ORIGINAL RESEARCH–OTOLOGY AND NEUROTOLOGY
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serum folate (correlation coefficient � �0.01, P � 0.01) was
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Study Design
Otolaryngology–Head and Neck Surgery (2010) 143, 826-830
019
doi
0.74) was not.
NCLUSION: Serum folate was significantly lower among
erly with ARHL. Trials on nutritional supplementation may
stantiate the role of serum folate in ARHL.
2010 American Academy of Otolaryngology–Head and Neck
rgery Foundation. All rights reserved.
This is a cross-sectional study of the immunobiology of HL
in apparently healthy elderly subjects. The participants were
drawn from the community tagged to an outreach program
organized for the detection and prevention of illnesses
among the elderly.
Included in the study were all elderly men and women
above 60 years of age who had no known medical condition,
Received June 21, 2010; revised August 24, 2010; accepted August 25, 2010.
4-5998/$36.00 © 2010 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
ge-related hearing loss, v
e elderly
keem Olawale Lasisi, MBChB, FWAC
tai A. Fehintola, MBBS, MSc, FMCP
adan, Nigeria
sponsorships or competing interests have been disclosed for
s article.
STRACT
JECTIVE: Determine the correlation between the hearing
eshold and the serum levels of vitamin B12 (cobalamin) and
ic acid among elderly subjects (� 60 years) with age-related
ring loss (ARHL).
UDY DESIGN: Cross-sectional.
TTING: Community.
BJECTS AND METHODS: Subjects included elderly who
re found apparently healthy following repeated examination by
ysicians. The pure tone average (PTA) for the speech and high
quencies, and the serum folate and cobalamin were determined
the correlation found.
SULTS: The mean � SD values of serum folate among the
jects with normal PTA in the speech frequencies (0-30 dB) was
2.3 nmol/L� 17.6 nmol/L, while among those with hearing loss
L), it was 279.1 nmol/L � 17.2 nmol/L (P � 0.01). In the high
quencies, the mean � SD values among the subjects with
rmal PTA was 426.3 nmol/L� 17.6 nmol/L, while among those
th HL, it was 279.14 nmol/L � 171.2 nmol/L. The serum
alamin among the subjects with normal PTA within the speech
quencies was 49.7 pmol/L � 9.4 pmol/L, while among those
th speech-frequency HL, it was 42.6 pmol/L � 10.2 pmol/L.
wever, for high frequencies, the mean � SD values among the
jects with normal PTA was 47.4 pmol/L � 7.3 pmol/L, while
ong those with HL, it was 41.3 pmol/L � 9.2 pmol/L. Spear-
n’s correlation revealed that low folate (correlation coefficient
�0.27, P � 0.01) and cyanocobalamin (correlation coefficient
�0.35, P � 0.02) were significantly associated with increasing
ring threshold in the high frequencies. After adjusting for age,
:10.1016/j.otohns.2010.08.031
min B12, and folate in
FMCORL,
d Oyindamola Bidemi Yusuf, PhD,
ge-related hearing loss (ARHL) has been associated
with environmental factors such as noise, malnutrition,
toxicity, infections, and genetics.1-6 Hearing loss (HL)
s been documented as one of the neuropathological ef-
ts of some vitamin deficiencies;7 however, the potential
uence of the deficiencies of the B group of vitamins on
ditory function has received little attention,3 and direct
idence linking ARHL with vitamin B12 (cobalamin) or
ate deficiency is scarce in the literature. Roman5 found
h-frequency sensorineural HL among elderly patients in
ba and ascribed it to cobalamin and folate deficiency.
ilarly, in a recent study of elderly female subjects, poor
balamin and folic acid status were found to be associated
th age-related auditory dysfunction.8 In addition, some
provements were found in some of these patients follow-
replacement therapy, suggesting a relationship between
deficiencies of these vitamins and auditory dysfunction.8
contrast, many works have found no association between
tritional biology and auditory function.1-4,9 This suggests
need for continued research into the role of vitamins in
ditory function, particularly in developing countries
ere malnutrition is still rife. Our hypothesis is that mul-
le vitamin deficiencies may be a significant contributor to
severity of ARHL. The objective of this study was to
termine, in a population of apparently healthy elderly
bjects with ARHL, the association, if any, between the
aring threshold and the serum levels of cobalamin and
ic acid.
ethod
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827Lasisi et al Age-related hearing loss, vitamin B12, and...
ile the exclusion criteria involved those with history of
betes, stroke, hypertension, ear diseases, exposure to
ise and ototoxic drugs such as aminoglycoside antibiotics
diuretics, ear infections, ear trauma, or ear surgery.
