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Relationship Between Systemic Markers of Inflammation and Serum ß-Carotene Levels
Thomas P. Erlinger, MD, MPH;
Eliseo Guallar, MD, DrPH;
Edgar R. Miller III, MD, PhD;
Rachael Stolzenberg-Solomon, PhD, RD;
Lawrence J. Appel, MD, MPH
Arch Intern Med. 2001;161:1903-1908.
ABSTRACT
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Background Low serum levels of ß-carotene have been associated with increased
risk of cancer and cardiovascular disease. However, in clinical trials, supplementation
of the diet with ß-carotene either had no benefit or caused harm. This
pattern of findings raises the possibility that confounding by other factors
might explain the association between serum ß-carotene level and disease
risk.
Methods We used data from 14 470 current smokers, ex-smokers, and never
smokers aged 18 years or older who participated in the Third National Health
and Nutrition Examination Survey to assess the relationship between serum ß-carotene
and markers of inflammation (C-reactive protein and white blood cell count).
Results After adjustment for ß-carotene intake and other factors, geometric
mean levels of serum ß-carotene for individuals with undetectable (<0.22
mg/dL), mildly elevated (0.22-0.99 mg/dL), and clinically elevated ( 1.0
mg/dL) C-reactive protein levels were 18.0, 16.1, and 13.6 µg/dL, respectively,
in never smokers; 18.1, 15.7, and 13.9 µg/dL in ex-smokers; and 11.3,
10.2, and 9.4 µg/dL in current smokers (P<.001
for all). In corresponding analyses, white blood cell count was also inversely
related to serum ß-carotene concentration (P<.05
for all).
Conclusions The strong and inverse association of serum ß-carotene level with
C-reactive protein level and white blood cell count suggests that the relationship
between serum ß-carotene concentration and disease risk might be confounded
by inflammation. More broadly, for ß-carotene and likely other nutrients,
it seems unwise to interpret biomarker data as prima facie evidence of dietary
intake without a more complete understanding of the physiologic processes
that affect nutrient levels.
INTRODUCTION
IN A LANDMARK article, Peto et al1 hypothesized
that low intake of ß-carotene was a modifiable risk factor for cancer.
This hypothesis was strongly supported by the consistent finding of an inverse
association between serum ß-carotene level and risk of cardiovascular
disease and certain types of cancer, especially lung cancer.2-3
However, in large-scale trials,4-10
supplementation of the diet with ß-carotene either had no benefit or
caused harm. There are several possible explanations for the discrepancy between
results of observational studies and clinical trials,2
including the possibility of confounding by other nutrients or lifestyle factors
that might be associated with ß-carotene intake. An alternative explanation
is that serum ß-carotene levels reflect not only ß-carotene intake
but also other physiologic processes related to disease occurrence. In that
case, low serum ß-carotene concentration might be an epiphenomenon, and
increased intake of ß-carotene would not be expected to reduce the risk
of disease. Although this is a well-known theoretical limitation of serum
biomarkers, it is seldom considered in the interpretation of biomarker data.
Preliminary evidence suggests that ß-carotene levels are associated
with inflammation. For example, it is well known that smoking increases systemic
markers of inflammation11 and that smokers
have lower levels of serum ß-carotene than nonsmokers independent of ß-carotene
intake.12-13 In elderly women
and in persons with lung cancer, an inverse relationship between inflammatory
markers and serum ß-carotene concentration has been documented.14-15 In middle-aged adults, serum level
of sialic acid, a systemic marker of inflammation, was inversely associated
with serum ß-carotene level.16 Inverse
associations between serum ß-carotene level and C-reactive protein (CRP)
level, an acute-phase reactant, have also been found in persons who are critically
ill17 or have other acute inflammatory conditions,
such as pancreatitits and tuberculosis.18-19
However, interpretation of these study results is complicated by the lack
of control of important confounders, including smoking status and dietary
intake of ß-carotene.
The importance of these findings is highlighted by the fact that systemic
markers of inflammation are consistently associated with arteriosclerotic
cardiovascular disease (ASCVD) events and tumor recurrence.20-21
Numerous studies22-27
have now shown that CRP level and white blood cell (WBC) count independently
predict ASCVD events. In this setting, we hypothesized that serum ß-carotene
level is inversely associated with systemic markers of inflammation in the
general population and that this association is independent of smoking status,
dietary intake of ß-carotene, and other potential confounders. To test
this hypothesis, we used data from the nationally representative cohort of
the Third National Health and Nutrition Examination Survey (NHANES III).
