Guillermo I. Perez-Perez

Helicobacter pylori Infection and Gastric Carcinoma among Japanese Americans in Hawaii

BACKGROUND Helicobacter pylori are gram-negative spiral bacteria that are associated with chronic gastritis, a known precursor of gastric carcinoma. Persons at high risk for gastric carcinoma have been shown to have a high prevalence of H. pylori infection. METHODS We studied the relation of H. pylori infection and gastric carcinoma in a cohort of Japanese American men living in Hawaii. The 5908 men were enrolled and examined from 1967 to 1970. By 1989, 109 cases of pathologically confirmed gastric carcinoma had been identified. The store serum of each patient with gastric carcinoma and of each matched control subject were tested for the presence of serum IgG antibody to H. pylori. RESULTS Ninety-four percent of the men with gastric carcinoma and 76 percent of the matched control subjects had a positive test for H. pylori antibodies, for an odds ratio of 6.0 (95 percent confidence interval, 2.1 to 17.3). As the level of antibody to H. pylori increased, there was a progressive increase in the risk of gastric carcinoma (P for trend = 0.0009). The association was strong even for men in whom the diagnosis was made 10 or more years after the serum sample was obtained (odds ratio, 10.5; 95 percent confidence interval, 2.5 to 44.8). CONCLUSIONS Infection with H. pylori is strongly associated with an increased risk of gastric carcinoma. However, most persons infected with H. pylori will never have gastric carcinoma. Therefore, other factors that increase the risk of gastric carcinoma among persons infected with H. pylori need to be identified.

Prevalence of Helicobacter pylori Infection and Histologic Gastritis in Asymptomatic Persons

We estimated the prevalences of Helicobacter pylori (formerly called Campylobacter pylori) infection and histologic gastritis in 113 asymptomatic persons, using endoscopic biopsy of the gastric antrum and corpus. Unsuspected lesions, mainly mucosal erosions, were revealed at endoscopy in 16 subjects (14 percent). Gastritis was found in 42 subjects (37 percent), of whom 36 (32 percent of the total) were found to be infected with H. pylori on the basis of hematoxylin-eosin staining. H. pylori was not found in any of the 71 subjects with normal histologic features. Gastritis and H. pylori were noted in both the antrum and corpus in 75 percent of those infected (n = 27). The prevalence of H. pylori infection increased from 10 percent (2 of 20 subjects) in those between the ages of 18 and 29, to 47 percent (7 of 15) in those between the ages of 60 and 69, but the effect of age did not reach statistical significance. The prevalence of gastritis increased significantly with advancing age. Stepwise logistic regression analysis revealed that the relative risk for H. pylori infection associated with recent (within six months) antibiotic use was 5.8 (95 percent confidence interval, 1.5 to 22.1), whereas the relative risk was 6.5 (95 percent confidence interval, 1.4 to 29.2) for those who had never used bismuth compounds. We conclude that histologic gastritis and H. pylori infection commonly occur in the stomach of apparently normal persons and increase in prevalence with advancing age. All the subjects with H. pylori infection had gastritis, suggesting a possible etiologic role for the bacterium in the histologic lesion.

Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection

BACKGROUND & AIMS Multiple tests are available for determining Helicobacter pylori infection. Our aim was to compare the sensitivity, specificity, and negative and positive predictive value of the most widely available tests for diagnosis of H. pylori. METHODS A total of 268 patients (mean age, 53.7 +/- 15.8 years; 142 male and 126 female; 125 white and 143 nonwhite) was tested for H. pylori infection by [13C]urea breath test (UBT), measurement of serum immunoglobulin (Ig) G and IgA antibody levels, and antral biopsy specimens for CLO test, histology, and Warthin-Starry stain. No patient received specific treatment for H. pylori before testing. The infection status for each patient was established by a concordance of test results. RESULTS Warthin-Starry staining had the best sensitivity and specificity, although CLO test, UBT, and IgG levels were not statistically different in determining the correct diagnosis. The absence of chronic antral inflammation was the best method to exclude infection. Stratification of results by clinical characteristics showed that UBT and chronic inflammation were the best predictors of H. pylori status in patients older than 60 years of age. IgA was a better predictor in white patients. CONCLUSIONS The noninvasive UBT and IgG serology test are as accurate in predicting H. pylori status in untreated patients as the invasive tests of CLO and Warthin-Starry.

