Abstract
Background
There is a need to identify individuals with gastric intestinal metaplasia, a precursor to gastric cancer, so they can be offered screening and surveillance. We examined the prevalence of gastric intestinal metaplasia, detected by upper endoscopy biopsy analysis, in different race and ethnic sub-groups. We also investigated the extent to which Helicobacter pylori infection, with or without acute and chronic gastritis, accounts for observed associations between race or ethnicity and risk of gastric intestinal metaplasia.
Methods
We used data from a cross-sectional study of consecutively recruited patients at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas from February 2008 to August 2013. All participants completed a study questionnaire on sociodemographic and clinical characteristics and underwent upper endoscopy with gastric mapping (7 biopsy sites). Cases were classified as having gastric intestinal metaplasia if intestinal metaplasia was detected in 1 or more non-cardia gastric biopsy; non-cases were participants without evidence of gastric intestinal metaplasia. We used logistic regression models to estimate odds ratios (OR) and 95% CI values to examine the association between race or ethnicity and gastric intestinal metaplasia and performed a mediation analysis to determine whether H pylori and gastritis affected observed associations.
Results
We included 415 cases with gastric intestinal metaplasia and 1764 non-cases. The prevalence of gastric intestinal metaplasia was highest among Hispanic patients (29.5%; 95% CI, 23.7%–36.1%), followed by African-American (25.5%; 22.4%–28.9%) and non-Hispanic white patients (13.7%; 11.9%–15.7%). After we adjusted for age, sex, and smoking, African-American (OR, 1.87; 1.44–2.44) and Hispanic race or ethnicity (OR, 2.32; 1.61–3.34) and H pylori infection (OR, 3.65; 2.79–4.55) were associated with increased risk of gastric intestinal metaplasia. H pylori infection alone accounted for 33.6% of the association of race or ethnicity with gastric intestinal metaplasia, and 55.5% of the association when combined with acute and chronic gastritis.
Conclusions
Hispanic and African-American patients have an increased risk for gastric intestinal metaplasia, determined by upper endoscopy biopsy analysis, compared with non-Hispanic white patients. This increase in risk was partially independent of H pylori infection.
Keywords: gastric intestinal metaplasia, race, risk factors, prevalence
INTRODUCTION
Gastric cancer is the fifth leading cause of cancer-related mortality worldwide1 with more than 1.03 million incident cases in 2018.1 In the United States (U.S.), over 26,000 persons are newly diagnosed with gastric cancer annually,2 and the 5-year survival rates for persons diagnosed with gastric cancer in the U.S. remain less than 30%.3 The most common (~70%) histologic subtype of gastric cancer in the U.S. is non-cardia intestinal-type gastric cancer (which we will refer to as gastric cancer).4 Gastric cancer is thought to develop in the setting of Helicobacter pylori from a prolonged precancerous process involving first chronic active gastritis, then atrophic gastritis, leading to gastric intestinal metaplasia (GIM), followed by dysplasia and invasive carcinoma.5 This sequence allows for the possibility of primary prevention strategies involving either population-based or targeted screening to identify patients with GIM who may need subsequent surveillance. Given the low overall incidence of gastric cancer in the U.S., population-based screening is not cost-effective and are not currently recommended.6 Thus, the most challenging, yet promising and economically viable, strategy is to identify persons at highest risk of GIM so that they can be offered optimum screening, surveillance and therapy.7
There are major race/ethnicity related differences in the risk of gastric cancer.8, 9 A study of 323,549 incident gastric cancer cases from the U.S. Cancer Statistics (USCS) registry from 2001–2015 found that age-standardized incidence rates for gastric cancer were 2-fold higher among Hispanics, African-Americans, and Asian-Americans compared to non-Hispanic whites.3 The reasons for these disparities could be related to differences in the prevalence of precursor lesions like GIM, but this has not been clearly shown. Likewise, if differences in GIM prevalence between race/ethnic subgroups exist, whether these differences are explained by racial/ethnic differences in the prevalence of the main risk factor, H. pylori infection, remains unclear. The implication for a GIM recognition screening and surveillance strategy is the possible use of race/ethnicity to stratify patients into high and low risk groups.
Few studies have examined the racial variations in GIM prevalence in the U.S. A study of 799,075 patients with gastric biopsies during 2008–2013 reported that prevalence of GIM was highest in Asian-Americans (30.2%), followed by Hispanics (12.0%) and non-Hispanic whites (7.6%).10 Another study of 487,587 patients with gastric biopsies from 2008–2014 found that East-Asians (26.1%) and Hispanics (13.5%) had a higher prevalence of GIM than the total study population (9.3%).11 A multi-center study of 17,710 patients referred during 1999–2014 for endoscopy and had at least one gastric biopsy found African-Americans (adjusted odds ratio [OR], 1.84), Hispanics (adj. OR, 4.30), and Asians (adj. OR, 3.51) had a higher risk of GIM compared to non-Hispanic whites.12 In these studies, endoscopy was not systematically performed in the underlying representative population, and therefore racial disparities in the prevalence of GIM were confounded by the indication for endoscopy and gastric biopsy. Lastly, a single-center study from Arizona in 1992 of 440 consecutive patients found that 50% of Hispanics, Asians-Americans, and African-Americans had GIM compared to 13% of non-Hispanic whites; these results may be outdated due to recent changing trends in gastric cancer.13 In these studies, it was also unclear how much of the racial/ethnic differences in GIM reflect racial/ethnic disparities in the prevalence of H. pylori infection,14–16 in which case, risk stratification for GIM could be more directly performed based on H. pylori status.
