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Long-term Nutrient Intake and Early Age-Related Nuclear Lens Opacities
Paul F. Jacques, ScD;
Leo T. Chylack, Jr, MD;
Susan E. Hankinson, ScD;
Patricia M. Khu, MD;
Gail Rogers, MA;
Judith Friend, MA;
William Tung;
John K. Wolfe, PhD;
Nita Padhye, MD;
Walter C. Willett, MD, DrPH;
Allen Taylor, PhD
Arch Ophthalmol. 2001;119:1009-1019.
ABSTRACT
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Objective To assess the relation between usual nutrient intake and subsequently
diagnosed age-related nuclear lens opacities.
Subjects Four hundred seventy-eight nondiabetic women aged 53 to 73 years from
the Boston, Mass, area without previously diagnosed cataracts sampled from
the Nurses' Health Study cohort.
Methods Usual nutrient intake was calculated as the average intake from 5 food
frequency questionnaires that were collected during a 13- to 15-year period
before the evaluation of lens opacities. The duration of vitamin supplement
use was determined from 7 questionnaires collected during this same period.
We defined nuclear opacities as a nuclear opalescence
grade of 2.5 or higher using the Lens Opacification Classification System
III.
Results The prevalence of nuclear opacification was significantly lower in the
highest nutrient intake quintile category relative to the lowest quintile
category for vitamin C (P<.001), vitamin E (P = .02), riboflavin (P = .005),
folate (P = .009),  -carotene (P = .04), and lutein/zeaxanthin (P = .03).
After adjustment for other nutrients, only vitamin C intake remained significantly
associated (P = .003 for trend) with the prevalence
of nuclear opacities. The prevalence of nuclear opacities was significantly
lower (P<.001) in the highest vitamin C intake
quintile category relative to the lowest quintile category (odds ratio, 0.31;
95% confidence interval, 0.16-0.58). There were also statistically significant
trends of decreasing prevalence of nuclear opacities with increasing duration
of use of vitamin C (P = .004 for trend), vitamin
E (P = .03 for trend), and multivitamin (P = .04 for trend) supplements, but only duration of vitamin C supplement
use remained significantly associated with nuclear opacities after mutual
adjustment for use of vitamin E (P = .05 for trend)
or multivitamin (P = .02 for trend) supplements.
The prevalence of nuclear opacities was significantly lower (P = .004) for women who used a vitamin C supplement for 10 or more
years relative to women who never used vitamin C supplements (odds ratio,
0.36; 95% confidence interval, 0.18-0.72). Plasma measures of vitamins C and
E taken at the eye examination were also inversely associated with the prevalence
of nuclear opacities.
Conclusion These results provide additional evidence that antioxidant nutrients
play a role in the prevention of age-related nuclear lens opacities.
INTRODUCTION
CATARACT, opacification of the crystalline lens of the eye, develops
later in life and is most likely the consequence of decades of accumulated
damage to the long-lived lens proteins. Animal and in vitro studies1 suggest that much of this damage is a result of oxidation
and that antioxidants might protect the lens against formation of cataract.
These observations are corroborated in humans by epidemiological studies1-2 that indicate a possible role for nutritional
antioxidants in the prevention of age-related cataract. However, there is
still much uncertainty regarding the role of antioxidant nutrients in the
development of cataract.3-22
Although most of these studies report associations between the risk of cataract
and at least 1 antioxidant nutrient, vitamin E,3, 6, 9-11,13-14,16-17
vitamin C,3, 5-6,8, 11, 15
or carotenoids,5, 8-9,18-20
they do not demonstrate consistent associations between intake or blood levels
of any one nutrient and the risk of cataract. This lack of specificity may
be a consequence of differences in the populations studied and the methods
used.
It was previously demonstrated in a subset of 247 women from the Nurses'
Health Study (NHS) cohort that use of vitamin C supplements for 10 or more
years was associated with an 80% lower odds of early nuclear opacities.15 However, because women with the highest and lowest
vitamin C intakes were oversampled in that study, the relation between intermediate
levels of vitamin C intake and the risk of opacification could not be examined;
also, associations with either vitamin E or the carotenoids could not be independently
considered. The present study, the Nutrition and Vision Project (NVP), is
based on a second, larger subset of women from the NHS cohort that was selected
without regard to nutrient intake. This study examines the relation between
newly diagnosed age-related nuclear opacities and usual nutrient intake, which
was calculated as the average intake from 5 food frequency questionnaires
that were collected during a 13- to 15-year period before the eye examination
at which lens status was assessed. To our knowledge, this is the first study
to assess intake over such an extended period in relation to early opacities.
