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Relation of Serum Ascorbic Acid to Helicobacter pylori Serology in US Adults: the Third National Health and Nutrition Examination Survey

General Internal Medicine Section, Medical Service, San Francisco Veterans Affairs Medical Center, (J.A.S.), New York, New York
Department of Epidemiology and Biostatistics (J.A.S., E.S.H.), New York, New York
University of California, San Francisco, California, Departments of Medicine and Microbiology, New York University School of Medicine, New York, New York (G.I.P.-P.)

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

	ABSTRACT

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Purpose: To examine the relation between serum ascorbic acid and Helicobacter pylori serology from a probability sample of US adults.

Subjects and Methods: Data from 6,746 adults (ages 20 to 90 years) enrolled in the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994 were analyzed. Multiple logistic regression models were examined taking into account sample weights and the complex survey design of NHANES III, and controlling for the effects of potential confounders. Because race appeared to modify the association between serum ascorbic acid and seropositivity to H. pylori, we conducted the analyses stratified by race.

Results: A total of 2,189 adults (32%) had a positive serology for H. pylori, and, of these, 1,175 (54%) were positive for the CagA antigen. Among whites, a 0.50 mg/dL increase in serum ascorbic acid level was associated with decreased seroprevalence of H. pylori (Odds Ratio (OR) = 0.89, 95% confidence interval (CI) CI 0.82–0.96, p < 0.01). In analyses that controlled for seroprevalence of H. pylori, a 0.50 mg/dL increase in serum ascorbic acid level among whites was independently associated with a decreased seroprevalence of the pathogenic cagA-positive strain of H. pylori (OR = 0.31, 95% CI 0.12–0.79, p < 0.05). Serum ascorbic acid levels were not significantly associated with H. pylori serology among non-whites (all p > 0.05).

Conclusions: Higher serum levels of ascorbic acid were associated with a decreased seroprevalence of H. pylori and of the pathogenic cagA-positive strain of H. pylori among whites. If these associations are related causally and are not the result of residual confounding by factors such as socioeconomic status, ascorbic acid may affect the risk of H. pylori infection and in turn, the risk for peptic ulcer disease and gastric cancer among white Americans.

Key words: ascorbic acid, Helicobacter pylori, vitamin C

	INTRODUCTION

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There is a long history relating ascorbic acid status to gastritis [1,2], ulcer disease [3–6] and risk for gastric cancer [7–9]. Epidemiologic reviews have also linked lower dietary ascorbic acid consumption with an increased risk for gastric cancer [10–12]. It is now known that chronic infection with Helicobacter pylori, and especially the strains encoding the cytotoxin-associated gene (cagA), are important risk factors for peptic ulcer disease [13,14] and gastric cancer [15–17]. In one animal study, increased consumption of ascorbic acid inhibited the growth of H. pylori [18]. Although H. pylori has been reported to reversibly lower gastric juice ascorbic acid [19–23], plasma ascorbic acid levels do not appear to change after successful treatment and eradication of H. pylori [19–21]. Most reports have not found an association between plasma ascorbic acid concentrations and H. pylori [19,21,23,24]. However, all but one of these studies [24] was conducted among a small number of subjects. To our knowledge, there are no published reports examining the relation between blood ascorbic acid status and H. pylori among a large population-based sample of Americans.

To ascertain whether serum ascorbic acid is associated with serologic evidence of infection with H. pylori and particularly with strains expressing the cagA virulence factor, we analyzed data collected from the Third National Health and Nutrition Examination Survey (NHANES III) that included serum ascorbic acid levels and H. pylori serology on more than 6,000 American adults.

	METHODS

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Study Population
NHANES III was a national probability survey of Americans conducted between 1988 and 1994 that employed a stratified, cluster sampling design to over sample populations of special interest [25]. Participants, two months to 90 years of age, were enrolled, interviewed and examined by study personnel [25]. NHANES III recorded subjects >90 years as being 90 years old. For these analyses, participants were excluded if there were missing data on variables judged to be potential predictors of H. pylori colonization. We restricted our analyses to adults with values for serum ascorbic acid and excluded 19 participants with serum ascorbic acid levels of questionable validity (i.e., >3.0 mg/dL) [26]. After these exclusions, complete data were available from 6,746 participants between the ages of 20 and 90 years for these analyses. Comparing included and excluded participants revealed no statistically significant differences in age, race, gender, level of education or level of physical activity (all p > 0.21).