Intrafamilial Clustering of Helicobacter pylori Infection

Colonization of the gastric antrum by Helicobacter pylori (formerly Campylobacter pylori) has been associated with primary gastritis. We determined the frequency of colonization by H. pylori in gastric-antrum biopsy specimens from 93 children undergoing gastroscopy for the evaluation of upper gastrointestinal symptoms. We also determined H. pylori IgG antibody levels by enzyme-linked immunosorbent assay in coded serum samples from these children, family members, and control subjects of comparable ages. Among 27 children with primary, or unexplained, gastritis, H. pylori was identified by silver staining in 24 biopsy specimens and by culture in 22; specific antibodies were present in 23 children (96 percent). Three children with unexplained gastritis had no evidence of H. pylori in the antrum, nor did any of 13 children with secondary gastritis or any of 53 children with normal antral histologic features; specific antibodies were present in only 1 of these 69 children. H. pylori antibody was detected in 25 of 34 parents of colonized children, but in only 8 of 33 parents of noncolonized children (P less than 0.001). Of 22 siblings of children colonized by H. pylori, 18 had specific antibodies, as compared with only 5 of 37 controls (P less than 0.001). We conclude that H. pylori-specific IgG antibodies are associated with bacterial colonization of the gastric antrum by this organism. The intrafamilial clustering of H. pylori infection suggests that there may be person-to-person spread of these bacteria.

Campylobacter pylori Antibodies in Humans

STUDY OBJECTIVE To determine the diagnostic value of assays to measure serum antibodies to Campylobacter pylori, and to use these assays to determine the prevalence of C. pylori infection in a healthy population. DESIGN A survey of patients having endoscopies for upper gastrointestinal symptoms, patients with other gastrointestinal illnesses, and healthy controls. SETTING Outpatients attending endoscopy suites in two university-affiliated medical centers. PATIENTS One hundred and twenty patients who had gastroduodenoscopies, 61 patients with lower intestinal illnesses, and 166 healthy controls. INTERVENTION Assay to detect serum IgA, IgG, and IgM antibodies specific for C. pylori. MEASUREMENTS AND MAIN RESULTS Absorption with other gram-negative pathogens showed that IgG and IgA assays, but not IgM assays, were specific for C. pylori. In patients in whom C. pylori had been isolated and who had gastritis diagnosed by histologic methods, significantly higher mean IgA and IgG levels were seen compared with patients without demonstrable C. pylori or gastritis. The sensitivity and specificity of a positive value in both IgA and IgG assays were more than 93%. Among healthy persons, IgG and IgA antibodies were rarely seen in patients less than 20 years old, but antibody prevalence progressed with age, reaching 50% in patients more than 60 years old. High IgA and IgG levels to C. pylori in five persons tested remained stable for more than 1 year, suggesting the organism persists for at least that period. In 61 patients with acute bacterial enteritis, acute pancreatitis, Crohn disease, or ulcerative colitis, prevalence of antibodies to C. pylori was consistent with age and unrelated to current disease. CONCLUSIONS Campylobacter pylori infection, which is highly associated with active gastritis, may be diagnosed by serologic assay. Acquisition of infection begins in adult life, and prevalence increases with age.

The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease

BACKGROUND & AIMS The role of Helicobacter pylori in the pathogenesis of gastroesophageal reflux disease (GERD) is unknown. We determined the prevalence of cagA-positive (cagA+) H. pylori strains in patients with GERD or its complications compared with controls of similar age. METHODS A total of 153 consecutive patients with GERD, Barretts esophagus, and Barretts esophagus complicated by dysplasia or adenocarcinoma were compared with 57 controls who underwent upper endoscopy for reasons other than GERD. H. pylori infection and CagA antibody status were determined by histology and enzyme-linked immunosorbent assay. RESULTS H. pylori prevalence was lower (34%) in patients with GERD and its sequelae than in the control group (45.6%)(P = 0.15). Regardless of the group, increasing age was associated with higher prevalence of H. pylori (P = 0.003). When compared with controls (42.3%), the prevalence of cagA+ H. pylori strains decreased (P = 0.008) in patients with more severe complications of GERD (GERD, 36.7% [nonerosive GERD, 41.2%; erosive GERD, 30.8%]; Barretts esophagus, 13.3%; and Barretts with adenocarcinoma/dysplasia, 0%). CONCLUSIONS Prevalence of H. pylori in patients with GERD and its sequelae was lower but not significantly different than that of a control group. However, patients carrying cagA+ strains of H. pylori may be protected against the complications of GERD, especially Barretts esophagus and its associated dysplasia and adenocarcinoma.