The availability of multiple measurements of intake allowed us to relate risk
of opacification with usual long-term intake or with intake from a specific
point. Because diets that are higher in one antioxidant nutrient also tend
to be higher in others, we also adjusted the intake of each nutrient for the
intakes of other nutrients to examine their unique contribution to the risk
of lens opacities.
SUBJECTS AND METHODS
SUBJECTS AND STUDY POPULATION
In 1976, 121 700 female nurses aged 30 to 55 years who resided
in 11 US states completed a mailed questionnaire on known and suspected risk
factors for cancer and heart disease. These women formed the NHS cohort.23 Every 2 years since 1976, these women have been contacted
by mail to update information on risk factors and disease status.
In 1993, we identified approximately 1707 NHS cohort members aged 53
to 73 years who resided in the Boston, Mass, area; were free of diagnosed
cancer other than nonmelanoma skin cancer; had complete dietary data; and
had both lenses intact. With a goal of enrolling 600 women into the NVP, all
1707 eligible NHS participants were initially contacted by a letter from the
NHS and requested to return an enclosed reply postcard indicating whether
they would be willing to participate in the study. To preserve their participation
in the NHS, women who did not return the postcard received no further mailings
or telephone contact. We received positive responses from 730 (43%) of the
women with this one mailing. Six hundred three of these volunteers were ultimately
scheduled and examined as part of the NVP from April 16, 1993, through August
4, 1995. Scheduling conflicts (due to work and travel) were the most common
reasons for failure to examine the 127 who agreed to participate but were
never seen. Informed consent was obtained from all study participants, and
all procedures were approved by the Human Investigations Review Committee
at the New England Medical Center and the Human Research Committee at the
Brigham and Women's Hospital, both in Boston.
ASSESSMENT OF NUTRIENT INTAKE
Since 1976, the members of the NHS cohort have received biennial questionnaires
requesting information on various health and lifestyle issues. A 61-item semiquantitative
food frequency questionnaire was initially incorporated into the biennial
questionnaire in 1980.24 The food frequency
questionnaire queried usual intake during the previous year, with 9 possible
response categories, ranging from "never or less than once per month" to "6
or more times per day." In addition, the 1980 questionnaire collected information
on vitamin supplement use in 1980 and duration of vitamin supplement use before
1980. In 1984, 1986, and 1990, revised and expanded versions of the food frequency
questionnaire were included in the biennial questionnaire. Every questionnaire
since 1980 has included questions on vitamin supplement use. The present version
of the food frequency questionnaire includes approximately 130 food items
and details of vitamin and mineral supplement use that collectively account
for more than 90% of the total absolute intake of the 70 nutrients measured
by this instrument.25 The food frequency questionnaire
has been extensively validated relative to long-term diet records24-25 and biochemical markers of nutrient
status.26-28 In
addition to the food frequency and vitamin questionnaires collected routinely
as part of the NHS, we administered an additional food frequency questionnaire
that included questions on vitamin supplement use as part of the NVP (1993-1995).
We used the data from women who completed 5 food frequency questionnaires
collected between 1980 and 1993-1995 to calculate the average total nutrient
intake (from food and supplements) for each participant. For these analyses,
we considered the intakes of vitamin C, vitamin E, folate, riboflavin, and
the individual carotenoids. We used 7 reports of vitamin supplement use from
1980 through 1993-1995 to categorize women by duration of vitamin C, vitamin
E, and multivitamin supplement use. We assigned 2 years of supplement use
to the duration-of-use variable for each report of supplement use between
1980 and 1990. For women reporting supplement use on the food frequency questionnaire
collected as part of the NVP, we added the interval between 1990 and the date
of the eye examination to the duration-of-use variable. Finally, we added
the reported duration of use before 1980 to the duration-of-use variable.
We assumed that a woman who started or stopped using supplements during the
interval between questionnaires did so halfway through the period.
PLASMA NUTRIENT MEASUREMENT
Fasting plasma samples were obtained at the eye examination for analyses
of plasma antioxidant concentrations. Plasma for the vitamin C analyses was
stabilized by the addition of an equal volume of perchloric acid, 0.35 mol/L,
containing EDTA, 0.26 mmol/L, and was centrifuged at 4000g within 30 minutes of venipuncture. Ascorbic acid (reduced vitamin
C) was determined on fresh plasma samples by reversed-phase high-performance
liquid chromatographic analyses with electrochemical detection.29
Samples for vitamin E and total carotenoids were frozen at -70°C
for up to 1 month. Vitamin E ( -tocopherol) was measured by reversed-phase
high-performance liquid chromatography by the method of Bieri et al,30 and total carotenoids were measured spectrophotometrically
by the method of Roels et al.31
ASSESSMENT OF LENS STATUS
All NVP participants underwent a detailed eye examination using standardized
techniques. The examination included an ocular and medical history, a Bailey
Lovie test of visual acuity and manifest refraction, an external ocular examination,
applanation tonometry, contrast sensitivity function and glare testing, and
a slitlamp examination of the anterior segment. The latter included an assessment
of the anterior chamber to determine the risk of angle-closure glaucoma. Measurement
of intraocular pressure was required to determine if it was safe to complete
the eye examination, including dilation. Before a slitlamp examination of
the lens was performed, the pupils were dilated to a minimum of 6 mm with
phenylephrine hydrochloride and tropicamide. The posterior segment was examined
by direct and indirect ophthalmoscopy. The examiner (L.T.C., P.M.K., N.P.,
and W.T.) had no knowledge of the nutrient status of any of the volunteers.
