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Journal of the American College of Nutrition, Vol. 20, No. 3, 255-263 (2001)
Published by the American College of Nutrition

Original Research

Relation of Serum Ascorbic Acid to Mortality Among US Adults

Joel A. Simon, MD, MPH, FACN,, Esther S. Hudes, PhD, MPH and Jeffrey A. Tice, MD,

General Internal Medicine Section, Medical Service, Veterans Affairs Medical Center (J.A.S.), University of California, San Francisco, California
Department of Epidemiology and Biostatistics (J.A.S., E.S.H., J.A.T.), University of California, San Francisco, California
Division of General Internal Medicine, Department of Medicine (J.A.T.), University of California, San Francisco, California

Address reprint requests to: Dr. Joel A. Simon, General Internal Medicine Section (111A1), San Francisco VA Medical Center, 4150 Clement Street, San Francisco, California, 94121. E-mail: jasimon{at}itsa.ucsf.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Purpose: To examine the relation between serum ascorbic acid (SAA), a marker of dietary intake (including supplements), and cause-specific mortality.

Subjects and Methods: We analyzed data from a probability sample of 8,453 Americans age >=30 years at baseline enrolled in the Second National Health and Nutrition Examination Survey (NHANES II), who were followed for mortality endpoints. We calculated relative hazard ratios as measures of disease association comparing the mortality rates in three biologically relevant SAA categories.

Results: Participants with normal to high SAA levels had a marginally significant 21% to 25% decreased risk of fatal cardiovascular disease (CVD) (p for trend = 0.09) and a 25% to 29% decreased risk of all-cause mortality (p for trend <0.001) compared to participants with low levels. Because we determined that gender modified the association between SAA levels and cancer death, we analyzed these associations stratified by gender. Among men, normal to high SAA levels were associated with an approximately 30% decreased risk of cancer deaths, whereas such SAA levels were associated with an approximately two-fold increased risk of cancer deaths among women. This association among women persisted even after adjustment for baseline prevalent cancer and exclusion for early cancer death or exclusion for prevalent cancer.

Conclusions: Low SAA levels were marginally associated with an increased risk of fatal CVD and significantly associated with an increased risk for all-cause mortality. Low SAA levels were also a risk factor for cancer death in men, but unexpectedly were associated with a decreased risk of cancer death in women. If the association between low SAA levels and all-cause mortality is causal, increasing the consumption of ascorbic acid, and thereby SAA levels, could decrease the risk of death among Americans with low ascorbic acid intakes.

Key words: antioxidants, ascorbic acid, cancer, cardiovascular disease, mortality, vitamin C


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Known cardiovascular disease (CVD) risk factors account for approximately 60% of coronary heart disease (CHD) risk [1]. Differences in antioxidant nutrients may explain part of the risk unexplained by conventional CVD risk factors [2,3]. Because ascorbic acid, an important water-soluble antioxidant [4], protects endogenous lipid-soluble antioxidants from oxidative damage as well as influences the production of endothelial prostacyclin, nitric oxide and the catabolism of cholesterol [5,6], it has been hypothesized that low SAA levels may be a risk factor for CVD [5]. In addition, increased consumption of ascorbic acid has been associated with a decreased risk of cancer in some studies [7–9].

We undertook this study in part to confirm our previous cross-sectional findings from the Second National Health and Nutrition Examination Survey (NHANES II) on the relation between SAA and CVD [10] and also to examine the relation of ascorbic acid to risk of non-CVD death. We reported previously that low to marginally low SAA levels were independently associated with an increased prevalence of self-reported CHD and stroke [10]. However, because those analyses were cross-sectional, we were unable to ascertain whether low SAA levels preceded the occurrence of CVD.