rticipants Recruitment
rticipants included elderly subjects who have been examined
eatedly by physicians in the outreach program; the blood
ssure and random blood sugar were tested, and urinalysis
s done. The subjects were repeatedly examined in order to
ruit them among those elderly with no known medical
ess. Consecutive eligible participants who were found to be
e of any medical conditions were counseled for consent and
ruitment into the study. Each participant was taken through
already prepared questionnaire for that purpose. Specifi-
ly, questions aimed at eliciting otological and general med-
l conditions were asked and these included: otorrhea, tinni-
, vertigo, otalgia, polyuria, polydipsia, significant weight
s, chronic cough, and palpitation. Participants were also
ed about history suggestive of allergy and use of such
dications as: aminoglycosides, diuretics, and 4-amino-
inolines antimalarial drugs. History of living near noise, as
for example, a blacksmith shop, radio room/disco room, or
lding shop for at least two hours per day for at least five
ys a week was also obtained.
This was followed by ENT examination and hearing test
ing pure tone audiometry. Specifically, subjects were ex-
ined for evidence of arteriosclerosis by palpating the
lls of the radial artery or presence of locomotor brachia-
—observing the pulsation of the brachial artery at the
ow. After the examination, collection of blood for esti-
tion of serum levels of folate and vitamin B12, and pure
e audiometry were done. The criteria for the diagnosis of
medical condition were based on simple definitions, and
the subjects with medical conditions were excluded.10,11
e study was approved by the Oyo State Research Ethical
view Committee.
ood Sample Collection and Storage
proximately 5 mL of whole blood was collected using
antecubital vein under aseptic conditions. The samples
re stored at �80°C in batches for quantitative assay of
ate and vitamin B12.
re Tone Audiometry
e pure tone audiometry was done using a computer au-
meter BA 20 Kamplex (Interacoustic A/S, DK 5610,
sens, Denmark) with the subjects in a sitting position in
soundproof (acoustic) booth in the ENT clinic. The
bjects were instructed to raise their hand if the tone
sented to the ears was heard. The hearing acuity was
asured in decibels (dB) at the frequencies 250 to 8000
. The average for the four frequencies, 250 Hz, 500 Hz,
00 Hz, and 2000 Hz was recorded as pure tone average
TA) for speech frequency, while the average for the 3000
for
fre
, 4000 Hz, 6000 Hz, and 8000 Hz was recorded as the
A for the high frequencies.
antitative Assay of Folate
sample was prepared by pipetting 1.5 mL of the sample
o a set of centrifuge tubes, and then 20.0 mL of ascorbic
id and 10.0 mL of sodium hydroxide (NaOH) were added
d mixed properly. To this was added 5.0 mL of hydrogen
loride (HCl), and the mixture was shaken for 30 minutes
d then centrifuged at 1500 revolutions per minute (rpm)
30 minutes. The supernatant was collected and trans-
red onto a set of clean vials, and determination of the
ate was done with high-performance liquid chromatog-
hy (HPLC).12
antitative Assay of Vitamin B12
o a clean beaker, 1.0 mL of the sample and 25 mL of 0.2
HCl was added and warmed in a water bath for 30
nutes, then cooled and the pH adjusted to 6.0 using
OH. This was followed by adding 1N HCL to lower the
to 4.5, then transferred into a set of 50.0-mL centrifuge
es, shaken for 30 minutes, and centrifuged for a period of
.0 minutes at 2000 rpm. The supernatant was collected,
d vitamin B12 determined by HPLC.12
As a quality control measure, control and standard sera
re included in the analysis at every sera assay to ensure
iability and quality of the procedure. An initial pilot study
s conducted to test all instruments, and this was followed
a preliminary statistical analysis to detect outliers and
rrect factors.
atistics
e main outcome variables were the serum levels of folate
d vitamin B12 in elderly subjects with audiometric evi-
nce of HL in the speech and high frequencies and those
th normal PTA. In this study, HL was defined as PTA �
dB, and the control subjects were selected among elderly
o have normal PTA (0-30 dB).
Data were initially explored using Stata software (Stata-
rp LP, College Station, TX), and Spearman’s correlation
s utilized to determine the correlation between ranked and
ntinuous variables. In order to adjust for the effect of age on
hearing threshold and the plasma levels of vitamin B12 and
ate, a linear regression model was used. Level of statistical
nificance was at P � 0.05 for all the analyses.
sults
e subjects included 126 elderly subjects (males and
ales) and the ages ranged from 60 to 98 years (mean �
� 66.9 � 0.77). Among the 126 subjects who had
diometry, the mean � SD of the PTA for the air conduc-
n was 29.4 dB � 1.6 dB, while for the bone conduction
C) it was 36.5 dB � 1.8 dB. The mean � SD of the PTA
the early frequency was 30.1 dB� 1.5 dB, while the late
quency was 50.8 dB � 2.0 dB.