PARTICIPANTS AND METHODS
STUDY POPULATION
The NHANES III is a national probability survey of Americans conducted
between 1988 and 1994 by the National Center for Health Statistics of the
Centers for Disease Control and Prevention. This survey used a complex, multistage,
stratified, cluster-sampling design to obtain a representative sample of the
noninstitutionalized civilian US population. Of the 19 618 NHANES III
participants aged 18 years and older, we excluded 2989 with missing serum ß-carotene
data, 1943 with unrealistic total caloric intake (<800 or >4200 kcal/d
in men and <600 or >3500 kcal/d in women), and 216 who were pregnant, leaving
14 470 individuals available for analysis.
MEASUREMENTS
A detailed description of survey methods and data collection procedures
has been published elsewhere.28-29
In brief, questionnaire data included self-reported age, race or ethnicity,
sex, and medical history. Nutrient intake was estimated from a single 24-hour
dietary recall. Nonfasting blood samples were used for analysis of inflammatory
markers, total cholesterol level, and ß-carotene concentration.
Serum ß-carotene level was measured using high-performance liquid
chromatography. The interbatch coefficient of variation of pooled samples
used for quality control varied between 5.7% and 10.0%. This assay could detect
a serum ß-carotene level of 0.67 µg/dL or greater. Only 5 participants
had serum ß-carotene levels below the limit of detection. The CRP level
was measured using latex-enhanced nephelometry. Pooled controls had a coefficient
of variation of 3.2% to 16.1% through the period of data collection. Because
74% of individuals had CRP levels below the detection limit for this assay
(0.22 mg/dL), we treated CRP level as a categorical variable: undetectable
(<0.22 mg/dL), mildly elevated (0.22-0.99 mg/dL), and clinically elevated
(1.00 mg/dL). The WBC count was determined using a fully automated hematology
analyzer (Counter Model S-PLUS JR; Coulter Electronics, Hialeah, Fla). Serum
cholesterol level was measured enzymatically (Hitachi 704 Analyzer; Boehringer
Mannheim Diagnostics, Indianapolis, Ind).
Participants were classified as never smokers, ex-smokers, and current
smokers. Never smokers and ex-smokers were defined by self-report, whereas
current smokers were defined by self-report or by a serum cotinine level greater
than 57 nmol/L, as measured by high-performance liquid chromatography and
atmospheric-pressure chemical ionization tandem mass spectroscopy. Diabetes
mellitus was defined by self-report of a physician diagnosis, by the presence
of a fasting plasma glucose level greater than 126 mg/dL (>7.0 mmol/L), or
by the presence of a 2-hour glucose tolerance test result greater than 200
mg/dL (>11.1 mmol/L). Prevalent cardiovascular disease was defined by self-report
of physician-diagnosed myocardial infarction or stroke or by angina as assessed
by the Rose questionnaire. Information on current use of estrogen replacement
therapy, use of vitamin or mineral supplements in the past month, and use
of aspirin or other nonsteroidal anti-inflammatory drugs during the past month
was based on self-report.
Body mass index (BMI) was calculated as weight in kilograms divided
by the square of height in meters. Waist circumference was measured at the
level of the high point of the iliac crest and hip circumference at the level
of maximum extension of the buttocks. The waist-hip ratio (WHR) was calculated
as waist circumference divided by hip circumference. Blood pressure measurement
was the average of measurements obtained at the household interview and the
mobile examination center (maximum of 3 measurements at each).
STATISTICAL METHODS
Because the distribution of serum ß-carotene levels was right-skewed,
we log-transformed this variable and then back-transformed the results for
this study. The association between serum ß-carotene concentration and
participant characteristics was evaluated by quintiles of serum ß-carotene
level using multiple linear regression for continuous outcomes and logistic
regression for dichotomous outcomes. Multiple linear regression was used to
determine whether serum ß-carotene level was independently associated
with markers of inflammation. In addition to age, race, and sex, variables
in this model included known determinants of serum ß-carotene levels
(total caloric intake, dietary fat and carotenoid intake, serum cholesterol
level, BMI, WHR, and use of vitamin or mineral supplements) and factors or
conditions associated with systemic markers of inflammation (estrogen replacement
therapy, aspirin, or other nonsteroidal anti-inflammatory drug use; diabetes
mellitus; and prevalent cardiovascular disease). These variables were selected
a priori, before introducing systemic markers of inflammation into the models.
Because of the well-known association of smoking with low levels of serum ß-carotene
and systemic markers of inflammation, all analyses were stratified by smoking
status (never smokers, ex-smokers, and current smokers).11, 25, 30
Tests for trend were performed by adding a continuous variable with the median
of each category into the regression models.
To account for the complex survey design and to obtain results generalizable
to the US noninstitutionalized population, we used SUDAAN software31 and applied NHANES III weights in all analyses. P<.05 was considered statistically significant (2-sided).
RESULTS
Table 1 displays characteristics
of the 14 470 participants included in our analyses. On average, ex-smokers
were older and were more likely to be white than never or current smokers.