To examine the relation of SAA level, which reflects dietary and supplement intake [11,12], to the risk of cause-specific and all-cause mortality, we analyzed data collected from a probability sample of the US population enrolled in NHANES II. A subset of NHANES II participants were followed between 12 and 16 years for mortality endpoints as part of the NHANES II Mortality Study (NH2MS).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Subjects
NHANES II was a national survey of over 20,000 Americans conducted between 1976 and 1980 that employed a stratified, cluster sampling design to oversample populations of special interest [13]. Participants were interviewed and examined by study personnel at two visits [13]. The NH2MS was restricted to subjects between the ages of 30 and 75 years at the baseline examination (n = 9,252). For our analyses, we excluded two participants who were missing data on vital status, 639 participants who were missing values for SAA level and 45 subjects who had very high SAA levels of questionable validity (>2.7 mg/dL) [5], leaving a total potential sample size of 8,566. Analyses of all-cause mortality excluded an additional 113 subjects who were missing data on relevant predictor variables (n = 8,453). For the analyses of cause-specific mortality, we excluded an additional 36 subjects with missing data on relevant outcome variables. Hence, data from 8,417 subjects were available for analysis of CVD and cancer mortality endpoints.

Measurements
NHANES II questionnaire data included self-reported age, race, gender, years of education completed, usual level of physical activity, and history of smoking (never/past/current), hypertension, diabetes, alcohol intake, multivitamin, vitamin C, and vitamin E supplement use, and aspirin use within the previous six months. We did not adjust for pack-year history of smoking because the large number of missing values for this variable would have resulted in a substantially lower sample size for the analyses. Participants were asked whether they had a history of angina pectoris, myocardial infarction or stroke. A positive response to any of the following questions was used as evidence of prevalent CHD: "Have you ever had any trouble with pain, discomfort or pressure in your chest when you walk fast or uphill?", "Have you ever had severe pain across the front of your chest lasting for half an hour or more", and "Has a doctor ever told you that you had a heart attack?" A diagnosis of prevalent cancer was made by a positive response to the question: "Has a doctor ever told you that you had cancer?" Nutrition data were collected using a 24-hour diet recall. Because quantitative data on vitamin supplement use were not available, intake estimates were based solely on the 24-hour diet recall. Weight, height and blood pressure were measured during the physical examination and body mass index (kg/m2) was calculated. The questionnaires and examination procedures have been described in detail elsewhere [13].

SAA levels were measured at the Centers for Disease Control using a standardized protocol [14]. SAA levels ranged from 0.1 to an upper cut point of 2.7 mg/dL [10]. We included total non-fasting serum cholesterol levels in the analyses; these levels have been shown to reflect fasting cholesterol levels accurately [15]. Serum cholesterol levels were assayed according to the Lipid Research Clinic Program protocols [16].

The National Center for Health Statistics established the cause of death from participants’ death certificates. The International Classification of Diseases, Ninth Revision, was used to classify deaths [17]. We grouped mortality endpoints into three categories: CVD deaths (coded 390 through 459), cancer deaths (coded 140 through 208) and all other (non-CVD/non-cancer) deaths.

Statistical Analysis
We examined the distribution of SAA levels and other variables using sample weights. We used Cox proportional hazards regression to examine the relation of SAA to all-cause and cause-specific mortality. The relation between SAA and mortality risk was examined using three biologically relevant SAA category levels (low to marginal <0.4 mg/dL, normal = 0.5 to 1.0 mg/dL, and high levels consistent with tissue saturation = 1.1 to 2.7 mg/dL) [5]. These three biologically relevant SAA categories were used in our previous reports from NHANES II and NHANES III on SAA and CVD, permitting direct comparison with the prior cross-sectional findings [10,18]. To test for monotonic trends, we assigned each participant the median value for the category and then analyzed these values as a continuous variable. In addition, we examined the relation of dietary ascorbic acid intake, a continuous variable, and vitamin C supplement use, a dichotomous variable, to mortality endpoints. Smoking was analyzed as an ordinal variable and as a categorical variable in all multivariate models with similar results. Because we identified an interaction between SAA and gender on the risk for cancer death (p = 0.02), but not for CVD death (p = 0.85), non-CVD/non-cancer death (p = 0.37) or all-cause mortality (p = 0.32), we conducted analyses of the relation between SAA and cancer death stratified by gender. We included participants with prevalent CVD (CHD and stroke) and cancer in the analyses because ascorbic acid may affect survival among such persons and to increase our statistical power. We adjusted for such prevalent disease after first testing for interactions with SAA on risk of death. We additionally conducted analyses that excluded participants with prevalent CVD for the CVD death outcome, prevalent cancer for the cancer death outcome and both prevalent CVD and cancer for the outcome of all cause mortality.

