin and mineral, B-complex, or individual supplement containing vitamin B-12 or folate). Chi-square tests were used to determine the percentages of participants that consumed less than the 1989 recommended dietary allowance (RDA; 35) for vitamin B-12 (<2 µg/d) and folate (<180 µg/d) from the diet, from supplements, and from the diet and supplements combined. Chi-square tests were also used to determine the percentages of participants with serum vitamin B-12 concentrations <221 pmol/L (300 pg/mL), 184 pmol/L (250 pg/mL), and 148 pmol/L (200 pg/mL), red cell folate concentrations <294 nmol/L (130 ng/mL), and serum folate concentrations <7.9 nmol/L (3.5 ng/mL). Logistic regression analyses were used to assess the relation between auditory function and vitamin B-12 or folate nutriture when controlled for age (34). Analyses were conducted in the total sample and in the subset of the sample not taking any of the following supplements: multivitamin, multivitamin and mineral, B-complex, or individual supplement containing vitamin B-12 or folate.
| RESULTS |
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The relations of auditory function to vitamin B-12 and folate status are shown in Table 2
. Pure-tone averages were inversely correlated (Spearman's rank-order correlation coefficient) with serum vitamin B-12 (r = -0.58, P = 0.0001), red cell folate (r = -0.37, P = 0.01), and serum folate (r = -0.36, P = 0.01). Compared with participants with normal hearing, participants with impaired hearing had 38% lower mean serum vitamin B-12, 31% lower mean red cell folate, and 25% lower mean serum folate. The associations between pure-tone averages and blood indexes of vitamin B-12 and folate status remained when these nutrient concentrations were dichotomized into values above and below the 15th percentile from NHANES III (36) and when various cutoff values for vitamin B-12, such as <148 pmol/L (<200 pg/mL), <185 pmol/L (<250 pg/mL), and <221 pmol/L (<300 pg/mL) were used (18, 37). These associations were attenuated when age was controlled for, but remained significant for serum vitamin B-12 and red cell folate. When both serum vitamin B-12 and red cell folate were entered into one logistic regression model as continuous variables, they were not significantly associated with pure-tone averages (P = 0.12 and P = 0.26, respectively, when controlled for age). When both serum vitamin B-12 and red cell folate were entered into one logistic regression model as dichotomous variables (with use of NHANES III cutoff values) they were not significantly associated with pure-tone averages (P = 0.36 and P = 0.07, respectively, when controlled for age).
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The association of supplement use with auditory function was weak and remained weak when age was controlled for (Table 2
). For these analyses, supplements included multivitamins, multivitamins with minerals, B-complex vitamins, vitamin B-12 alone, and folate alone.
Associations between auditory function and vitamin B-12 and folate status were not markedly altered when examined in the subgroup of participants not taking multivitamin or multivitamin and mineral supplements (n = 33; Table 3
). This subgroup was similar to the total sample in that mean serum vitamin B-12 was 48% lower, mean red cell folate was 43% lower, and mean serum folate was 46% lower in women with impaired hearing than in women with normal hearing. These associations were attenuated when age was controlled for, but they remained significant. Women with hearing impairment consumed significantly less vitamin B-12 and folate than women with normal hearing, and these associations remained significant after age and energy intake were controlled for.
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10 and <20 dB hearing level), and impaired hearing (
20 dB hearing level). Dose-response relations between auditory function and blood indexes of folate status were observed in all subjects. However, in the subgroup of participants not taking supplements, blood indexes of folate status were lowest in women with impaired hearing compared with the other 2 groups. The associations between auditory function and serum vitamin B-12 and red cell folate remained significant when age was controlled for. Serum pepsinogen I concentrations, shown in Table 5
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| DISCUSSION |
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Because our sample size was relatively small and serum vitamin B-12 and red cell folate were highly correlated (r = 0.64, P = 0.001), it was not possible to determine which of these 2 nutrients might be more strongly associated with pure-tone averages. Specifically, logistic regression analysis models that included both serum vitamin B-12 and red cell folate did not clearly identify which of these nutrients was more closely associated with pure-tone averages. Also, the metabolic roles of vitamin B-12 and folate are interrelated and several signs of their deficiencies are similar (22). Low red cell folate concentrations may reflect vitamin B-12 deficiency because during vitamin B-12 deficiency there is inadequate synthesis of tetrahydrofolate, a lack of polyglutamate folate, and leakage of methyltetrahydrofolate-monoglutamate from cells (25).
Auditory function appeared to be more strongly associated with folate intake than with vitamin B-12 intake, perhaps because the absorption of vitamin B-12 may be limited by malabsorption associated with atrophic gastritis, which is common in the elderly (1618). Only one participant, who was hearing impaired, had a serum pepsinogen I concentration indicative of possible atrophic gastritis (<10 µg/L). However, serum pepsinogen I concentrations were
50% lower in women with hearing impairment than in women with normal hearing. Modest decreases in serum pepsinogen I were associated with mild-to-moderate atrophic gastritis established by histologic examination of the fundic gland mucosa (38). However, future studies should include measurement of both serum pepsinogen I and serum pepsinogen II, because the ratio of pepsinogen I to pepsinogen II may provide a more definitive indication of atrophic gastritis (38).