We, therefore, analyzed data from a large cross-sectional study in which patients representative of the underlying population consecutively underwent endoscopy with gastric mapping biopsies to examine the prevalence of GIM in major race/ethnic sub-groups and to investigate the extent to which H. pylori infection and other known risk factors for GIM explains the observed association between race/ethnicity and risk of GIM.
METHODS
Study Population and Design
We used data from a cross-sectional study of patients attending elective endoscopy as well as those in primary care clinics at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas from February 2008 to August 2013. The details of the study design have been previously described.17 Briefly, we randomly sampled and consecutively invited patients scheduled for a non-urgent, elective esophagogastroduodenoscopy (EGD) at the MEDVAMC. We also recruited from seven primary care clinics at the MEDVAMC a random sample of patients who were eligible for screening colonoscopy and invited them to undergo study EGD at the time of screening colonoscopy. None of the primary care patients were primarily referred for endoscopy, and all were approached at the primary care clinic visit and not at time of colonoscopy. Study eligibility was based on: (1) age 40–80 years (50–80 years for screening colonoscopy participants based on colon cancer screening commencing at age 50); (2) no previous gastroesophageal surgery; (3) no previous/current gastric or esophageal cancer; (4) no active lung, colon, or breast cancer; (5) no current use of anticoagulants (a relative contraindication for mucosal biopsy during endoscopy); (6) no significant liver disease; and (7) no history of major stroke or mental condition that would limit ability to answer questions. The study was approved by the Institutional Review Board for Human Subjects Research for Baylor College of Medicine and the VA Research and Development Committee of the MEDVAMC. All participants provided written informed consent to take part in the study.
In the endoscopy group, among eligible patients who presented for their previously scheduled upper endoscopy and were invited to participate in the study, 70% completed the study. In the primary care group, 43% of invited eligible patients completed the study (i.e., underwent the study EGD and completed the study questionnaire).
Study Questionnaire and Anthropometric Measurements
Prior to the study EGD, research assistants interviewed all study participants and completed a questionnaire reporting race/ethnicity (non-Hispanic white, African-American, Hispanic, Asian-American, American Indian or native Alaskan, native Hawaiian or other Pacific Islander, and unknown), age, sex, education level, household income, alcohol and smoking history, medical history, gastroesophageal reflux disease (GERD) symptoms, and use of medications (proton pump inhibitor [PPI], histamine-2 receptor antagonists [H2RA], aspirin, and nonsteroidal anti-inflammatory drug [NSAID]). Each participant had height and weight measured and body mass index (BMI; kg/m2) calculated. Finally, we used a flexible tape measure to obtain waist and hip circumferences, and we calculated waist-to-hip ratio (WHR) as waist circumference divided by hip circumference.
Study Endoscopy
All participants underwent study EGD with gastric mapping including 7 gastric biopsy sites: 2 from the antrum (from greater and lesser curvatures), 4 from the corpus (from distal greater and lesser curvatures and proximal greater and lesser curvatures), and 1 from the cardia. Biopsy from the incisura was considered corpus. Endoscopic findings from upper endoscopy were systematically recorded.
Histopathology Methods
Biopsy specimens were embedded in paraffin, oriented on edge, sectioned in 5-μ sections, and stained with hematoxylin and eosin, alcian blue at pH 2.5; and in case of negative staining for H. pylori, a modified silver stain; and alcian blue–periodic acid Schiff stain. To process cultures for H. pylori, frozen tissue specimens were thawed, homogenized, and inoculated onto two types of selective media: (1) Brain Heart Infusion (nutrient rich agar ideal for culturing fastidious microorganisms) and (2) H. pylori Special Peptone Agar plates with 7% horse blood. The plates were incubated at 37°C under micro-aerophilic conditions (5% O2, 10% CO2, and 85% N2) in an Anoxomat jar for up to two weeks. Positive growth was transferred to a fresh, nonselective Brain Heart Infusion blood agar plate and incubated for 48–72 hours. H. pylori were identified when the oxidase, catalase, and urease reactions were positive with compatible Gram stain. To obtain a pure culture, we selected and sub-cultured several small round colonies from each patient’s plate 1 or 2 times. Isolated strains were then stored at −80°C in cysteine storage medium containing 20% glycerol. Patients were considered to have H. pylori infection if H. pylori organisms were isolated on gastric tissue culture18 or found on histopathology of ≥1 gastric biopsy site. Previously treated H. pylori infection was unable to be assessed.
Active and chronic gastritis were defined on histopathology as at least grade 2 neutrophils or mononuclear cells, respectively, in ≥1 gastric biopsy site or at least grade 1 in ≥2 gastric biopsy sites. Nongastritis was defined as all grade 0 for neutrophils or mononuclear cells in all gastric biopsy sites.