Analyses were performed using SUDAAN [19] and Stata software [20] that included commands for the analysis of complex survey data. We used proportional hazards regression to calculate relative hazard ratios and their 95% confidence intervals. For the calculation of attributable risk percent and the population attributable risk percent, standard equations were employed [21,22]. We considered two-tailed p values <0.05 to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
SAA levels and other predictor variables were available from 8,453 participants, age 30 to 74 years at baseline. Most participants had SAA levels within the normal range (>0.4 mg/dL) [5]; the mean (standard deviation) level was 1.0 (0.5) mg/dL. Approximately 17.5% of the participants had SAA levels consistent with marginal or frank deficiency (<0.4 mg/dL) [5] (Table 1). Women had higher SAA levels than men and non-smokers had higher SAA levels than smokers. Mean dietary ascorbic acid intake (standard deviation) level was 98 (98) mg/day.


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  		Table 1. Characteristics of the study subjects across categories of serum ascorbic acid level among 8,453 participants >=30-years-old followed in the NH2MS

 
Cardiovascular Disease Death
Over the mean 14 years of follow-up, there was an approximately 7% cumulative incidence of CVD death (n = 561) among NH2MS participants. In models that adjusted for age only, participants with normal and high levels of SAA had a respective 36% and 49% decreased risk of CVD death, compared to participants with lower SAA levels. (Table 2) The magnitude and strength of the association decreased somewhat after multivariate adjustment (see multivariate model 1). Because baseline CVD (defined as self-reported angina, myocardial infarction or stroke) could affect SAA levels and risk of subsequent CVD death, we examined the relation of SAA to the risk of CVD death after adjustment for prevalent CVD. We examined whether prevalent CVD modified the association between SAA levels and risk of CVD death and found no evidence for such interactions (both p >0.11), i.e., the relation between SAA and risk of CVD death did not differ between participants with and without prevalent CVD. Risk estimates were little changed after further adjustment for level of HDL cholesterol (Table 2). We analyzed an additional multivariate model (see model 3) restricted to participants without prevalent CVD (n = 6,249). Among this subgroup, participants with normal and high levels of SAA had a respective 33% and 34% decreased risk of CVD death, compared to participants with lower SAA levels.


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  		Table 2. Risk of cardiovascular disease death (ICD9 390–459) across categories of serum ascorbic acid level among participants >=30-years-old followed in the NH2MS

 
We also analyzed the relation of SAA to CVD death among never smokers (n = 3,205). Among this subgroup, there was a non-significant 14% to 26% decreased risk of CVD death associated with normal and saturation levels of SAA compared with low to marginally low SAA levels (p for trend = 0.11).

We examined whether dietary ascorbic acid consumption and vitamin C supplement use were associated with risk of CVD death. In multivariate models that substituted dietary ascorbic acid intake for SAA category, we observed no relation between ascorbic acid intake and risk of CVD death (p = 0.30). Use of vitamin C supplements was not associated with risk of CVD death when added to these models (p = 0.35).

Among individuals with low to marginally low SAA levels, approximately 23% of all CVD deaths may be attributable to such SAA levels, independent of other CVD risk factors (based on multivariate model 1 in Table 2). A total of 5% of CVD deaths in the entire cohort may be independently attributable to lower SAA levels.

Cancer Death
NH2MS participants had an approximately 5% cumulative incidence of fatal cancer (n = 405), and, of these, lung cancer was the most common cause of cancer death (n = 138). Because gender appeared to modify the association between SAA level and all cancer death, we conducted these analyses stratified by gender (Table 3).