Color film images were taken with a photographic slitlamp (Carl Zeiss,
Oberkochen, West Germany) and film (Ektachrome 200) to assess the degree of
nuclear color and opalescence. The Lens Opacity Classification System III
(LOCS III) was used to measure the degree of nuclear opalescence, the degree of light scattering from the nucleus, with possible grades
ranging from 0.1 to 6.9.32-33
To do the grading, each of 2 individual graders (L.T.C. and J.K.W.) wrote
down a score for the photograph on a score sheet. The graders then compared
scores and arrived at a consensus score, which was recorded on the third form.
Consensus scores typically fell between the 2 individual scores, but were
not true averages. All photographs were graded in several sessions within
a 2-month period after all photographs and images were obtained. We considered
eyes to have nuclear opacities if the nuclear opalescence grade was 2.5 or
higher. This threshold represents an early stage of opacification and is not
associated with symptoms such as reduced vision.
DEFINING POTENTIAL CONFOUNDERS
Data on known or suspected nonnutritional determinants of cataract risk
were obtained from the 1980 through 1990 biennial NHS questionnaires. For
the present analyses, we considered confirmed history of diabetes and hypertension
(yes or no) as reported on the 1990 or previous questionnaires, cigarette
pack-years smoked through 1990 (0, 1-29, and  30 pack-years), summertime
sunlight exposure (8 h/wk) as reported on the 1980 questionnaire, alcohol
use based on the average from 5 food frequency questionnaires, and height
and weight as reported on the 1980 questionnaire. The latter 2 measures were
used to calculate body mass index (calculated as weight in kilograms divided
by the square of height in meters).
STATISTICAL METHODS
We estimated the odds ratios (ORs) relating prevalence of nuclear opacities
to average nutrient intake and duration of vitamin supplement use from logistic
regression with the SAS GENMOD procedure.34
This procedure allowed the individual eyes to be the unit of observation and
requires that information for both eyes is available. This generalized estimating
equation approach to estimate logistic regression models adjusts the SEs of
the model parameters for the correlated data resulting from repeated measurements
on the same individual.
The primary independent variable used to examine the relation between
usual nutrient intake and prevalence of nuclear opacities was average nutrient
intake, previously described. This variable was classified into quintile categories
derived from the entire NVP sample of 603 women. These intake categories were
modeled with indicator variables using women in the lowest quintile category
as the reference category. To test for trend across quintile categories, we
assigned the median intake of each quintile category to everyone with intakes
in the category, and then included this quintile median variable as a continuous
factor in the logistic regression models. We also used the quintile median
variable to test for possible interactions between our nutritional measures
and age (<60 or 60 years) and smoking (never smokers or current or
past smokers). Because of the number of interactions considered, we used P = .01 as the cutoff to indicate the presence of an interaction.
To determine if there was an advantage to the use of multiple measurements
of intake relative to the use of a single measurement, we considered the relation
between nutrient intake reported at the eye examination (single measurement)
and prevalent nuclear opacities. The form of these analyses was otherwise
identical to those we used to examine the relation between usual (average)
nutrient intake and prevalence of opacities.
To examine the relation of duration of vitamin supplement use to the
prevalence of nuclear opacities, categories of duration of vitamin supplement
use were modeled with indicator variables, using women who reported no vitamin
supplement use as the reference category. A test for trend of prevalence across
supplement duration categories was performed by assigning participants the
median value of their duration category and then entering this as a continuous
variable into the logistic regression model. The P
for trend was the resulting P for the associated
logistic regression coefficient.
To investigate the relation between plasma nutrient measures and nuclear
opacification, the nutrient measures were also modeled using quintile categories
with indicator variables. Women in the lowest quintile category served as
the reference category. Trend across quintile categories was assessed in the
same way as it was for the intake variables.