Symptoms and risk factors of Helicobacter pylori infection in a cohort of epidemiologists

To identify symptoms and risk factors associated with Helicobacter pylori infection, a cohort of 341 epidemiologists was studied. All subjects had one banked serum (collected between 1969 and 1987) and one recent serum sample (collected in 1988) evaluated for H. pylori immunoglobulin G by enzyme-linked immunosorbent assay; subjects provided information on gastrointestinal symptoms and risk factors for gastritis and peptic ulcer disease. Prevalence of infection decreased from the early 1970s to the present. Eleven subjects (3% of the total cohort) seroconverted during the interval between serum samples, giving a crude conversion rate of 0.49% per person-year (95% confidence interval, 0.3-0.9). Nonreactors on the 1988 serum sample described similar symptoms to reactors. However, subjects who seroconverted in the interval between the two serum samples were more likely than either persistent nonreactors [relative risk (RR), 4.1] or persistent reactors (RR, 3.7) to have experienced upper gastrointestinal symptoms in the interval years. Consumption of caffeinated beverages (RR, 4.6) and residence in the northeastern United States (RR, 5.3) seemed to increase risk for infection. Because pain was similarly common in H. pylori-positive and -negative patients, H. pylori cannot be summarily accepted as the cause of dyspeptic symptoms even when infection is confirmed.