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  		Table 3. Risk of cancer death (ICD9 140–208) across categories of serum ascorbic acid level among participants >=30-years-old followed in the NH2MS

 
Among men, increasing SAA levels were associated with a decreased risk of cancer death. The association between SAA and risk of cancer death was somewhat attenuated after adjustment for prevalent cancer and other risk factors. Compared with low to marginally low SAA levels, men with normal to high SAA levels had an approximately 30% reduction in the risk of dying from cancer. Excluding participants who died during the first two years of follow-up attenuated the association slightly. Among women, and in contrast to the findings for men, increasing SAA levels were associated with an increased risk for cancer death. The magnitude of the relation increased after adjustment for prevalent cancer and with the exclusion of deaths occurring within the initial two years of follow-up. Analyses of the subgroup of participants who were never smokers revealed no association between SAA level and risk of cancer death in men, but an approximately twofold increased risk among women in the highest SAA category (Table 3).

Additional analyses that excluded participants with prevalent cancer produced similar results (see Table 3). Among women, the RH was 2.19 (95% CI: 1.08 to 4.44, p = 0.03) for women with normal SAA levels and was 2.00 (95% CI: 1.12 to 3.58, p = 0.02) for women with SAA levels consistent with tissue saturation compared to women with low to marginally low SAA levels. After similar exclusions for men, the RH was 0.66 (95% CI: 0.48 to 0.92, p = 0.02) for men with normal SAA levels and was 0.67 (95% CI: 0.46 to 0.98, p = 0.04) for men with SAA levels consistent with tissue saturation.

We also examined the relation between SAA and specific cancers. Because gender did not modify the association between SAA and lung cancer risk (p = 0.64), we conducted these analyses unstratified by gender. SAA was inversely associated with the risk of fatal lung cancer; in multivariate models that included smoking, participants with SAA levels consistent with tissue saturation had a 45% decreased risk of lung cancer death (95% CI: 9% to 68%, p <0.001). In the entire cohort, the proportion of deaths from fatal lung cancer potentially attributable to lower SAA levels was 13%, independent of other cancer risk factors. No other fatal cancer was significantly associated with SAA. However, there were few cases of fatal breast (n = 37), colorectal (n = 41), gastroesophageal (n = 17), pancreatic (n = 20) and urinary tract tumors (n = 16) and, consequently, low statistical power to detect associations.

We examined the relation of dietary ascorbic acid consumption to cancer death in multivariate models that substituted dietary ascorbic acid intake for SAA category. We found no association between ascorbic acid intake and risk of fatal cancer (p = 0.50). When use of vitamin C supplements was added to these multivariate models, such use was associated with a 65% decreased risk of fatal cancer among men (RH = 0.35, 95% CI: 0.12–0.98, p = 0.046), but was not associated with fatal cancer risk among women (RH = 0.78, 95% CI: 0.32–1.90, p = 0.57).

All-Cause Mortality
The relation of SAA to all-cause mortality is presented in Table 4. Participants with low baseline SAA levels were at increased risk compared to participants with normal and saturation levels of SAA. Excluding deaths that occurred during the initial two years of follow-up did not appreciably affect the association. Among never smokers (n = 3,220), there was a significant 12% to 26% decreased risk of all-cause death associated with normal to saturation levels of SAA compared with low to marginally low SAA levels (p for trend = 0.02).


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  		Table 4. Risk of all-cause mortality across categories of serum ascorbic acid level among participants >=30-years-old followed in the NH2MS

 
In part, the association between SAA and all-cause death reflects the relation of ascorbic acid to CVD death. However, when examining the multivariate relation of SAA to non-CVD/non-cancer deaths, participants with normal SAA levels and levels consistent with tissue saturation had an approximately 43% to 48% decreased risk of non-CVD/non-cancer death, respectively (p for trend <0.001), compared to participants with low to marginally low SAA levels. In multivariate models that substituted dietary ascorbic acid intake for SAA category and included vitamin C supplement use, we observed no significant association between either ascorbic acid intake or vitamin C supplement use and risk of all-cause death (both p >=0.19).