The presence and severity of GIM and atrophic gastritis were independently determined by two gastrointestinal pathologists, blinded to endoscopic findings and patient questionnaires.
Disagreements in pathology reads were determined by a third pathologist (MR). Participants were classified as a GIM case if there was evidence of intestinal metaplasia on ≥1 non-cardia gastric biopsy. Non-cases were defined as patients who underwent a study EGD and did not have GIM on any gastric biopsy. We further stratified gastric intestinal metaplasia cases according to severity as focal (limited to either antrum or corpus) or extensive (involving both antrum and corpus) using the Operative Link for Gastric Intestinal Metplasia (OLGIM) Assessment criteria.19 Atrophic gastritis cases were defined gastric atrophy on ≥1 non-cardia gastric biopsy. Severity and extent of atrophy was evaluated by Operative Link for Gastritis Assessment (OLGA) staging.20
Statistical Analysis
Due to too few study participants from some racial/ethnic subgroups of the population (i.e., Asian-American, American Indian or native Alaskan, native Hawaiian or other Pacific Islander), we excluded these patients from the analysis. We compared prevalence (as proportions) and accompanying 95% confidence intervals (95% CI) of GIM between non-Hispanic whites, African-Americans, and Hispanics. We compared sociodemographic and clinical characteristics between GIM cases and non-cases using chi-square tests for categorical variables and Student’s t-test for continuous variables, both overall and within each major ethnic/racial group. We estimated ORs and 95% CIs for associations with risk of GIM using logistic regression models. We performed multivariate models stratified by race/ethnicity, including factors associated with GIM in the univariate models (p<0.10) to identify those factors independently associated with GIM within each racial/ethnic group.
We used a series of mediation models using a bootstrap procedure with 5,000 resamples to test if established GIM risk factors (i.e., smoking, H. pylori infection, active gastritis, or chronic gastritis) mediated the effect of race/ethnicity on risk of GIM.21 Variables may mediate the association between race/ethnicity and GIM if the following criteria are met (Supplementary Figure 1): 1) race/ethnicity is associated with GIM; 2) race/ethnicity is associated with the potential mediating factor; 3) the potential mediating factor is associated with GIM); and 4) including both race/ethnicity and the mediating factor in a single multivariable model changes the association between race/ethnicity and risk of GIM observed in criteria 1. For those factors identified as mediators, we entered them simultaneously into the multiple mediation model to quantify their combined mediating effect on the association between race/ethnicity and GIM. The mediation analysis gives the average total direct effect, average indirect effect, and total effect (combined indirect and direct effects) across bootstrap samples. Statistically significant mediation was present when the 95% CI for the average indirect effect did not contain zero.
All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and Stata version 15.1, and a 2-tailed p-value of < 0.05 was considered statistically significant.
RESULTS
We analyzed data on 2,179 patients among whom we identified 415 GIM cases and 1,764 non-cases. The overall GIM prevalence was 19.0% (95% CI, 17.5%–20.7%). The prevalence of GIM in those primarily referred for endoscopy was 18.3% versus 21.4% among those recruited from primary care clinics (p=0.106). The GIM prevalence was highest among Hispanics (29.5%; 95% CI, 23.7%–36.1%), followed by African-Americans (25.5%; 95% CI, 22.4%–28.9%), and non-Hispanic whites (13.7%; 95% CI, 11.9%–15.7%). GIM cases were older than non-cases (mean age, 62.1 years vs. 59.9 years; p<0.001) and more likely to be male (97.2% vs. 90.8%, p<0.001), and to have H. pylori infection (52.3% vs. 22.1%, p-value <0.001). Similar associations with age, sex and H. pylori infection were observed within the separate race/ethnic subgroups (Table 1).
Table 1.
Clinical characteristics of 415 cases with gastric intestinal metaplasia compared to 1,764 non-cases stratified by race.