Helicobacter pylori Infection and the Risk for Duodenal and Gastric Ulceration

Infection with Helicobacter pylori probably increases the risk for developing duodenal and gastric ulcer disease. Previous studies have shown that 75% to 100% of patients with duodenal ulcer and 35% to 86% of patients with gastric ulcer have evidence of an H. pylori infection [1]. The finding that eradication of H. pylori in patients with duodenal ulcer is associated with a statistically significant decrease in the recurrence rate of the disease further supports the association [2-5]. However, these observations may just reflect the frequent coexistence of duodenal ulcer with antral gastritis [6], which has been shown to be caused by H. pylori [7, 8]. Wormsley [9] has noted that the Henle-Koch postulates have not been satisfied for causation of duodenal ulcer by H. pylori because the organism has not been shown to produce the disease. The evidence is weaker that H. pylori causes gastric ulcer because only a single study with 26 patients has shown that antimicrobial therapy directed against H. pylori decreased the gastric ulcer recurrence rate [5]. None of the previous studies evaluated patients with duodenal or gastric ulcers before they were diagnosed or hospitalized with their disease. The usual temporal sequence is that patients with peptic ulcer disease are examined to detect H. pylori infection at the time the diagnosis is made or after they have had treatment to eradicate the organism. Consequently, peptic ulceration could possibly predispose persons to colonization by H. pylori [9]. We did a prospective study in a large population-based cohort using serum specimens that were obtained from study participants before they were diagnosed with peptic ulcer. We tried to determine whether H. pylori infection, as shown by the presence of specific IgG antibodies, is a risk factor for the subsequent development of either duodenal or gastric ulceration. Methods Study Population Japanese-American men born from 1900 to 1919, who were identified by the Honolulu Heart Program in 1965 by using the comprehensive 1942 Selective Service draft registration files [10], composed the study population. Of 11 148 eligible men, 8006 (72%) were interviewed and examined from 1965 to 1968, 180 (2%) died before they could be examined, and 2962 (26%) did not participate in the program. Study participants ranged in age from 45 to 68 years. The data collected included birthplace, marital status, history of alcohol use, blood pressure, and body mass index (the weight in kilograms divided by the square of the height in meters). Serum cholesterol values were determined by the Auto Analyzer N-24A method, and serum glucose values were determined by the Auto Analyzer N-2B method 1 hour after a 50-g glucose load had been given [11]. A total of 7498 (94%) men returned for a second examination between 1967 and 1970, and a serum specimen was obtained at this time. Serum specimens for a 20% random sample of the men were sent to the U.S. Public Health Service Hospital in San Francisco, whereas specimens for the remaining 5924 men were stored at 20C at the study site. Four hundred eighty-one patients with previous gastrectomy or a previous diagnosis of peptic ulcer disease were excluded from the study. The average age of the remaining 5443 patients at the time of their second examination was 56.6 years. Surveillance Methods Surveillance of the cohort to identify incident patients with peptic ulcer was done by a continuous review of discharge records of all general hospitals on Oahu. Based on a 19-year follow-up survey of the study patients from the time of their examination in 1965 to 1968, only 1.3% of the men could not be located on Oahu. Thus, surveillance was nearly complete. Two hundred fifty-eight patients were hospitalized with peptic ulcer disease from 1968 to 1989. One hundred sixty (62%) patients had their diagnosis confirmed by examination of tissue obtained by either surgery or biopsy, 36 (14%) were diagnosed by radiologic examination, and 62 (24%) were clinically diagnosed based on the endoscopic or surgical report of the presence of an ulcer. One hundred sixty-nine incident patients had gastric ulcer, 73 had duodenal ulcer, and 16 had gastric and duodenal ulcers. Seventeen of the 169 patients with gastric ulcer, 6 of the 73 patients with duodenal ulcer, and 2 of the 16 patients with gastric and duodenal ulcers were removed from study because they had an insufficient amount of serum in the freezer repository. Selection of Controls Each of the remaining patients was matched with one control from the study cohort based on age at examination (47 to 70 years) and date of serum collection. If a potential control had a diagnosis of gastric cancer before or after the serum was obtained, he was excluded from the study. As a consequence, 160 patients (3.1%) were removed from the control pool of 5185 men because of the reported association between H. pylori infection and gastric cancer [12, 13]. Of the remaining 5025 men, 336 (6.7%) were excluded because they previously had cardiovascular disease or other cancer, and 1532 (30.5%) were excluded because they were diagnosed with cardiovascular disease or other cancer after their serum collection. This exclusion was done because the serum specimens from these patients are going to be used for other studies. A total of 3157 patients remained in the pool of controls from which 233 (7.4%) were matched to incident case-patients with peptic ulcer. Each control participant was alive at the time of hospitalization of the matched case-patient, so that death was not a competing factor. Serologic Testing The presence of serum IgG antibodies to H. pylori was determined by enzyme-linked immunosorbent assay (ELISA), using the Pyloristat kit (Whittaker Bioproducts, Inc., Walkersville, Maryland). As validated by the manufacturer, the results of this assay closely mirror those of a previously described IgG ELISA [13-18]. In brief, serum specimens from patients were diluted 1:20 for use in the kit, and IgG levels of sera were determined according to the manufacturers instructions. The serum specimens were coded so that the laboratory technician could not distinguish case-patients from controls. A ratio of 1.00 or greater was considered positive, a ratio of less than 0.80 was considered negative, and a ratio of 0.80 to 0.99 was considered equivocal, as calibrated in the kit. Two patients with gastric ulcer and two patients with duodenal ulcer or their controls had equivocal values, so they were excluded from the study. Statistical Analysis A matched casecontrol study design was used to identify the patients and controls for serum tests. As a result, odds ratios, based on the results of the H. pylori IgG antibody test, were determined using conditional logistic regression methods [19]. When odds ratios were indeterminable, approximate confidence intervals (CIs) were determined by the method of Breslow and Day [19]. Tests for trend in the logit of risk were derived from conditional logistic regression models by using grouped H. pylori test results (coded as 1, 2, 3, and 4). All conditional logistic regression models were fitted using iterative maximum likelihood methods and a special application of the proportional hazards regression model [20]. Results The characteristics of the 229 patients with peptic ulcer and of their matched controls are presented in Table 1. The two groups of men were similar with respect to demographic characteristics and laboratory values. Table 1. Characteristics of Patients with Peptic Ulcer and of Controls The mean age at diagnosis was 67.5 years (range, 52.7 to 87.2 years) for the 150 patients with gastric ulcer, 64.5 years (49.4 to 80.0 years) for the 65 patients with duodenal ulcer, and 63.5 years (52.4 to 83.1 years) for the 14 patients with gastric and duodenal ulcers. Table 2 shows the association between the H. pylori test result and peptic ulcer by specific type. Ninety-three percent (139 of 150) of the patients with gastric ulcer and 78% (117 of 150) of the matched controls had a positive H. pylori-specific IgG antibody level, yielding an odds ratio of 3.2 (P = 0.001). (The odds ratio is determined by dividing 32 pairs by 10 -/+ pairs.) Ninety-two percent of the case-patients with duodenal ulcer and 78% of the matched controls had a positive test result, yielding an odds ratio of 4.0 (P = 0.03). If a patient had either a gastric or duodenal ulcer, then the odds ratio was 3.4 (P = 0.0001). Only 14 patients had both gastric and duodenal ulcers. The odds ratio was 1.3 (P > 0.2), based on these patients. Table 2. Odds Ratio for the Association between Helicobacter pylori Seropositivity and Type of Peptic Ulcer Because some of the hospitalized patients with peptic ulcer may have developed their ulcers after the use of adrenocorticosteroids or nonsteroidal anti-inflammatory drugs, we systematically reviewed the hospital records of the patients. A similar review could not be done for the controls because they were not hospitalized. We found that 18 of the 150 patients with gastric ulcer and 9 of the 65 patients with duodenal ulcer had taken these medications at the time of hospitalization. If these patients and their matched controls were excluded, the odds ratio would have been 3.3 (95% CI, 1.6 to 7.0) for gastric ulcer, 3.3 (CI, 0.9 to 12.1) for duodenal ulcer, and 3.3 (CI, 1.7 to 6.4) for either gastric or duodenal ulcer. Of the 215 patients with either gastric or duodenal ulcer, 100 also had a hospital-based diagnosis of cardiovascular disease or cancer. If these patients were excluded from the study, as were controls with these diseases, 115 patients with gastric or duodenal ulcer would have remained in the study. Ninety-four percent of these case-patients and 77% of their controls had a positive test result for H. pylori antibody. The odds ratio for peptic ulcer was 4.3 (CI, 1.8 to 10.5) in this group of patients. When the patients with gastric ulcer who had positive antibody resu