Among individuals with low to marginally low SAA levels, the proportion of all deaths potentially attributable to such SAA levels was 27%, independent of other risk factors. For the entire cohort, approximately 6% of deaths from all causes may be independently attributable to lower SAA levels.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Low SAA levels were independently associated with a increased risk of fatal CVD, lung cancer and all-cause mortality among participants >=30-years-old enrolled in NHANES II, and potentially account for a significant proportion of mortality, especially among individuals with sub-optimal levels. Based on our findings, as many as 5% of CVD deaths in the US, 13% of lung cancer deaths and 6% of all-cause mortality may be independently attributable to lower SAA levels. These results concur with the findings from our previous cross-sectional analysis of prevalent CVD among NHANES II participants [10], where we found that low SAA levels were independently associated with an increased prevalence of self-reported CHD and stroke [10]. Our findings among women regarding cancer death, however, were unexpected; low SAA levels were associated with a decreased risk of cancer death. We observed no association between dietary ascorbic acid intake and any of the mortality endpoints, but did find that vitamin C supplement use was associated with a decreased risk for cancer death among men. Analyses using dietary ascorbic acid intake may have yielded different findings compared with SAA levels because of the imprecision and inaccuracy in estimating intake based on a single 24-hour diet recall.

Ascorbic acid may reduce the risk of CVD by several mechanisms. Antioxidant status has been hypothesized to be an important factor in atherogenesis [23,24], and ascorbic acid is a highly effective water-soluble antioxidant [4], capable of inhibiting lipid peroxidation [25–29]. In some studies, ascorbic acid blood levels and dietary intake have been associated with increased levels of HDL cholesterol and decreased levels of total cholesterol [5,30–32]. The inverse relation between SAA level and fatal CVD that we observed, however, was independent of cholesterol levels. Ascorbic acid has been observed to be a promoter of endothelial prostacyclin [33–35] and also improves endothelium-dependent vasodilation [6,36–38], factors that may be associated with CVD risk.

Our findings are consistent with results from some correlational [39], cross-sectional [40] and longitudinal studies [41–45] that have found low blood ascorbic acid levels to be a risk factor for CHD and stroke. Several recent prospective studies that used dietary intake of ascorbic acid as a predictor of CVD produced contradictory results. An analysis of data from the NHANES I Epidemiologic Follow-up Study found that individuals with the highest intakes of ascorbic acid had a 25% to 50% reduction in CVD mortality [46]. Dietary ascorbic acid intake was also associated with a decreased risk of CHD death among Finnish women [47] and a group of 747 noninstitutionalized elderly Massachusetts residents [48]. However, the Nurses Health Study [3] and the Health Professionals Follow-up Study [2] found no significant association between ascorbic acid intake and risk of CHD. The Health Professionals Follow-up Study did report a non-significant decrease in CHD risk with ascorbic acid supplement use of two or more years duration [2]. Because the median ascorbic acid intake among men in the lowest quintile of ascorbic acid consumption was 92 mg/day, the Health Professionals Follow-up Study was unable to determine whether marginal or frank ascorbic acid deficiency was associated with increased CHD risk [2]. There are no published clinical trial data examining the effect of ascorbic acid on CHD [49].

Similar to a recent report by Loria et al. that also analyzed data from the NH2MS [50], we also found that higher SAA levels were inversely associated with the risk of cancer death among men. However, unlike that study, which excluded all participants with baseline CVD and cancer, we found that women with normal to high SAA levels had an increased risk of cancer death, even after adjustment for baseline cancer and after excluding women who had died during the first two years of follow-up. These findings seem counter-intuitive, contradict published reviews [7–9] and may, therefore, be the result of residual confounding or chance. Reviews of observational studies have either reported no association between ascorbic acid and cancer or a protective association from higher dietary or blood levels [7,9]. We did find that lower levels of SAA were independently associated with an increased risk of fatal lung cancer, the most common cause of cancer death among NH2MS participants. Compared with non-smokers, smokers generally consume lower levels of ascorbic acid [51]. Furthermore, smoking increases the turnover and decreases the absorption of ascorbic acid, further contributing to reduced SAA levels [5,52,53]. Nevertheless, we found that even after controlling for differences in smoking status, lower SAA levels were associated with an increased risk of fatal lung cancer.