NHANES III data were collected in two phases. The first phase was conducted from October 18, 1988 through October 24, 1991, and the second phase was conducted between September 20, 1991 and October 15, 1994 [25]. Only serum specimens collected in Phase 1 were assayed for evidence of seropositivity to H. pylori.

Measurements
NHANES III questionnaire data included self-reported age, race, gender, annual household income, history of smoking, level of physical activity and medication use [25]. Body mass index (kg/m²) was calculated from weight and height data recorded during the physical examination. Dietary intake estimates were based on a 24-hour diet recall. The questionnaires and examination procedures used in NHANES III have been described elsewhere in detail [25].

From stored serum samples among Phase I participants, H. pylori serology was performed using a commercial IgG ELISA assay (Wampole Laboratories, Cranbury, NJ) [27]. In brief, each 96-well plate contained the manufacturer’s three cutoff controls (negative, high positive and low positive) in addition to three positive and two negative controls. For each specimen, an immune status ratio (ISR) was calculated by dividing the specimen optical density by the mean optical density of the three cutoff controls. Specimens were considered negative if the ISR was 0–0.90, equivocal if the ISR was 0.91–1.09 and positive if the ISR was 1.10. This assay has demonstrated a sensitivity of 91 percent and specificity of 96 percent [27]. In additional analyses, there was little overall disagreement (3%) between duplicate tests for overall H. pylori serology.

Using stored serum specimens, the presence of specific serum antibodies to H. pylori CagA protein was determined, as reported previously [16]. As part of another research project, the assays were performed by a team of investigators that included one of the authors of this paper (G.I.P.-P.) [27]. We used an ELISA that has been previously validated with a sensitivity and specificity of 94.4 percent and 92.5 percent, respectively [16]. We used a recombinant CagA antigen provided by Oravax, Cambridge MA. The results of each sample were expressed as the ratio of the optical density value of the sample to the four positive controls (ODR). The absorbance index cutoff value for a positive test was established as an ODR >0.35, as previously described [28]. Of the 4557 participants who were H. pylori negative, 461 had a positive serologic test for CagA antigen, i.e., an ostensible false positive rate of 10.1%. In additional recently published analyses that examined the test reliability of the serologic assays, repeat CagA serologies were performed among participants who tested positive, equivocal and negative to the CagA subtype [29]. Reproducibility for the CagA antibody test was 93.4% if the initial H. pylori test was positive, 91.1% if it was equivocal and 86.3% if it was negative [29]. Serum ascorbic acid levels were measured at the Centers for Disease Control and Prevention in Atlanta, GA by high performance liquid chromatography [30] and ranged from 0.0 mg/dL to an upper cut point of 3.00 mg/dL. Specimens were prepared from fresh serum and immediately mixed with metaphosphoric acid. The samples were then centrifuged, frozen at -70°C and shipped on dry ice by overnight mail to the CDC for analysis [30].

Statistical Analysis
We examined the distribution of ascorbic acid levels and other variables of interest using complex survey design and Phase I sample weights. Phase I sample design and sample weights were used because information on H. pylori serology was collected only during Phase I of the study. Means of continuous variables were compared using linear regression for weighted survey data. Proportions for categorical variables were compared using cross tabulation for weighted survey data with an F statistic.