| Hispanic | African-American | Non-Hispanic White | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Cases (n=62) | Non-Cases (n=148) | p-value | Cases (n=178) | Non-Cases (n=521) | p-value | Cases (n=175) | Non-Cases (n=1095) | p-value | |
| Recruitment source | 0.445 | 0.522 | 0.326 | ||||||
| Endoscopy | 46 (31.1%) | 102 (68.9%) | 117 (24.7%) | 356 (75.3%) | 133 (13.3%) | 868 (86.7%) | |||
| Primary Care | 16 (25.8%) | 46 (74.2%) | 61 (27.0%) | 165 (73.0%) | 42 (15.6%) | 227 (84.4%) | |||
| Age | 0.002 | 0.011 | 0.002 | ||||||
| <60 | 12 (19.3%) | 65 (43.9%) | 74 (41.6%) | 280 (53.7%) | 48 (27.4%) | 398 (36.3%) | |||
| 60–69 | 43 (69.4%) | 65 (43.9%) | 82 (46.1%) | 201 (38.6%) | 90 (51.4%) | 566 (51.7%) | |||
| ≥70 | 7 (11.3%) | 18 (12.2%) | 22 (12.3%) | 40 (7.7%) | 37 (21.2%) | 131 (12.0%) | |||
| Sex | 0.999 | <.0001 | 0.012 | ||||||
| Male | 60 (96.8%) | 142 (96.0%) | 174 (97.8%) | 451 (86.6%) | 170 (97.1%) | 1007 (92.0%) | |||
| Female | 2 (3.2%) | 6 (4.0%) | 4 (2.2%) | 70 (13.4%) | 5 (2.9%) | 88 (8.0%) | |||
| BMI (kg/m2) | 0.299 | 0.586 | 0.306 | ||||||
| <25 | 10 (16.1%) | 20 (13.5%) | 44 (24.7%) | 108 (20.7%) | 33 (18.8%) | 181 (16.5%) | |||
| 25–29 | 27 (43.6%) | 51 (34.5%) | 61 (34.3%) | 182 (34.9%) | 71 (40.6%) | 388 (35.4%) | |||
| ≥30 | 25 (40.3%) | 77 (52.0%) | 73 (41.0%) | 229 (44.0%) | 71 (40.6%) | 524 (47.9%) | |||
| Unknown | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (0.4%) | 0 (0.0%) | 2 (0.2%) | |||
| Waist-to-hip ratio | 0.426 | 0.993 | 0.038 | ||||||
| Low | 6 (9.7%) | 14 (9.5%) | 40 (22.5%) | 115 (22.1%) | 11 (6.3%) | 111 (10.1%) | |||
| High | 56 (90.3%) | 130 (87.8%) | 133 (74.7%) | 391 (75.1%) | 155 (88.6%) | 958 (87.5%) | |||
| Unknown | 0 (0.0%) | 3 (2.7%) | 5 (2.8%) | 15 (2.8%) | 9 (5.1%) | 26 (2.4%) | |||
| Smoking status | 0.490 | <.0001 | 0.415 | ||||||
| Never smoked | 20 (32.3%) | 38 (25.6%) | 24 (13.5%) | 170 (32.6%) | 35 (20.0%) | 282 (25.8%) | |||
| Current smoker | 12 (19.3%) | 34 (23.0%) | 73 (41.0%) | 138 (26.5%) | 53 (30.3%) | 293 (26.7%) | |||
| Former smoker | 29 (46.8%) | 68 (46.0%) | 74 (41.6%) | 179 (34.4%) | 77 (44.0%) | 459 (41.9%) | |||
| Unknown | 1 (1.6%) | 8 (5.4%) | 7 (3.9%) | 34 (6.5%) | 10 (5.7%) | 61 (5.6%) | |||
| Alcohol status | 0.229 | 0.229 | 0.788 | ||||||
| Never drinker | 4 (6.5%) | 38 (25.7%) | 7 (3.9%) | 40 (7.7%) | 12 (6.8%) | 94 (8.6%) | |||
| Current drinker | 28 (45.1%) | 34 (23.0%) | 97 (54.5%) | 138 (26.5%) | 85 (48.6%) | 544 (49.7%) | |||
| Former drinker | 29 (46.8%) | 68 (45.9%) | 65 (36.5%) | 179 (34.3%) | 68 (38.9%) | 390 (35.6%) | |||
| Unknown | 1 (1.6%) | 8 (5.4%) | 9 (5.1%) | 34 (6.5%) | 10 (5.7%) | 67 (6.1%) | |||
| GERD symptoms | 0.125 | 0.741 | 0.613 | ||||||
| No | 38 (61.3%) | 70 (47.3%) | 98 (55.1%) | 273 (52.4%) | 82 (46.9%) | 470 (42.9%) | |||
| Yes | 23 (37.1%) | 70 (47.3%) | 71 (39.9%) | 215 (41.3%) | 84 (47.2%) | 568 (51.9%) | |||
| Unknown | 1 (1.6%) | 8 (5.4%) | 9 (5.0%) | 33 (6.3%) | 9 (5.1%) | 57 (5.2%) | |||
| Helicobacter pylori | 0.001 | <.0001 | <.0001 | ||||||
| No | 28 (45.2%) | 100 (67.6%) | 72 (40.5%) | 320 (61.4%) | 93 (53.1%) | 932 (85.1%) | |||
| Yes | 34 (54.8%) | 45 (30.4%) | 104 (58.4%) | 193 (37.1%) | 79 (45.1%) | 150 (13.7%) | |||
| Unknown | 0 (0.0%) | 3 (2.0%) | 2 (1.1%) | 8 (1.5%) | 3 (1.7%) | 13 (1.2%) | |||
| Active Gastritis | 0.003 | <.0001 | <.0001 | ||||||