Ex-smokers also had higher blood pressure, cholesterol levels, BMI, and WHR,
as well as a higher prevalence of diabetes mellitus and ASCVD. Current smokers
had higher CRP levels and WBC counts and lower levels of serum ß-carotene
than ex-smokers or never smokers.
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Table 1. Characteristics of 14 470 Adults Who Participated in
the Third National Health and Nutrition Examination Survey According to Smoking
Status*
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In the 3 smoking categories, individuals with higher levels of serum ß-carotene
tended to be older and were more likely to be female and white than those
with lower serum ß-carotene levels (Table 2). After adjusting for age, sex, and race, serum ß-carotene
level was positively associated with total serum cholesterol level, carotenoid
intake, and use of vitamin or mineral supplements during the past month and
inversely associated with BMI and WHR in the 3 smoking categories. Total caloric
intake was positively associated with serum ß-carotene level, but the
trend reached statistical significance in never smokers only (P<.001). Fat intake was inversely associated with serum ß-carotene
level in never smokers and ex-smokers but positively associated in current
smokers. Finally, an inverse association between alcohol intake and serum ß-carotene
level was present only in current smokers.
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Table 2. Factors Associated With Serum ß-Carotene Level According
to Smoking Status*
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ASSOCIATIONS BETWEEN ß-CAROTENE AND CRP LEVELS
The level of CRP was strongly and inversely related to serum level of ß-carotene.
After adjusting for age, sex, and race (Table 3, model 1), the geometric mean levels of serum ß-carotene
in never-smokers with undetectable, mildly elevated, and clinically elevated
CRP levels were 18.9, 14.7, and 11.0 µg/dL, respectively (P<.001 for trend). After further adjustment for serum cholesterol
level, BMI, WHR, total caloric intake, alcohol intake, use of vitamin or mineral
supplements, systolic blood pressure, use of aspirin or nonsteroidal anti-inflammatory
drugs, estrogen replacement therapy, diabetes mellitus, and prevalent cardiovascular
disease (Table 3, model 2), the
relationship between ß-carotene and CRP levels persisted. The corresponding
geometric means were 18.0, 16.1, and 13.6 µg/dL, respectively (P<.001 for trend).
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Table 3. Serum ß-Carotene Level by Level of C-Reactive Protein*
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The association between CRP and serum ß-carotene levels in ex-smokers
was similar to that of never smokers. In multivariate analysis (Table 3, model 2), geometric mean levels of serum ß-carotene
in ex-smokers with undetectable, mildly elevated, and clinically elevated
CRP were 18.1, 15.7, and 13.9 µg/dL, respectively (P<.001 for trend). Current smokers had markedly lower levels of
serum ß-carotene, but an inverse association with CRP level was still
evident. In multivariate analysis (Table
3, model 2), serum ß-carotene levels in smokers with undetectable,
mildly elevated, and clinically elevated CRP levels were 11.6, 11.7, and 8.3
µg/dL, respectively (P<.001 for trend).
ASSOCIATION BETWEEN ß-CAROTENE LEVEL AND WBC COUNT
A strong inverse association was also present between WBC count and
serum ß-carotene level (Table 4).
After adjusting for age, sex, and race, the geometric mean levels of serum ß-carotene
for never smokers in the lowest and highest quintiles of WBC count were 19.1
and 14.1 µg/dL, respectively (P<.001 for
trend). After multivariate adjustment, the geometric mean levels for the first
and fifth quintiles of WBC count were 18.3 and 15.4 µg/dL in never smokers,
18.5 and 16.5 µg/dL in ex-smokers, and 11.9 and 10.5 µg/dL in
current smokers (P = .001 for trend for all).
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Table 4. Serum ß-Carotene Levels by Quintile of White Blood Cell
(WBC) Count*
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To evaluate the possibility that the inverse association between serum ß-carotene
levels and markers of inflammation was due to the presence of clinical conditions
that might affect ß-carotene levels, inflammatory markers, or both, we
repeated our analyses after excluding 3038 individuals who had prevalent diabetes
mellitus or cardiovascular disease. As displayed in Figure 1, the results were essentially unchanged.
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Geometric mean levels of serum ß-carotene by category of C-reactive
protein (A) and the first, third, and fifth quintiles of white blood cell
(WBC) count (B) adjusted for systolic blood pressure, serum cholesterol, body
mass index, waist-hip ratio, total energy intake, alcohol intake, use of vitamin
or mineral supplements, use of aspirin or nonsteroidal anti-inflammatory drugs,
and estrogen replacement therapy and excluding persons with diabetes mellitus
and prevalent cardiovascular disease. Error bars indicate 95% confidence intervals.
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COMMENT
In a nationally representative survey (NHANES III), we documented that
serum ß-carotene concentration is strongly and inversely associated with
systemic markers of inflammation (CRP level and WBC count). After adjustment
for carotene intake and other possible confounders, persons with elevated
systemic markers of inflammation had significantly lower levels of serum ß-carotene.