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828 Otolaryngology–Head and Neck Surgery, Vol 143, No 6, December 2010
The prevalence of speech-frequency HL increased with
reasing age; Spearman’s correlation revealed that the asso-
tion was significant (P� 0.03). Similarly, the prevalence of
h-frequency HL increased with increasing age, although
earman’s correlation was not significant (P � 0.09). In
dition, increasing age was significantly associated with de-
asing levels of serum cyanocobalamin (P � 0.04), while it
s not significant for serum folate (P � 0.2).
Tables 1 and 2 show the frequency distribution of the
um levels of folate and cobalamin, respectively, accord-
to the range of the PTA among the elderly subjects.
ble 1 shows that the mean serum levels of folate among
subjects with normal hearing threshold (0-30 dB) was
2.3 nmol/L, while among those with hearing threshold
ove 30 dB, the mean was between 195.1 nmol/L and
0.0 nmol/L. Table 2 shows that the mean serum levels of
anocobalamin among the subjects with a normal hearing
eshold (0-30 dB) was 49.7 pmol/L, while among those
th a hearing threshold above 30 dB, the mean was be-
een 39.9 pmol/L and 46.4 pmol/L.
The mean � SD values of serum levels of folate among
elderly subjects with normal hearing threshold in the
eech frequencies (0-30 dB) was 412.3 nmol/L � 17.6
ol/L, while among the elderly subjects with HL, it was
able 1
erum folate in nmol/L and pure tone average, in decibe
ean hearing threshold
(PTA), in decibels
Number of
subjects M
0-30 38
31-40 20
41-50 15
51-60 24
61-70 14
71-80 15
TA, pure tone average.
able 2
erum levels of cyanocobalamin in pmol/L and pure ton
ean hearing threshold
(PTA), in decibels
Seru
Number of
subjects M
0-30 38
31-40 20
41-50 15
51-60 24
61-70 14
71-80 15
TA, pure tone average.
9.1 nmol/L � 17.2 nmol/L. In the high frequencies, the
an � SD values of serum levels of folate among the
erly subjects with normal hearing threshold was 426.3
ol/L � 17.6 nmol/L, while among those with HL, it was
9.14 nmol/L � 171.2 nmol/L.
For the serum cobalamin, the serum levels among the
erly subjects with normal hearing threshold within the
eech frequencies was 49.7 pmol/L � 9.4 pmol/L, while
ong those elderly with speech-frequency HL, it was 42.6
ol/L � 10.2 pmol/L. However, for high frequencies, the
an � SD values of serum levels of cobalamin among the
erly subjects with normal hearing threshold was 47.4
ol/L � 7.3 pmol/L, while among those with HL, it was
.3 pmol/L � 9.2 pmol/L.
Spearman’s correlation revealed that decreasing serum fo-
e (P � 0.01) and cyanocobalamin (P � 0.02) were signif-
ntly associated with increasing hearing threshold among
jects with high-frequency HL (Table 3). However, after
justing for age, linear regression revealed significant corre-
ion between the levels of serum folate (P � 0.01) and
aring threshold in the high frequencies (Table 4).
On the other hand, the serum levels of folate and cya-
cobalamin did not show any significant correlation with
m levels of folate in nmol/L
m Maximum Mean SD
589.0 412.3 17.6
587.3 287.9 16.7
499.3 195.2 9.7
581.5 284.5 16.5
581.5 273.5 16.2
581.5 380.0 12.4
rage, in decibels
els of cyanocobalamin in pmol/L
m Maximum Mean SD
62.1 49.7 9.2
66.7 42.9 11.8
66.7 39.9 10.9
58.1 42.0 9.4
70.2 42.9 13.5
65.0 46.4 10.6
e ave
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inimu
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27.2
26.0
29.0
26.2
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ls
Seru
inimu
135.0
134.3
100.1
126.0
134.0
121.1
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829Lasisi et al Age-related hearing loss, vitamin B12, and...
aring threshold among subjects with speech-frequency
(Table 5).
scussion
e main finding in this study is that low serum levels of
ic acid are significantly associated with HL in high fre-
encies among apparently healthy elderly people. Also, we
nd correlation between high-frequency HL and low-
um vitamin B12, although serum vitamin B12 seemed to
affected by increasing age, hence the correlation with
amin B12 was not found to be significant after adjusting
age. These findings suggest that the low levels of these
tritional markers, particularly folate, may be significant
the development of HL among these elderly subjects.