To help evaluate the independent contribution of each nutrient, all
nutrients that were significantly associated with nuclear opacities when entered
individually into the logistic regression models (based on a P for trend of <.10) were simultaneously entered into a logistic
regression model using the nutrient quintile median variables. This model
also included all covariates previously listed. Using a backward selection
procedure, nutrients were removed based on level of significance until only
those nutrients that were significantly associated with the prevalence of
nuclear opalescence (P<.05) remained. Because
only 3 types of supplements were considered, the vitamin supplement associations
were adjusted for one another in a pairwise manner. Likewise, the plasma associations
were also adjusted in a pairwise manner.
Odds ratios for the prevalence of nuclear opacities for the nutrient
intake and plasma quintile categories and the supplement duration categories
were calculated as the antilogarithm of the logistic regression coefficient
for each of these categories. All ORs were adjusted for age and other potential
confounders previously described.
RESULTS
COMPARISON OF PARTICIPANTS AND NONPARTICIPANTS
There were few notable differences between participants and nonparticipants
(Table 1). They were similar in
age, alcohol consumption, body mass index, reported summertime sunlight exposure,
prevalence of hypertension, and vitamin C and multivitamin supplement use
between 1980 and 1995. Participants reported fewer pack-years of smoking and
were also slightly more likely to have used vitamin E supplements between
1980 and 1995.
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Table 1. Characteristics of Participants and Nonparticipants*
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PARTICIPANT CHARACTERISTICS
Of the 603 women examined as part of the NVP, we excluded 76 who reported
a history of cataract to avoid the possibility that prior knowledge of lens
opacification might influence nutrient intake and 9 with a confirmed diagnosis
of diabetes in 1990 or earlier because of our concern that diabetes might
alter the association between nutrition and nuclear opacification. In addition,
33 women with lens photographs that were missing or could not be graded or
with questionable nuclear lens data and 7 with missing information for covariates
were not included in these analyses. Four hundred seventy-eight remaining
women were included in these analyses.
The 478 women who were included in the analyses were different from
the 85 who were excluded for the following characteristics: women included
in the analyses were younger (aged 61 vs 65 years; P<.001),
had a lower average nuclear opalescence score (2.2 vs 2.6; P<.001), had a lower body mass index in 1980 (24.3 vs 25.3; P = .05), and consumed more alcohol (7.8 vs 5.1 g/d; P = .005) than women who were excluded. There were no differences
between those included and those excluded from analyses for vitamin C intake,
lutein/zeaxanthin intake, pack-years smoked, reported summer sunlight exposure,
prevalence of high blood pressure, or use of vitamin C supplements for 10
or more years. Women who were missing data were the same average age as women
included in the analyses, and did not differ on any other covariate or nutrient
measures for which data were available. The comparison of nuclear lens scores
was not possible because all but 7 of these women were missing lens data.
The distribution of LOCS III nuclear opalescence scores is displayed
in Figure 1 for the 956 eyes available
for analyses. The mean score and its SD were 2.2 and 0.6, respectively. The
median and 5th and 95th percentile values were 2.1, 1.3, and 3.4, respectively.
Two hundred forty-nine eyes (26.0%) from 163 women had nuclear opacities (ie,
an LOCS III grade 2.5). Selected characteristics of the women included
in the analyses are given in Table 2
according to the presence or absence of nuclear opacities. Women with nuclear
opacities were significantly older than women without opacities and were less
likely to use vitamin C and vitamin E supplements (P<.05).
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Distribution of Lens Opacity Classification System III nuclear opalescence
scores for 956 eyes available for analyses.
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Table 2. Characteristics of Study Participants by Presence of Nuclear
Opacities*
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Table 3 displays the quintile
values used to define the nutrient intake and plasma categories. The dietary
reference intake estimated average requirement (EAR) values for 51- to 70-year-old
women35-36 and cutoff values for
adequate plasma nutrient concentrations37-38
are also shown to allow comparisons between the quintile cutoff values and
these normative values. This sample of women appears to be generally well
nourished with respect to most nutrients considered. The 20th percentile values
exceeded the EARs for vitamin C and riboflavin. In other words, more than
80% of the women reported intakes greater than the EARs for these nutrients.
Between 60% and 80% of the women had intakes that exceeded the EAR for folate,
and between 40% and 60% had intakes that exceeded the EAR for vitamin E. For
plasma ascorbic acid and -tocopherol, the 20th percentile value was
well above the cutoff point for adequacy. There are no established normative
intake or plasma values for carotenoids, but the carotenoid intakes and total
plasma carotenoid levels in this sample were high compared with those of other
samples.39-40
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Table 3. Nutrient Quintiles Used to Define Intake and Plasma Nutrient
Categories
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Table 4 and Table 5 show that our measures of average nutrient intakes are all
correlated with one another (P<.05 for all correlation
coefficients). Many of these correlation coefficients approached or exceeded
0.6. The plasma measures were also all significantly correlated, and correlation
coefficients ranged from 0.28 to 0.33. The correlation coefficients between
the plasma and intake measures were, with 2 exceptions, statistically significant
and ranged from 0.53 for plasma -tocopherol and vitamin E intake to
0.08 for plasma -tocopherol and total carotenoid intake. The duration
of use of different types of vitamin supplements was also highly correlated.