| No | 25 (40.3%) | 100 (67.6%) | 72 (40.5%) | 326 (62.6%) | 90 (51.4%) | 945 (86.3%) | |||
| Yes | 36 (58.1%) | 47 (31.8%) | 104 (58.4%) | 191 (36.7%) | 83 (47.4%) | 149 (13.6%) | |||
| Unknown | 1 (1.6%) | 1 (0.7%) | 2 (1.1% | 4 (0.8%) | 2 (1.2%) | 1 (0.1%) | |||
| Chronic Gastritis | <.0001 | <.0001 | <.0001 | ||||||
| No | 8 (12.9%) | 68 (46.0%) | 22 (12.4%) | 193 (37.0%) | 44 (25.1%) | 730 (66.7%) | |||
| Yes | 53 (85.5%) | 80 (54.0%) | 156 (87.6%) | 328 (63.0%) | 130 (38.4%) | 363 (33.1%) | |||
| Unknown | 1 (1.6%) | 0 (0/0%) | 0 (0.0%) | 0 (0.0%) | 1 (0.6%) | 2 (0.2%) | |||
| PPI/H2RA use | 0.574 | 0.518 | 0.480 | ||||||
| No | 27 (43.6%) | 53 (35.8%) | 82 (46.1%) | 234 (44.9%) | 65 (37.1%) | 356 (32.5%) | |||
| Yes | 31 (50.0%) | 84 (56.8%) | 86 (48.3%) | 244 (46.8%) | 99 (56.6%) | 667 (60.9%) | |||
| Unknown | 4 (6.4%) | 11 (7.4%) | 10 (5.6%) | 43 (8.3%) | 11 (6.3%) | 72 (6.6%) | |||
| NSAID use | 0.718 | 0.124 | 0.361 | ||||||
| No | 22 (35.5%) | 59 (39.9%) | 72 (40.5%) | 228 (43.8%) | 56 (32.0%) | 418 (38.2%) | |||
| Less than daily | 4 (6.5%) | 12 (8.1%) | 4 (2.2%) | 29 (5.6%) | 9 (5.1%) | 42 (3.8%) | |||
| At least daily | 27 (43.6%) | 52 (35.1%) | 75 (42.1%) | 179 (34.3%) | 83 (47.4%) | 461 (42.1%) | |||
| Unknown | 9 (14.5%) | 25 (16.9%) | 27 (15.2%) | 85 (16.3%) | 27 (15.4%) | 174 (15.9%) | |||
Among GIM cases, we identified 303 patients with focal GIM disease and 112 patients with extensive GIM disease (Figure 1). The prevalence of focal GIM was highest among Hispanics (21.4%; 95% CI, 16.4%–27.5%), followed by African-Americans at 16.0% (95% CI, 13.5%–18.9%) and non-Hispanic whites (11.5%; 95% CI, 9.9%–13.4%). The prevalence of extensive GIM was highest among African-Americans at 9.4% (95% CI, 7.5%–11.8%), followed by Hispanics at 8.1% (95% CI, 5.1%–12.7%) and non-Hispanic whites (2.3%; 95% CI, 1.6%–3.3%).
Figure 1.
Severity and distribution of gastric intestinal metaplasia per racial/ethnic group.
All GIM cases had concomitant atrophic gastritis; 27.7% of those with concomitant atrophic gastritis had extensive atrophic gastritis (Supplementary Tables 1 and 2). Of the overall study population, 610 patients (28.0%) had active gastritis, and 1,110 patients (50.9%) had chronic gastritis. Of 663 patients with H. pylori infection, 529 (79.8%) had active gastritis and 618 (93.2%) had chronic gastritis. Of 253 non-Hispanic whites with H. pylori, 187 (73.9%) had active gastritis and 227 (89.7%) had chronic gastritis. Of 319 African-Americans with H. pylori infection, 267 (83.7%) had active gastritis and 307 (96.2%) had chronic gastritis. Among 91 Hispanics with H. pylori infection, 75 (82.4%) had active gastritis and 84 (92.3%) had chronic gastritis.
In the multivariable model containing all 415 GIM cases and 1,764 non-cases, race/ethnicity was a strong risk factor for GIM (Table 2). Compared to non-Hispanic whites, African-Americans (adjusted OR, 1.87; 95% CI, 1.44–2.44) and Hispanics (adjusted OR, 2.32; 95% CI, 1.61–3.34) had approximately 2-fold higher GIM risk. Male sex (adjusted OR, 2.60; 95% CI, 1.36–4.97), older age (60–90 years: adjusted OR, 1.69; 95% CI, 1.29–2.21; ≥70 years: adjusted OR, 2.44; 95% CI, 1.66–3.59), current smoking (adjusted OR, 2.06; 95% CI, 1.48–2.86), and H. pylori infection (OR, 3.65; 95% CI, 2.79–4.55) were also independently associated with a statistically significant increase in GIM risk.
Table 2.