is is similar to the findings of Roman,5 who reported
sorineural hearing impairment in the high frequencies in
ba. In that study on an epidemic of peripheral neuropa-
, he found association between sensorineural HL and low
akes of vitamin B12, folate, thiamine, and sulfur amino
ids. It is also supported by an animal experiment, which
nd impairment in the cellular mechanism involving both
nervous and vascular systems, hence, it was concluded
t B12 deficiency is responsible for the neuropathological
ect.6 The fact that our selected subjects were apparently
althy elderly people suggests to us that the low-serum
ate and cobalamin might be the factor responsible for the
. This could be due to the eighth-nerve neuropathy or
chleopathy, or both. A controlled study by Houston et al8
amined 55 healthy elderly women and found that PTAs
er the 500- to 4000-Hz range were inversely correlated
th serum vitamin B12 and red cell folate, and that women
th impaired hearing had a 38 percent lower B12 vitamin
able 3
pearman’s coefficient comparing the levels of
lasma folate and cyanocobalamin with hearing
hreshold among subjects with high-frequency
earing loss
Variables
Spearman’s
coefficient Significance
olate �0.27 0.01
yanocobalamin �0.35 0.01
able 4
inear regression comparing plasma folate and cyanocob
igh-frequency hearing loss
Variables Coefficient
olate* �0.01
yanocobalamin* �0.01
Adjusted for age.
el and a 31 percent lower red cell folate level. In contrast,
rner et al13 did not find any association between hearing
els and either B12 vitamin, folic acid, or homocysteine
els in elderly subjects.
In our study, the serum levels of folate were between 100.1
ol/L and 589.0 nmol/L, while the levels of vitamin B12
re between 26.2 pmol/L and 70.2 pmol/L. This was low
mpared to the work of Berner et al,13 which reported folate
tween 295 nmol/L and 1160 nmol/L and vitamin B12 be-
een 90 pmol/L and 737 pmol/L. But it is comparable to the
ort of Houston et al8 on elderly women, which reported
ate to be between 79 nmol/L and 380 nmol/L and vitamin
2 between 28 pmol/L and 502 pmol/L. These two studies
ed are from developed countries of the West; however, in
dically underserved populations like ours, these relatively
levels of vitamins are expected. Although there is no
cumented figure for the country as of now, these figures may
a reflection of the low levels of the vitamins in the general
pulation. It may be due to poor nutrition and may also be due
problems with storage of specimens and other stages in the
ay procedure.
In addition, our findings revealed that increasing age had
nificant effect on hearing threshold in the speech frequen-
s and the serum levels of vitamin B12, but not folate. Thus,
is suggested that low serum folate could account for the
reased hearing threshold observed among those with high-
quency HL. Similar to the question raised for reduction in
other medical conditions,14,15 one main issue arising from
s study is whether elderly people should, in general, receive
ate and vitamin B12 supplements in order to reduce the risk
hearing impairment. It has been proposed that low levels of
amin B12 and folate are associated with destruction of the
crovasculature of the stria vascularis, which might result in
in with hearing threshold among subjects with
ignificance 95% confidence interval
0.01 �0.01–0.01
0.74 �0.01–0.01
able 5
pearman’s coefficient comparing the levels of
lasma folate and cyanocobalamin with hearing
hreshold among subjects with speech-frequency
earing loss
Variables
Spearman’s
coefficient Significance
olate 0.04 0.68
yanocobalamin –0.08 0.39
T
S
p
t
h
decreased endocochlear potential and hence, hearing impair-
ment.16-18 Vitamin B12 has been used in conjunction with
other agents, such as clarithromycin, prednisolone, and immu-
no
co
sym
bo
ma
rel
dis
Co
Se
wi
sta
Ac
We
Iba
Gu
Au
Fro
Cli
of
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Co
CO
Co
Nig
E-m
Au
Ak
and
imp
lish
dat
app
and
con
Di
Co
Sp
Re
1.
2. Willot JF. Anatomic and physiologic aging: a behavioral neuroscience
perspective. J Am Acad Audiol 1996;7:141–51.
3. Shemesh Z, Attias J, Ornan M, et al. Vitamin B12 deficiency in
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
830 Otolaryngology–Head and Neck Surgery, Vol 143, No 6, December 2010
globulin G, to treat auditory dysfunction.19-25 In addition,
gnitive indexes 25 and peripheral and central nervous system
ptoms26 indicating deficiencies of vitamin B12, folate, or
th, have been sometimes reversed following repletion. This
y change our present belief about the irreversibility of age-
ated hearing impairment, thus improving the outcome of the
ease and quality of life of the affected elderly people.
nclusion
rum folate was significantly lower among elderly people
th ARHL. Trials on nutritional supplementation may sub-
ntiate the role of serum folate in ARHL.
knowledgments
thank Prof. B. L. Salako, who was generous with the facilities of the
dan-Loyola University Genetics of Hypertension project, and Prof. Oye
reje of the Iba
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