Seventy-nine percent of women who consumed vitamin E supplements for 10 or
more years also consumed vitamin C supplements for 10 or more years. Of those
who used multivitamins for 10 or more years, 25% and 17% also used vitamin
C and vitamin E supplements, respectively, for this length of time, and two
thirds of the long-term vitamin C and vitamin E supplement users also took
multivitamins for 10 or more years.
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Table 4. Spearman Rank Correlation Coefficient Matrix for Vitamins
and Total Carotenoids*
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Table 5. Spearman Rank Correlation Coefficient Matrix for Individual
and Total Carotenoids*
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NUTRIENT INTAKE AND PREVALENCE OF OPACITIES
Table 6 displays the relations
between nuclear opalescence and usual nutrient intake (from food and supplements)
measured during a 13- to 15-year period. All ORs are adjusted for age, smoking,
history of hypertension, body mass index, summertime sunlight exposure, and
alcohol intake. Significant inverse trends of decreasing prevalence of nuclear
opacification with increasing intake were seen for vitamin C (P = .003), riboflavin (P = .03), and folate
(P = .005). No significant trends were observed for
vitamin E (P = .06), -carotene (P = .08), or lutein/zeaxanthin (P = .08) intake,
but the prevalence of nuclear opacification was significantly lower in the
highest -carotene quintile category (P = .04),
the upper 2 vitamin E quintile categories (P = .02
and .03, respectively), and the upper 4 lutein/zeaxanthin quintile categories
(P = .03, .03, .04, and .02, respectively) than in
the lowest quintile category for each of these nutrients. None of the interactions
between nutrient intake and either age or smoking were statistically significant.
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Table 6. Relation Between the Prevalence of Nuclear Lens Opacities
and Total Nutrient Intake From Food and Supplements*
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To determine if the observed associations between risk of nuclear opacification
and intakes of each nutrient were independent of the other nutrients, we mutually
adjusted the relations between odds of nuclear opalescence and intake of vitamin
C, vitamin E, riboflavin, folate, -carotene, -cryptoxanthin, and
lutein/zeaxanthin using a backward selection procedure. Only vitamin C intake
remained significantly associated with nuclear opalescence (P = .003) after stepwise removal of nonsignificant nutrients. Moreover,
none of the other nutrients remained significantly associated with the prevalence
of nuclear opacities in models that included these nutrients in a pairwise
adjustment with vitamin C, whereas vitamin C remained significantly associated
with nuclear opalescence in all of the pairwise models.
ASSESSMENT OF INTAKE BASED ON MULTIPLE AND SINGLE MEASUREMENTS
We examined the effect of characterizing intake with multiple measurements
of intake over an extended period relative to one cross-sectional measurement
of intake obtained at the eye examination. The Spearman rank correlation coefficient
between the average and single time point measures was 0.80 for vitamin C
intake. When the measurement of intake was limited to a single cross-sectional
measurement, the ORs (95% confidence intervals) for nuclear opalescence in
the second to fifth quintile categories of vitamin C intake relative to the
first category were as follows: 0.56 (0.28-1.10), 0.38 (0.21-0.69), 0.29 (0.14-0.62),
and 0.34 (0.19-0.59). The P for trend was .003. These
ORs and confidence intervals are similar to those based on the average of
5 measurements of vitamin C intake (Table
6).
DURATION OF VITAMIN SUPPLEMENT USE AND PREVALENCE OF OPACITIES
Table 7 displays the relation
between duration of vitamin supplement use and the prevalence of nuclear opacification.
The prevalence of nuclear opacities was 64% or 43% lower among women who used
vitamin C or multivitamin supplements, respectively, for 10 or more years.
There was a statistically significant trend of decreasing prevalence of nuclear
opalescence with increasing duration for users of either supplement. The prevalence
of nuclear opacities among women who used vitamin E supplements for 5 to 9
years and 10 or more years was less than 50% of the prevalence among those
who did not use vitamin E supplements, but the number of users in these duration
categories was small and the ORs were not significantly lower than 1.0. However,
the trend across duration categories was statistically significant (P = .03). After mutual adjustment of the vitamin supplement
associations for one another, only the association between nuclear opalescence
and vitamin C supplements remained largely unaffected and statistically significant
(Table 8). None of the interactions
between vitamin supplement use and either age or smoking were statistically
significant.