We used age-adjusted and multivariate logistic regression, taking into account sampling weights and the complex survey design of NHANES III, to examine the relation of serum ascorbic acid to H. pylori serology. Because we identified a cross-product interaction between serum ascorbic acid, race and H. pylori serology (p < 0.05), we conducted our analyses stratified by race (white vs. non-white). Multivariate models controlled for the effects of self-reported age (years), gender (male vs. female), level of education (years completed), cigarette smoking (never, past, current), alcohol intake (grams per day), usual level of physical activity (self-reported as "less active," "about the same," and "more active" than peers) and use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). We selected these variables as potential confounders based on their previously reported association with either serum ascorbic acid, peptic ulcer disease or H. pylori infection. Participants whose H. pylori serology was equivocal were included with seronegative participants for all analyses [27]. We also examined the relation of serum ascorbic acid to H. pylori’s CagA serology status in age- and multivariate-adjusted logistic regression models. The age-adjusted and the multivariate models examining CagA serology controlled for the same variables as the H. pylori serology analyses, but additionally controlled for H. pylori serology status. We also analyzed the relation between serum ascorbic acid and seropositivity to H. pylori by quartile of serum ascorbic acid. To test for monotonic trends across quartiles, we assigned each participant the median value for the category and then analyzed these values as a continuous variable.

Analyses were performed using Stata software that included commands for the analysis of complex survey data [31]. Stata uses the Taylor linearization method to estimate standard errors from complex surveys. We calculated odds ratios (OR) and 95 percent confidence intervals (CI) to examine the association of serum ascorbic acid level to H. pylori seropositivity. We considered two-tailed p values of <0.05 to be statistically significant.

	RESULTS

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The baseline characteristics of 6,746 adult participants enrolled in NHANES III with complete data available for these analysis are presented in Table 1. A total of 2,189 participants (32%) had positive serologic results for H. pylori, and, of those with positive serology, 1,175 (54%) were positive for the cagA strain. The gender, percentage of current cigarette smokers and self-reported use of non-steroidal anti-inflammatory drugs among participants who were seropositive and seronegative for H. pylori were similar. However, some other variables differed by seropositivity status. Serum ascorbic acid levels were consistent with normal levels for this micronutrient in both groups [26], although mean levels were, on average, slightly lower among seropositive participants.

Additional models that analyzed the relation of serum ascorbic acid (by quartile) as a predictor of H. pylori seropositivity were examined (Table 3). For whites, there was a trend for seropositivity to H. pylori to decrease as serum ascorbic acid increased (p for trend = 0.08) that was not observed among non-whites (p = 0.81).

	DISCUSSION

 
Our principal finding was that serum ascorbic acid was inversely related to seroprevalence of both H. pylori and the pathogenic cagA-positive strain of H. pylori among whites enrolled in NHANES III. The associations remained statistically significant after multivariable adjustment. Although we did not observe a significant association between serum ascorbic acid and H. pylori serology among non-whites, the magnitude of the inverse association between serum ascorbic acid and CagA seroprevalence was similar for both whites and non-whites. We cannot exclude the possibility that the non-significant association between serum ascorbic acid and H. pylori CagA serology among non-whites may reflect inadequate statistical power. However, black-white differences in H. pylori infection rates [27,32,33] or in gastric ascorbic acid concentrations among infected blacks and whites have been reported previously [20]. Blacks have higher H. pylori infection rates than whites [27,32,33], and seropositive blacks have been reported to have lower levels of gastric ascorbic acid than whites [20]. Hence, the difference that we observed between whites and non-whites in the relation of serum ascorbic acid to H. pylori seropositivity may reflect true biologic variability.

Because of the cross-sectional design of NHANES III, we cannot be certain that colonization with or gastric inflammation caused by H. pylori does not lower serum ascorbic acid levels directly (by increasing ascorbic acid turnover) or indirectly (by causing a change in the pattern of consumption of ascorbic acid-containing foods or a change in the absorption of ascorbic acid) [34]. It has been reported, however, that ascorbic acid inhibits the growth of H. pylori in animal models [18,35]. It is therefore possible that higher serum levels of ascorbic acid may decrease the risk of H. pylori infection, perhaps by affecting gastric juice ascorbic acid concentrations. This possibility is somewhat increased by reports which indicate that the successful treatment and eradication of H. pylori does not appear to affect plasma ascorbic acid levels [19–21]. That is, if serum ascorbic acid levels were lowered by H. pylori infection thereby producing the inverse relation that we observed, it might be expected that treatment for H. pylori would result in increased post-treatment blood ascorbic acid levels, which has not been reported. Consistent with our findings, Fontham et al. [32] and Goodman et al. [36] have reported that adequate vitamin C intake was associated with a decreased prevalence of H. pylori infection.