As defined in the exclusion criteria, participants in this study had sensorineural hearing loss. However, the auditory assessment we used cannot absolutely differentiate cochlear hearing loss from auditory (eighth cranial) nerve pathologies. Therefore, the anatomical areas where vitamin B-12 and folate may be influencing hearing function are not known. Most hearing loss in the elderly is peripheral and is associated with cochlear dysfunction (23). Cochlear function is dependent on an adequate vascular supply (39, 40) and normal function of nerve tissue (41). Homocysteine is elevated during deficiencies of vitamin B-12, folate, or both (18, 42), and homocysteine is believed to be a vascular toxin (43, 44) and a neurotoxin (45). Thus, poor vitamin B-12 or folate nutriture might impair the vascular and nervous system of the auditory system through direct or indirect effects, or both, on cellular metabolism, vascular perfusion, and myelin synthesis. Vascular risk factors such as high blood pressure were associated with peripheral hearing loss in large samples of adults, such as the Framingham Heart Study (n = 1662; 21) and the Baltimore Longitudinal Study of Aging (n = 531; 20), but were not associated with hearing loss in our sample. There is also central nervous system involvement in some cases of auditory dysfunction (40). Poor vitamin B-12 and folate status might adversely influence the central nervous system because of the numerous roles that these nutrients play in cellular metabolism, vascular function, and myelin synthesis.
To our knowledge, the potential influence of folate deficiency on auditory function has received little attention (8). Several investigators have examined the association between vitamin B-12 status and auditory function (8, 9, 14, 2628). However, there is no direct evidence in the literature that age-related hearing loss is associated with vitamin B-12 deficiency. As will be discussed further, most investigators, except for Roman (8), have not conducted valid tests of the type and degree of peripheral hearing loss in their subjects. Vitamin B-12 deficiency and auditory dysfunction have been linked primarily in studies of neuropathology (14), tinnitus (8, 9), and abnormal auditory brainstem response (ABR; 2628).
The influence of vitamin B-12 deficiency on the auditory nerve in rhesus monkeys was examined over a 5-y period (14). Although peripheral hearing thresholds were not monitored, the auditory nerve and other nerves developed active lesions associated with vitamin B-12 deficiency. Shemesh et al (9) examined serum vitamin B-12 in 113 noise-exposed subjects with a mean age of 39 y. Subjects with chronic tinnitus and noise-induced hearing loss were
2.6 times more likely to be vitamin B-12deficient (defined as serum vitamin B-12
250 ng/L) than subjects with normal hearing. Shemesh et al suggested that inadequate vitamin B-12 may be associated with myelin damage in persons with repeated noise exposure. Although the cause of vitamin B-12 deficiency (low intake, malabsorption, or both) was not determined, some subjective improvement in tinnitus was observed in 12 subjects after vitamin B-12 replacement therapy (parenteral, 1 mg/d for 4 mo) (9).
Processing of sound and speech requires both peripheral and central mechanisms. According to Bess and Humes (46), retrograde degeneration of the first-order auditory neurons and degenerative changes in the brainstem and cortex of older individuals can accompany peripheral hearing impairment of the cochlea. Although we did not assess the auditory brainstem in the present study, relations between ABR and vitamin B-12 deficiency in humans have been examined by others (2628). The lack of control groups and the small sample sizes (310 subjects) make it difficult to reach meaningful conclusions about the role of vitamin B-12 deficiency in ABR. Furthermore, although peripheral hearing loss often leads to abnormal ABR, an abnormal ABR does not necessarily indicate either peripheral hearing loss or a central auditory processing disorder. These studies (2628) involved examination of a total of 20 subjects, 3 of whom had abnormal ABR (prolonged IV interpeak latencies). Two of these 3 subjects' IV latencies were within normal limits when they were retested after repletion with vitamin B-12. Although information about remyelination of the cochlear nerve in the elderly is very limited, Parent (47) states that spontaneous remyelination after an episode of demyelination is the rule rather than the exception in adult peripheral and central pathways.
Vitamin B-12 has also been used in conjunction with other agents, such as clarythromycin, prednisolone, and immunoglobulin G, to treat auditory dysfunction (48, 49). However, a specific rationale for the nutritional component of these treatments was generally not discussed, and the study designs did not allow identification of the unique contribution of vitamin B-12 to changes in auditory function. It is not known whether supplements of vitamin B-12 or folate would improve hearing function or slow the rate of hearing loss in elderly individuals with hearing impairment associated with deficiencies of these nutrients. Cognitive indexes (50) and peripheral and central nervous system symptoms (51) indicating deficiencies of vitamin B-12, folate, or both are sometimes, but not always, improved with repletion.
An epidemic of peripheral neuropathy associated with low intakes of vitamin B-12, folate, thiamine, and sulfur amino acids occurred in Cuba in 1992 and 1993, affecting >50000 people (8). Sensorineural deafness characterized by high-frequency hearing loss (48 kHz) was generally bilateral and usually symmetrical. Abnormal ABR occurred in 35% of the patients with abnormal audiometry. The investigators reported that treatment of patients with B vitamins produced "rewarding results" but they also noted that "there was minimal return of hearing in response to treatment" (8). Details of the intervention protocol (such as dose and duration) and the postintervention audiologic assessment were not described, and thus, it is difficult to interpret this report.
Our sample size was relatively small and consisted of healthy white women aged 6071 y with relatively mild hearing loss. Thus, additional studies are needed to determine the roles of vitamin B-12 and folate in auditory dysfunction occurring in men, in adults aged
70 y, in other ethnic groups, and in elderly persons with more severe hearing loss. The roles of vitamin B-12 and folate nutriture in both the peripheral and central auditory systems also require investigation.
To our knowledge, this is the first study to show a relation between age-related hearing impairment and vitamin B-12 and folate status. Additional research is needed to confirm our findings and to determine whether, similar to high blood pressure (20, 21), poor vitamin B-12 and folate nutriture might be considered modifiable risk factors for age-related hearing impairment.
| FOOTNOTES |
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2 Address reprint requests to MA Johnson, Department of Foods and Nutrition, Dawson Hall, The University of Georgia, Athens, GA 30602. E-mail: mjohnson{at}fcs.uga.edu.
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