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Table 7. Relation Between the Prevalence of Nuclear Lens Opacities
and the Duration of Vitamin Supplement Use*
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Table 8. Relation Between the Prevalence of Nuclear Lens Opacities
and the Duration of Vitamin Supplement Use After Mutual Adjustment for Use
of Other Supplements*
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PLASMA NUTRIENTS AND PREVALENCE OF OPACITIES
There was a significant inverse association between plasma ascorbic
acid measured at baseline and the prevalence of nuclear opacities (Table 9). The OR relating the prevalence
of opacities in the fourth ascorbic acid quintile category to that in the
lowest category was statistically significant, but the OR in the highest quintile
category was only marginally significant. For plasma -tocopherol, the
OR in the highest quintile category was significantly less than 1, but the
inverse trend across quintile categories was only marginally significant.
On the mutual adjustment of these 2 plasma vitamins, neither remained significantly
associated with prevalent nuclear opacification. Total plasma carotenoids
were unrelated to the prevalence of nuclear opacities. None of the interactions
between these plasma nutrients and age or smoking were statistically significant.
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Table 9. Relation Between the Prevalence of Nuclear Lens Opacities
and Plasma Nutrient Concentrations*
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COMMENT
Results from the NVP provide further evidence that antioxidant nutrients
are associated with risk of age-related lens opacification. Total vitamin
C intake from diet and supplements was associated with a lower prevalence
of nuclear opalescence. Although the vitamin C intake in the lowest intake
quintile category ranged up to 140 mg/d, which is nearly twice the recommended
daily allowance of 75 mg/d for women,36 there
was a significant 48% lower odds of nuclear opacities for usual intakes between
140 and 180 mg/d, a 53% lower odds for intakes between 180 and 240 mg/d, and
a 66% lower odds for intakes between 240 and 360 mg/d. There was little additional
lowering of the odds of nuclear opalescence at higher intakes. These data
are consistent with the prior observation that human eye tissues saturate
at intakes of vitamin C between 200 and 300 mg/d.41
The intake data are also supported by our plasma measures that suggest a lower
prevalence of nuclear opacification with increasing plasma ascorbic acid concentrations.
We also observed an inverse association between nuclear opacities and
duration of vitamin C supplement use. This corroborates earlier work8, 15 demonstrating that a significantly
lower risk of opacities is not seen until vitamin C supplements are used for
10 or more years. This observation should not be interpreted to suggest that
higher supplemental levels of vitamin C would be required to alter cataract
risk for the reasons previously noted. Together, the data relating vitamin
C intake and vitamin C supplement use to nuclear opacities argue that intake
of vitamin C in excess of the recommended daily allowance may play a useful
role in maintaining lens health, but that vitamin C consumption of more than
300 mg/d may provide little added benefit to the lens.
Our results also suggest that women with lutein/zeaxanthin intake above
2.4 mg/d may have a lower risk of nuclear cataract. Lutein and zeaxanthin
are the predominant carotenoids found in the human eye lens.42
However, this association was not clearly independent of the relation between
vitamin C and nuclear opacities. The association that we observed before adjusting
for vitamin C intake is consistent with the results from the Beaver Dam Eye
Study,18 which showed a strong inverse association
between past lutein intake and incidence of nuclear cataract and a 30% to
40% reduction in risk of incident nuclear opacities for persons with serum
lutein concentrations in the highest tertile category relative to those in
the lowest tertile category.17 Two recent reports
from the NHS19 and the Health Professionals
Follow-up Study20 demonstrated that women and
men with lutein/zeaxanthin intakes of approximately 4 to 6 mg/d had reduced
rates of cataract extraction.
We also observed inverse associations between the risk of nuclear opalescence
and several other nutrient measures, including vitamin E intake, duration
of vitamin E supplement use, plasma vitamin E concentrations, and duration
of multivitamin supplement use. Multivitamin and vitamin E supplement use
was related to the risk of nuclear opacification in the Longitudinal Study
of Cataract,16 and there was an inverse association
between plasma vitamin E concentrations and incidence of nuclear opacities
in the Beaver Dam cohort.17 However, as with
lutein/zeaxanthin intake, it is not certain that the relations between nuclear
opacification and vitamin E or multivitamin supplements in the present study
were independent of the vitamin C relationship.
Our data clearly demonstrate the difficulties in determining and interpreting
the independent contribution of different nutrients or types of supplements
to the risk of nuclear opacities. The strong correlation between the intakes
of most nutrients and between the plasma measures in this study indicates
the need to consider the interrelationships between nutrients. Intakes of
many nutrients are correlated because they are found together in many foods
and supplements. Our ability to accomplish the mutual adjustment may be limited
by the high correlation between some nutrients and types of supplements. For
example, the correlation coefficient for the measures of usual vitamin C and
vitamin E intake was 0.62, and 79% of women who consumed vitamin E supplements
for 10 or more years also consumed vitamin C supplements for 10 or more years.