This inverse association between serum ß-carotene levels and systemic
markers of inflammation was demonstrated in never smokers, ex-smokers, and
current smokers and persisted after exclusion of persons with clinical conditions
that might confound the association.
An inverse association between serum ß-carotene level and systemic
markers of inflammation in a healthy population is biologically plausible.
In adults with an acute illness, there is a transient decrease in serum ß-carotene
level with a simultaneous increase in CRP level, both of which normalize with
resolution of the illness.18-19
A similar acute-phase reaction has been shown for vitamin A and other serum
vitamins and minerals.32 In children, serum
retinol levels decrease during acute infection and return to normal, without
vitamin A supplementation, once the acute process has passed.33
This pattern of findings could result from decreased production of retinol
binding protein by the liver and/or increased urinary excretion of retinol
during acute inflammation.32, 34
Thus, although stores of vitamin A might be depleted during acute inflammation,
the decreases seem to be primarily due to the timing and magnitude of the
acute-phase response. With the recent identification of a binding protein
for ß-carotene,35 a similar relationship
between the acute-phase response and serum ß-carotene level could be
hypothesized.
Although reduced serum ß-carotene concentration is probably the
result of systemic markers of inflammation, another interpretation of these
findings is that ß-carotene has anti-inflammatory properties. This conclusion
is not supported by trials that show either no effect or a modest enhancement
of immune system activity with supplemental ß-carotene,36-42
but additional data from clinical trials are needed to determine whether supplemental ß-carotene
affects systemic markers of inflammation.
Among the strengths of our analyses are the large, nationally representative
survey and the remarkable consistency of our results in each category of smoking
status, which persisted after adjustment for multiple potential confounders.
One potential limitation is the imprecision of the measurements of CRP, WBC,
serum ß-carotene, and dietary intake, all based on single determinations.
Still, we found highly significant associations between inflammatory markers
and serum levels of ß-carotene.
Results from our analyses have several implications. These findings
might partially explain the discrepancy between observational studies that
associated low serum ß-carotene levels with increased disease risk and
clinical trials of ß-carotene supplements. For instance, in the Alpha-Tocopherol,
Beta-Carotene trial,6 low baseline serum levels
of ß-carotene were associated with an increased risk of lung cancer,
whereas supplementation of the diet with ß-carotene for 5 to 8 years
actually increased incident lung cancer and cardiovascular disease events.
One reason for these discordant results might be that low levels of serum ß-carotene
reflect systemic markers of inflammation, itself a risk factor for cardiovascular
disease and perhaps cancer. To this end, prospective observational studies
of serum ß-carotene and subsequent disease risk, adjusted for inflammatory
markers, would be informative, as would clinical trials that assess the effect
of ß-carotene supplementation on markers of inflammation.
More broadly, our findings document the potential limitations of using
serum nutrient levels as a surrogate for dietary intake, particularly in observational
studies that assess the relationship between nutrient intake and subsequent
disease. Serum nutrient levels have appeal in epidemiologic studies in that
they are more objective and might even be more precise than corresponding
estimates from a single food frequency questionnaire or multiple 24-hour dietary
recalls. However, as documented in this study, physiologic processes also
affect serum levels and might reduce precision. Furthermore, serum nutrient
levels are still subject to confounding with other nutrients and, in fact,
are subject to additional confounding from physiologic determinants.
In summary, serum ß-carotene level is strongly and inversely associated
with systemic markers of inflammation, which themselves are markers of increased
ASCVD risk and perhaps cancer. These findings have important implications
for the interpretation of studies that show an increased risk of cancer and
ASCVD in persons with reduced levels of serum ß-carotene. More broadly,
these results highlight the potential limitations of using serum nutrient
levels as a surrogate for dietary intake in observational studies. For ß-carotene
and likely other nutrients, it seems unwise to interpret biomarker data as
prima facie evidence of dietary intake without a more complete understanding
of the physiologic processes that affect nutrient levels.
AUTHOR INFORMATION
Accepted for publication February 22, 2001.
This work was supported in part by grant T32PE10025 from the National
Institutes of Health, Bethesda, Md.
Corresponding author and reprints: Thomas P. Erlinger, MD, MPH, Welch
Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins
Medical Institutions, 2024 E Monument St, Suite 2-600, Baltimore, MD 21205
(e-mail: terlinge{at}jhmi.edu).
From the Welch Center for Prevention, Epidemiology, and Clinical Research
(Drs Erlinger, Guallar, Miller, and Appel) and the Departments of Medicine
(Drs Erlinger, Miller, and Appel) and Epidemiology (Drs Guallar and Appel),
Johns Hopkins Medical Institutions, Baltimore, Md; and the National Cancer
Institute, National Institutes of Health, Bethesda, Md (Dr Stolzenberg-Solomon).
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