Results of multivariable logistic regression analyses of potential predictors of gastric intestinal metaplasia.
| All Races Adjusted OR* (95% CI) | Hispanic Adjusted OR* (95% CI) | African-American Adjusted OR* (95% CI) | Non-Hispanic White Adjusted OR* (95% CI) | |
|---|---|---|---|---|
| Race (ref: Non-Hispanic White) | ||||
| African-American | 1.87 (1.44–2.44) | --- | --- | --- |
| Hispanic | 2.32 (1.61–3.34) | --- | --- | --- |
| Male Sex (ref: Female) | 2.60 (1.36–4.97) | 0.80 (0.12–5.22) | 3.88 (1.36–11.11) | 2.24 (0.86–5.83) |
| Age (ref: <60 years) | ||||
| 60–69 years | 1.69 (1.29–2.21) | 3.89 (1.77–8.56) | 1.66 (1.10–2.49) | 1.42 (0.93–2.15) |
| ≥70 years | 2.44 (1.66–3.59) | 2.42 (0.75–7.82) | 2.63 (1.36–5.09) | 2.39 (1.40–4.10) |
| Smoking Status (ref: Never Smoker) | ||||
| Former Smoker | 1.37 (1.00–1.87) | 0.69 (0.32–1.48) | 2.49 (1.46–4.23) | 1.08 (0.68–1.70) |
| Current Smoker | 2.06 (1.48–2.86) | 0.80 (0.32–2.00) | 4.13 (2.38–7.15) | 1.49 (0.92–2.43) |
| H. pylori Infection (ref: no) | 3.56 (2.79–4.55) | 2.92 (1.52–5.60) | 2.37 (1.63–3.45) | 5.52 (3.84–7.94) |
Models retained variables with p<0.1.
Abbreviations: OR (odds ratios), CI (confidence intervals).
We observed differences in GIM risk factor profile according to race/ethnicity. Among Hispanics, older age (60–69 years: OR, 3.89; 95% CI, 1.77–8.56) and H. pylori infection (OR, 2.92; 95% CI, 1.52–5.60) were associated with increased GIM risk, but there was no association with male sex or smoking history (Table 2). Among African-Americans, male sex (OR, 3.88; 95% CI, 1.36–11.11), older age (60–69 years: OR, 1.66; 95% CI, 1.10–2.49; ≥70 years: OR, 2.63; 95% CI, 1.36–5.09), tobacco smoking (former: OR, 2.49; 95% CI, 1.46–4.23; current: OR, 4.13; 95% CI, 2.38–7.15), and H. pylori infection (OR, 2.37; 95% CI, 1.63–3.45) were all independently associated with GIM. Finally, among non-Hispanic whites, older age (≥70 years, OR, 2.39; 95% CI, 1.40–4.10) and H. pylori infection (OR, 5.52; 95% CI, 3.84–7.94) were the only variables associated with GIM risk. The magnitude of the association of H. pylori infection with GIM risk was highest among non-Hispanic whites.
Mediation Analysis
Given that H. pylori is strongly associated with both race and GIM risk, we performed a mediation analysis to evaluate the degree to which H. pylori mediates the association between race/ethnicity and GIM risk (Supplementary Figure 1). Overall, H. pylori infection explained 33.6% of the association of race/ethnicity with GIM risk. H. pylori infection explained slightly more of the increased risk of GIM among African-Americans (18.6%) than among Hispanics (15.0%).
Likewise, active gastritis and chronic gastritis mediated the association between race/ethnicity and GIM. When examined separately, active gastritis accounted for 37.1% (20.0% among African-Americans and 17.1% among Hispanics) and chronic gastritis accounted for 43.8% (24.2% among African-Americans and 19.6% among Hispanics) of the effect of race/ethnicity on GIM risk.
In cumulative mediation analysis, H. pylori infection was introduced to the model and explained 33.6% of the association of race/ethnicity with GIM risk. Active gastritis was added with H. pylori infection, and these two variables together explained 41.3% of the effect of race/ethnicity on GIM risk. Lastly, chronic gastritis was added to the mediation model with H. pylori infection and active gastritis, and all three variables together explained 55.1% of the effect of race/ethnicity on GIM risk (30.2% in African-Americans and 24.9% in Hispanics compared to non-Hispanic whites). Smoking did not mediate the effect of race/ethnicity on GIM risk.
DISCUSSION
In this large study, 2,179 consecutively recruited veterans underwent endoscopy and gastric mapping biopsies. GIM prevalence was higher among Hispanics (29.5%) and African-Americans (25.5%) compared to non-Hispanic whites (13.7%). Additionally, extensive GIM prevalence was higher among African-Americans (9.4%) and Hispanics (8.1%) compared to non-Hispanic whites (2.3%). These disparities persisted after accounting for differences in distribution of age, sex, smoking, and H. pylori infection between the race/ethnic subgroups. H. pylori infection, the strongest risk factor for GIM, explained 33.6% of the observed association between race/ethnicity and GIM risk.
Our findings indicate that H. pylori infection status alone cannot be used as an adequate surrogate for the presence of GIM for screening purposes. H. pylori infection is a known risk factor associated with both race and GIM.14, 15 In our study, H. pylori infection was a consistent GIM risk factor among racial/ethnic groups, but the strength of association with H. pylori infection was stronger in non-Hispanic whites (conferring >5-fold increased risk) than African-Americans and Hispanics (conferring 2- to 3-fold increased risk). Furthermore, racial differences in the prevalence of H. pylori infection were estimated to account for only 34.0% of the racial variation in GIM risk. Active and chronic gastritis were also found to be mediators in the association of race with GIM. However, in the multiple mediation analysis, H. pylori infection, active gastritis, and chronic gastritis explained 55.1% of the association between race/ethnicity and GIM risk, and 44.9% of the racial variation in GIM risk was independent of these three factors. The etiologies for racial disparities in GIM are unknown, only partially explained by H. pylori infection and gastritis, and may be modulated further by other bacterial and host characteristics; further research is needed in this area.