In contrast to our findings, other investigators have not reported an association between plasma ascorbic acid and H. pylori seropositivity among predominantly white study subjects [19,21,23,24]. Four of these studies [19,21,23,37] were small, enrolling a convenience sample of between 29 and 69 participants with dyspepsia or ulcer disease. The larger EUROGAST study, which also examined the cross-sectional relation between plasma ascorbic acid and H. pylori infection and reported no significant association, enrolled 1404 participants at nine clinical centers, including one in the US [24]. This study, however, did note that H. pylori seropositive participants had slightly lower plasma ascorbic acid levels compared with seronegative participants (p = 0.20). Our probability sample of Americans analyzed in NHANES III was almost fivefold greater in size compared with the EUROGAST study; consequently, we had considerably greater statistical power to detect an association. We are unaware of prior studies that may have examined the relation of blood ascorbic acid levels to CagA seropositivity. Seropositivity to the CagA antigen of H. pylori has been associated with increased pathogenicity and risk for gastric cancer [16,38].

H. pylori is now recognized as an important cause of peptic ulcer disease and gastric cancer [15,17,39]. The epidemiologic evidence also suggests that dietary ascorbic acid may decrease the risk of gastric cancer [10–12,40]. Hayat and Everett [41] hypothesized that ascorbic acid may be a factor in the causal pathway that links H. pylori infection with gastric cancer. From our study, we cannot reach such a conclusion, but our findings do confirm that serum ascorbic acid and H. pylori are associated inversely and that the association is independent of a number of other factors for which we were able to control. If the associations we observed are not the result of residual confounding, it would suggest two possibilities: that higher levels of ascorbic acid may have the potential to decrease the risk of peptic ulcer disease and perhaps gastric cancer and that H. pylori seropositive individuals may need to increase their intake of dietary ascorbic acid to prevent an H. pylori-associated decrease in serum ascorbic acid levels. Because over 50% of older Americans have serologic evidence of H. pylori infection [27], our findings could have public health significance.

Our study was limited by several factors. NHANES III did not measure gastric juice ascorbic acid levels; hence, we are unable to comment on the relation of gastric juice ascorbic acid to H. pylori seropositivity. Although it is biologically plausible that ascorbic acid may affect the risk of infection with H. pylori, we cannot exclude the possibility that infection with H. pylori lowers serum ascorbic acid levels. There likely was some degree of measurement error regarding the determination of serum ascorbic acid levels and the classification of H. pylori status. However, such measurement error, if non-differential, would tend to result in a decreased probability of being able to detect positive findings and an attenuation of the magnitude of the relation. Although we adjusted for differences in level of education (a proxy for socioeconomic status), physical activity, cigarette smoking and alcohol consumption, it is nevertheless possible that the effects of such factors were only partially accounted for in the multivariable modeling, i.e., our findings may have resulted from residual confounding. Such concern is warranted for socioeconomic status, especially during childhood, which is associated with both poorer nutrition and H. pylori infection. Therefore, we cannot be certain that differences in serum ascorbic acid level preceded infection with H. pylori, and inferences regarding causality should not be made based on the results of this study.

In conclusion, serum ascorbic acid is significantly correlated with seropositivity to both H. pylori and to the pathogenic cagA-positive strain of H. pylori among white Americans. To our knowledge, this report is the first population-based study of Americans to report such associations. If these findings are confirmed by other investigators and are linked causally, higher intakes of ascorbic acid may be a protective factor in the prevention of H. pylori infection.

	ACKNOWLEDGMENTS

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This study was supported by a donation from Roche Vitamins, Inc. and Public Health Service grant HL53479.

Received June 21, 2002. Accepted December 12, 2002.

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