Two thirds of the long-term vitamin C and vitamin E supplement users also
took multivitamins for 10 or more years. Even though we tried to assess the
independent contribution of the different nutrients and types of vitamin supplements,
we may not have been completely effective because of the large overlap in
their intake and use. Therefore, we may be limited in our ability to identify
the separate contributions of the different antioxidant nutrients to the lower
prevalence of opacities, but we can be fairly certain that 1 or more of these
antioxidant nutrients are associated with a lower risk of nuclear opacities.
We undertook the present study with the hypothesis that intake based
on multiple dietary assessments should be more strongly associated with the
prevalence of nuclear opacities than intake based on one dietary assessment.
Surprisingly, we observed similar associations between the risk of nuclear
opacities and vitamin C intake measured either as the average of 5 values
over 13 to 15 years or as a single value from the end of this interval. The
apparent reason for the similarity of the relation is that women tended to
maintain their intake levels over time in our sample. For example, of women
in the lowest quintile category for the average intake measurement, 69% were
also in the lowest category for the single measurement and 89% were in the
lowest 2 quintile categories for the single measurement. Of women in the highest
intake quintile category for the average intake measurement, 82% were also
in the highest category for the single intake measurement and 92% were in
the highest 2 quintile categories for the single measurement.
Interpretation of results from the present study is subject to some
additional caveats. We considered the relations between nuclear opalescence
and 10 measures of nutrient intake, 3 measures of plasma nutrient concentrations,
and 3 measures of vitamin supplement use. Therefore, we must consider the
possibility that some of these associations are spurious. However, the associations
with vitamin C intake and supplement use would remain statistically significant
even under the most conservative adjustments for multiple comparisons. While
we controlled for the most likely known or suspected determinants of cataract
risk, it is also possible that we have not adequately controlled for some
of these or that the observed associations between these antioxidant nutrients
and nuclear opacities might be the result of confounding by other unmeasured
nutrients, such as flavonoids or nonnutritional factors. However, for the
association between nuclear opacification and vitamin C to be a consequence
of unidentified confounding by other unmeasured lifestyle factors, one must
presume a potent unknown risk factor for lens opacification that also closely
parallels vitamin C intake and vitamin C supplement use. It is difficult to
conceive of potential candidates that would produce such strong confounding.
Another potential limitation is the retrospective nature of the study.
However, the nutrient intake data were collected prospectively and well before
any of the women knew that they had lens opacities (since we excluded women
diagnosed as having cataract). Furthermore, most of the women had early opacities
and so should not have experienced any visual symptoms. In fact, visual acuity
did not differ between those with and those without opacities in this study
(data not shown). Despite the early nature of these opacities, our observations
should be relevant to more advanced opacities since it has been demonstrated
that approximately 50% of opacities graded as 2 or higher using LOCS III show
significant progression during a 5-year period.43
Approximately 50% of our sample had LOCS III scores of 2 or greater.
The epidemiological evidence for a relation between antioxidant vitamins
and nuclear opacification is promising. Most recent studies report an association
between nuclear opacities and one or more antioxidant nutrients. However,
these studies do not uniformly demonstrate relations between any particular
antioxidant nutrient and risk of nuclear opacification. There are many possible
reasons for the lack of consistency between studies of vitamins and lens opacities.
Important causes of discordance between studies might be differences in the
study samples and methods. For example, Leske and coworkers16
recently reported that multivitamin supplements, vitamin E supplements, and
higher plasma vitamin E concentrations were associated with a lower risk of
increased nuclear opacification during a 5-year follow-up period in the Longitudinal
Study of Cataract. However, these investigators did not see any relation between
vitamin C supplement use and nuclear opacification. This is in contrast to
results from the NVP and from an earlier study15
performed in a subset of participants from the NHS cohort. However, in the
Longitudinal Study of Cataract,16 only 10%
of the participants were vitamin C supplement users, while in the NVP sample,
approximately 40% used vitamin C supplements and one quarter of these users
consumed the supplements for 10 or more years. Also, the Longitudinal Study
of Cataract combined changes in existing and newly diagnosed nuclear opacities.