Apart from H. pylori infection, we found few differences in GIM risk profiles within each race/ethnic group. Only older age was an additional GIM risk factor within each race (non-Hispanic whites, African-Americans, and Hispanics), whereas smoking history (current more than former) and male sex were also risk factors in African-Americans. This is consistent with a previous study that found a strong association between H. pylori infection, African-American race, and smoking.22
A study by Saumoy et al. examined the cost-effectiveness of gastric cancer screening according to race using a hypothetical cohort of 50-year old individuals over a 30-year time period comparing no screening, biennial screening, and one-time screening upper endoscopy with continued surveillance only when indicated.23 The no-screening strategy was cost-effective only for non-Hispanic whites, while screening with continued surveillance when indicated was most cost-effective for Hispanics ($76,070/QALY) and African-Americans ($80,278/QALY) compared to no screening or biennial screening.23 Our study supports the notion that screening for GIM and surveillance if indicated may be most cost-effective in Hispanics and African-Americans. However, we believe that other factors in addition to race need to be added to GIM risk models in order to identify subsets within each race/ethnic group (such as older African-American male smokers) that may benefit more from screening and surveillance.
Our study was performed in a veteran population and contained a low proportion of females, limiting the median and multivariable analyses of sex, which may limit the generalizability of the findings to nonveterans and women. We were also unable to examine risk factors among Asians, a race/ethnic group where GIM is likely highly prevalent. Previous studies have shown that the rise in gastric cancer incidence in the U.S. may be due to immigration;24 however, we did not have information regarding patients’ birth origin and immigration status, so findings may not be generalizable to immigrant populations. While we captured H. pylori infection using histopathology and culture, we did not capture previously treated H. pylori infection. As 27.0% of our GIM cases had extensive GIM which may represent previous longstanding H. pylori infection,12, 25 we may have underestimated the association of H. pylori with GIM, especially in symptomatic patients referred for upper endoscopy. However, patients recruited from primary care clinics were less likely to have been previously evaluated for H. pylori infection due to lack of symptoms. Although high resolution chromoendoscopy, a method which is superior to high definition white-light endoscopy alone for diagnosing gastric precancerous conditions, was not used in this study,26 all patients underwent systematic gastric mapping biopsies regardless of indication for endoscopy or endoscopic findings, minimizing selection bias.
There are several strengths to this study. Our study population was a representative sample of the MEDVAMC population, because we examined a random sample of asymptomatic patients from primary care clinics as well as patients with gastrointestinal symptoms previously referred for upper endoscopy. In addition, gastric intestinal metaplasia and atrophic gastritis were confirmed by two gastrointestinal pathologists blinded to the endoscopic findings, minimizing misclassification bias.
In conclusion, we found that Hispanics and African-Americans had a higher risk of GIM compared to non-Hispanic whites; this elevated risk remained after accounting for H. pylori infection. Race/ethnicity should be considered an important risk factor when developing risk models to identify patients at highest risk of GIM to be referred for screening in the U.S.
Supplementary Material
Supplementary Figure 1. Description of mediation analysis. Variables may mediate the association between race/ethnicity and risk of GIM if the following criteria are met: 1) race/ethnicity is associated with GIM (path a); 2) race/ethnicity is associated with the potential mediating factor (path b); 3) the potential mediating factor is associated with GIM (path c); and 4) including both race/ethnicity and the mediating factor in a single multivariable model changes the association between race/ethnicity and GIM observed in criteria 1 (path d).
What You Need to Know.
Background:
There is a need to identify individuals with gastric intestinal metaplasia, a precursor to gastric cancer, so they can be offered screening and surveillance. It is important to determine the prevalence of gastric intestinal metaplasia in different race and ethnic sub-groups, and whether it associates with Helicobacter pylori infection.
Findings:
Hispanic and African-American patients have an increased risk for gastric intestinal metaplasia, determined by upper endoscopy biopsy analysis, compared with non-Hispanic white patients. This increase in risk was partially independent of H pylori infection.
Implications for patient care:
Hispanic and African-American patients, especially those with H pylori infection, have an increased risk for gastric intestinal metaplasia.
Acknowledgements:
We would like to acknowledge and thank our two gastrointestinal pathologists, Gordana Vestovsek and Paula Parente, for their assistance.
GRANT SUPPORT: This work was supported in part by National Institutes of Health grant P30 DK056338 (Study Design and Clinical Research Core), which supports the Texas Medical Center Digestive Diseases Center. This research was supported in part with resources at the VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413), at the Michael E. DeBakey VA Medical Center, Houston, TX. The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs, the U.S. government or Baylor College of Medicine.
Footnotes
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CONFLICT OF INTEREST: The authors report no personal or financial conflicts of interest.