Some other differences between our study and that of Loria et al. [50] may have resulted from the manner in which the SAA categories were defined. Loria et al. used categories based on statistical criteria (quartiles), whereas we employed categories based on biological criteria. Although Loria et al. adjusted for many similar confounders, some variables were defined differently. For example, hypertension was defined by baseline systolic blood pressure whereas we used a history of hypertension because even successfully treated hypertension confers an increased risk for CVD events [54]. Additionally, we controlled for HDL cholesterol and aspirin use for the CVD analyses and for dietary energy and fat intake for the cancer and all-cause mortality analyses. However, the largest difference likely results from the inclusion and adjustment for participants with prevalent disease, for whom the relation between SAA and mortality was no different among participants with and without such disease. The inclusion of the additional high-risk participants resulted in somewhat increased statistical power in our study.

Our most important finding was the observation that higher levels of SAA were independently associated with a large decrease in all-cause mortality. Similar findings using dietary intake and qualitative vitamin supplement use were reported in the NHANES I Epidemiologic Follow-up Study [46]. Sahyoun et al. also observed that higher plasma ascorbic acid levels and dietary ascorbic acid intake were associated with a decreased risk of all-cause mortality among a group of elderly Massachusetts residents [48]. Because ascorbic acid is a water-soluble antioxidant important in maintaining normal immune function [52], it is conceivable that low SAA levels may also contribute to an increased risk of non-CVD/non-cancer death.

Our study has a number of strengths and limitations. Because NH2MS followed a probability sample of the US population, our findings should be generalizable. Further, the measurement of SAA levels on a large sample of the population permits a more precise and accurate assessment of ascorbic acid status as a correlate of mortality than studies using dietary intake estimations [55]. The correlation between dietary estimates and measured blood levels of ascorbic acid is modest (r = 0.43) [56], whereas the correlation between SAA and leukocyte ascorbic acid levels, a measure of tissue levels, is strong (r = 0.92) [11,57]. Our study was, however, limited by a number of factors. We had only a single measurement of SAA which may not reflect long term intake patterns optimally. The 24-hour diet recall used in NHANES II did not provide estimates of dietary folate, vitamin B6 or fiber intake, and we were also unable to control for the effects of several other CVD risk factors (e.g., serum homocysteine, fibrinogen and lipoprotein(a) levels). Therefore, we cannot exclude the possibility that our findings were affected by residual confounding (particularly from cigarette smoking in men where SAA was strongly associated with fatal cancer risk in models that included smokers, but was not associated in identical models restricted to never-smokers only). We also cannot exclude the possibility that SAA levels are simply a healthy lifestyle marker. However, the association of low SAA levels with increased risk of CVD was independent of the effects of other lifestyle-related variables, such as education, exercise, smoking and vitamin E supplement use. Furthermore, the increased risk was seen only among individuals with the lowest SAA levels; that is, having SAA levels consistent with tissue saturation did not appear to confer any additional benefit over having normal SAA levels. Disease ascertainment was based on death certificate diagnoses; therefore, some misclassification of mortality diagnoses likely occurred. Based on recent findings from the Framingham Heart Study, the sensitivity and specificity of a combined all-CVD-death category (including CHD, stroke and other CVD deaths) was 90% and 74%, respectively [58]. Such misclassification would tend to bias the results toward the null hypothesis [58]. Despite any misclassification, we were able to detect a strong and independent (albeit marginally significant) inverse relation between baseline SAA levels and subsequent CVD mortality.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Low SAA levels were marginally associated with an increased risk of fatal CVD and significantly associated with an increased risk for all-cause mortality. Low to marginally low SAA levels were a risk factor for lung cancer death in both men and women and for all-cancer death in men, but unexpectedly were associated with a decreased risk of cancer death in women. If the association between low SAA levels and all-cause mortality is causal, increasing the consumption of ascorbic acid and, in turn, SAA levels could decrease the risk of death among Americans with low ascorbic acid intakes.


   ACKNOWLEDGMENTS
 
Supported by Roche Vitamins, Inc. and Public Health Service grant HL53479.

Received October 3, 2000. Accepted March 15, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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