Soluble surface proteins from Helicobacter pylori activate monocytes/macrophages by lipopolysaccharide-independent mechanism.

The inflammatory lesions associated with Helicobacter pylori gastritis and duodenitis contain large numbers of mononuclear cells. The close proximity of H. pylori to gastric mucosa suggests that the organism interacts with mononuclear cells, thereby modulating the inflammatory response. To investigate the role of monocytes/macrophages in this response, we examined the effect of whole H. pylori bacteria, H. pylori surface proteins, and H. pylori lipopolysaccharide (LPS) on purified human monocytes. Whole H. pylori and the extracted LPS induced expression of the monocyte surface antigen HLA-DR and interleukin-2 receptors, production of the inflammatory cytokines interleukin 1 and tumor necrosis factor (peptide and messenger RNA), and secretion of the reactive oxygen intermediate superoxide anion. Since H. pylori in vivo does not invade mucosal tissue, we determined whether soluble constituents of the bacteria could activate monocytes. Soluble H. pylori surface proteins, which are enriched for urease and do not contain LPS, stimulated phenotypic, transcriptional, and functional changes consistent with highly activated monocytes. These findings indicate that H. pylori is capable of activating human monocytes by an LPS-independent as well as an LPS-dependent mechanism. H. pylori activation of resident lamina propria macrophages and monocytes trafficking through the mucosa, leading to the secretion of increased amounts of inflammatory cytokines and reactive oxygen intermediates, could play an important role in mediating the inflammatory response associated with H. pylori gastritis and duodenitis.

Seroprevalence and Ethnic Differences in Helicobacter pylori Infection among Adults in the United States

The seroprevalence of Helicobacter pylori infection was examined in the adult US population and among different ethnic groups. Stored sera from 7465 adult participants in the first phase of the third National Health and Nutritional Examination Survey (1988-1991) were tested with a sensitive and specific IgG ELISA, to diagnose infection. Seroprevalence of H. pylori among all participants was 32. 5%. This increased with age, from 16.7% for persons 20-29 years old to 56.9% for those > or =70 years old. Age-adjusted prevalence was substantially higher among non-Hispanic blacks (52.7%) and Mexican Americans (61.6%) than among non-Hispanic whites (26.2%). After controlling for age and other associated factors, the odds ratios relative to non-Hispanic whites decreased for non-Hispanic blacks, from 3.9 (95% confidence interval [CI], 3.1-4.9) to 3.3 (95% CI, 2. 6-4.2), and for Mexican Americans, from 6.3 (95% CI, 4.8-8.3) to 2.3 (95% CI, 1.6-3.5). The high prevalence of H. pylori infection among non-Hispanic blacks and Mexican Americans is partially explained by other factors associated with infection.