REFERENCES
- 1.Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. [DOI] [PubMed] [Google Scholar]
- 2.Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. CA Cancer J Clin 2018;68:7–30. [DOI] [PubMed] [Google Scholar]
- 3.Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gupta S, Tao L, Murphy JD, et al. Race/ethnicity-, socioeconomic status-, and anatomic subsite-specific risks for gastric cancer. Gastroenterology 2019;156:59–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Correa P Gastric Cancer: Overview. Gastroenterol Clin North Am 2013;42:211–217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Li D, Bautista MC, Jiang S-F, et al. Risks and predictors of gastric adenocarcinoma in patients with gastric intestinal metaplasia and dysplasia: a population-based study. Am J Gastroenterol 2016;111:1104–13. [DOI] [PubMed] [Google Scholar]
- 7.Rugge M, Genta R, Di Mario F, et al. Gastric cancer as preventable disease. Clin Gastroenterol Hepatol 2017;15:1833–43. [DOI] [PubMed] [Google Scholar]
- 8.Balakrishnan M, George R, Sharma A, et al. Changing trends in stomach cancer throughout the world. Curr Gastroenterol Rep 2017;19:36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Islami F, DeSantis CE, Jemal A. Incidence trends of esophageal and gastric cancer subtypes by race, ethnicity, and age in the United States, 1997–2014. Clin Gastroenterol Hepatol 2019;17:429–39. [DOI] [PubMed] [Google Scholar]
- 10.Choi CE, Sonnenberg A, Turner K, et al. High prevalence of gastric preneoplastic lesions in East Asians and Hispanics in the USA. Dig Dis Sci 2015;60:2070–2076. [DOI] [PubMed] [Google Scholar]
- 11.Genta RM, Turner K, Sonnenberg A. Demographic and socioeconomic influences on Helicobacter pylori gastritis and its pre-neoplastic lesions amongst US residents. Aliment Pharmacol Ther 2017;46:322–30. [DOI] [PubMed] [Google Scholar]
- 12.Huang RJ, Ende AR, Singla A, et al. Prevalence, risk factors, and surveillance patterns for gastric intestinal metaplasia among patients undergoing upper endoscopy with biopsy. Gastrointest Endosc 2020;91:70–7. [DOI] [PubMed] [Google Scholar]
- 13.Fennerty MB, Emerson JC, Sampliner RE, et al. Gastric intestinal metaplasia in ethnic groups in the southwestern United States. Cancer Epidemiol Biomarkers Prev 1992;1:293–6. [PubMed] [Google Scholar]
- 14.Nguyen T, Ramsey D, Graham D, et al. The prevalence of Helicobacter pylori remains high in African American and Hispanic veterans. Helicobacter 2015;20:305–15. [DOI] [PubMed] [Google Scholar]
- 15.Liu KS, Wong IO, Leung WK. Helicobacter pylori associated gastric intestinal metaplasia: Treatment and surveillance. World J Gastroenterol 2016;22:1311–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.El-Serag HB, Kao JY, Kanwal F, et al. Houston consensus conference on testing for Helicobacter pylori infection in the United States. Clin Gastroenterol Hepatol 2018;16:992–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kramer JR, Fischbach LA, Richardson P, et al. Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett’s esophagus in white men. Clin Gastroenterol Hepatol 2013;11:373–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Shiota S, Thrift AP, Green L, et al. Clinical manifestations of Helicobacter pylori-negative gastritis. Clin Gastroenterol Hepatol 2017;15:1037–46. [DOI] [PubMed] [Google Scholar]
- 19.Rugge M, Fassan M, Pizzi M, et al. Operative link for gastritis assessment vs operative link on intestinal metaplasia assessment. World J Gastroenterol 2011;17:4596–4601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Rugge M, Meggio A, Pennelli G, et al. Gastritis staging in clinical practice: the OLGA staging system. Gut 2007;56:631–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 2008;40:879–91. [DOI] [PubMed] [Google Scholar]
- 22.Fontham ET, Ruiz B, Perez A, et al. Determinants of Helicobacter pylori infection and chronic gastritis. Am J Gastroenterol 1995;90:1094–101. [PubMed] [Google Scholar]
- 23.Saumoy M, Schneider Y, Shen N, et al. Cost effectiveness of gastric cancer screening according to race and ethnicity. Gastroenterology 2018;155:648–60. [DOI] [PubMed] [Google Scholar]
- 24.Balakrishnan M, George R, Sharma A, et al. An investigation into the recent increase in gastric cancer in the USA. Dig Dis Sci 2018;63:1613–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Brawner KM, Morrow CD, Smith PD. Gastric microbiome and gastric cancer. Cancer J 2014;20:211–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Pimentel-Nunes P, Libanio D, Marcos-Pinto R, et al. Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019. Endoscopy 2019;51:365–388. [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supplementary Figure 1. Description of mediation analysis. Variables may mediate the association between race/ethnicity and risk of GIM if the following criteria are met: 1) race/ethnicity is associated with GIM (path a); 2) race/ethnicity is associated with the potential mediating factor (path b); 3) the potential mediating factor is associated with GIM (path c); and 4) including both race/ethnicity and the mediating factor in a single multivariable model changes the association between race/ethnicity and GIM observed in criteria 1 (path d).