The opacities in our study were newly diagnosed and mostly early grade. It
is possible that vitamin C has a differential impact on development and progression
of nuclear opacities. This might also explain the discrepant findings between
our study and the expanded reanalysis of the relation between vitamin C supplement
use and cataract extraction in the complete NHS cohort.21
In the original analysis,8 duration of vitamin
C supplement use was strongly associated with a reduced rate of cataract extraction
in this cohort. However, the later expanded analysis,21
which included a longer follow-up and more age-eligible women, failed to show
any relation between duration of vitamin C supplement use and rate of cataract
extraction in the full eligible group of women, but it did suggest a lower
risk with long-term vitamin C supplement use among subsets of younger women
and those who never smoked. The association between vitamin C intake and incident
nuclear opacities was not statistically significant in the entire Beaver Dam
Eye Study cohort, but there were significant inverse associations reported
in subgroups, such as persons with a low glycosylated hemoglobin level, those
with hypertension, and heavy smokers.18 Such
data suggest that dissimilar associations seen between vitamin C and opacities
in various cohorts might also result from different health and behavioral
characteristics of the participants. There was also no association between
vitamin E intake and incident nuclear opacities in the Beaver Dam Eye Study,18 although higher plasma vitamin E concentrations were
associated with a reduced incidence in this cohort,17
suggesting that methodological differences in the same population might produce
varying results. In contrast to the inconsistencies for vitamins C and E,
our results relating lutein/zeaxanthin intake to opacification are consistent
with results from the Beaver Dam,18 the NHS,19 and the Health Professionals Follow-up Study20 cohorts.
In summary, the inverse association observed in this study between vitamin
C intake and the prevalence of nuclear opacification provides added support
for a protective role of antioxidant nutrients against formation of nuclear
opacities. Given some limitations of our study, we cannot rule out possible
inverse associations between risk of nuclear opacities and other nutrients,
including lutein/zeaxanthin and vitamin E. Although our data add more weight
to the accumulated evidence that antioxidant nutrients play a role in the
development of age-related opacities, our results also are not completely
consistent with the results of earlier epidemiological studies. We have attempted
to raise some possible reasons for the discordance in results. Consistency
of an association is one of the most important criteria in assessing the potential
causal nature of a relationship.44 If future
epidemiological studies are to play a credible role in addressing the causal
nature of the relation between antioxidant nutrients and age-related lens
opacities, these studies will need to address the reasons for the lack of
consistency.
AUTHOR INFORMATION
Accepted for publication December 21, 2000.
This study was supported by agreement 58-1950-9-001 from the US Department
of Agriculture; grants 98-01023 and 92-37200-7704 from the National Research
Initiative Competitive Grant Program; the Brigham Surgical Group, Boston,
Mass; research grant EYE-09611 from the National Eye Institute, Bethesda,
Md; research grant CA40356 from the National Institutes of Health, Bethesda;
and a grant from the Florida Department of Citrus, Lakeland.
We thank the project staff for their assistance and the many others
whose effort supported this project, especially Laura Bury, Rosaline Bowen,
Ester Epstein, Mini Balaram, MD, Sheila Crosby, Karen Corsano, Kate Saunders,
Suzen Mueller, Tom Nowell, and Gayle Petty; the nurses who participated in
the study for their continuing contributions and cooperation; and Frank E.
Speizer, MD, overall principal investigator for the Nurses' Health Study,
for his support.
Any opinions, findings, conclusion, or recommendations expressed in
this publication are those of the authors and do not necessarily reflect the
view of the US Department of Agriculture.
Corresponding author and reprints: Allen Taylor, PhD, Laboratory
for Nutrition and Vision, US Department of Agriculture Human Nutrition Research
Center on Aging, Tufts University, 711 Washington St, Boston, MA 02111.
From the Jean Mayer US Department of Agriculture Human Nutrition Research
Center on Aging (Drs Jacques and Taylor and Ms Rogers) and the School of Nutrition
Science and Policy (Drs Jacques and Taylor), Tufts University; the Departments
of Ophthalmology (Dr Chylack) and Medicine (Drs Hankinson and Willett), Harvard
Medical School, Brigham and Women's Hospital, and the Channing Laboratory
(Drs Hankinson and Willett); the Center for Ophthalmic Research (Drs Chylack,
Khu, Wolfe, and Padhye, Ms Friend, and Mr Tung); and the Departments of Epidemiology
(Drs Hankinson and Willett) and Nutrition (Dr Willett), Harvard School of
Public Health, Boston, Mass.
REFERENCES
1. Taylor A. Nutritional and environmental influences on risk for cataract. In: Taylor A, ed. Nutritional and Environmental
Influences on the Eye. Boca Raton, Fla: CRC Press LLC; 1999:53-93.
2. Jacques PF. The potential preventive effects of vitamins for cataract and age-related
macular degeneration. Int J Vitam Nutr Res. 1999;69:198-205.
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3. Robertson JM, Donner AP, Trevithick JR. Vitamin E intake and risk of cataracts in humans. Ann N Y Acad Sci. 1989;570:372-382.
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