Caroline M. den Hoed

Identification of genetic loci associated with Helicobacter pylori serologic status.

IMPORTANCE Helicobacter pylori is a major cause of gastritis and gastroduodenal ulcer disease and can cause cancer. H. pylori prevalence is as high as 90% in some developing countries but 10% of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H. pylori susceptibility. OBJECTIVE To identify genetic loci associated with H. pylori seroprevalence in 2 independent population-based cohorts and to determine their putative pathophysiological role by whole-blood RNA gene expression profiling. DESIGN, SETTING, AND PARTICIPANTS Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H. pylori IgG serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n = 3830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS-II (recruitment, 2000-2001 [n = 7108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n = 991]), and fecal H. pylori antigen in SHIP-TREND (n = 961). MAIN OUTCOMES AND MEASURES H. pylori seroprevalence. RESULTS Of 10,938 participants, 6160 (56.3%) were seropositive for H. pylori. GWASs identified the toll-like receptor (TLR) locus (4p14; top-ranked single-nucleotide polymorphism (SNP), rs10004195; P = 1.4 × 10(-18); odds ratio, 0.70 [95% CI, 0.65 to 0.76]) and the FCGR2A locus (1q23.3; top-ranked SNP, rs368433; P = 2.1 × 10(-8); odds ratio, 0.73 [95% CI, 0.65 to 0.81]) as associated with H. pylori seroprevalence. Among the 3 TLR genes at 4p14, only TLR1 was differentially expressed per copy number of the minor rs10004195-A allele (β = -0.23 [95% CI, -0.34 to -0.11]; P = 2.1 × 10(-4)). Individuals with high fecal H. pylori antigen titers (optical density >1) also exhibited the highest 25% of TLR1 expression levels (P = .01 by χ2 test). Furthermore, TLR1 exhibited an Asn248Ser substitution in the extracellular domain strongly linked to the rs10004195 SNP. CONCLUSIONS AND RELEVANCE GWAS meta-analysis identified an association between TLR1 and H. pylori seroprevalence, a finding that requires replication in nonwhite populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H. pylori infection.

Helicobacter Pylori and the Birth Cohort Effect: Evidence for Stabilized Colonization Rates in Childhood

Background:  The prevalence of Helicobacter pylori has declined over recent decades in developed countries. The increasing prevalence with age is largely because of a birth cohort effect. We previously observed a decline in H. pylori prevalence in 6‐ to 8‐year‐old Dutch children from 19% in 1978 to 9% in 1993. Knowledge about birth‐cohort‐related H. pylori prevalence is relevant as a predictor for the future incidence of H. pylori‐associated conditions.

THE IMPACT OF HELICOBACTER PYLORI ON ATOPIC DISORDERS IN CHILDHOOD

Background:  The prevalence of Helicobacter pylori in Western populations has steadily decreased. This has been suggested as one of the factors involved in the recent increase of asthma and allergy. Some studies have reported a negative association between H. pylori and asthma and allergy, but data are inconsistent and there are a few studies in children.

Ethnicity is a strong predictor for Helicobacter pylori infection in young women in a multi-ethnic European city.

At the same time that Helicobacter pylori prevalence is declining in Western countries, immigrants from developing countries with high H. pylori prevalence have settled in Western urban areas. Actual epidemiological data on H. pylori in a migrant community may help in realizing a more selective approach to assess H. pylori‐related diseases. We aimed to define H. pylori prevalence as well as risk groups for H. pylori in a cohort of young women living in a multi‐ethnic European city.

Gastric Cancer: How Can We Reduce the Incidence of this Disease?

Gastric cancer remains a prevalent disease worldwide with a poor prognosis. Helicobacter pylori plays a major role in gastric carcinogenesis. H. pylori colonization leads to chronic gastritis, which predisposes to atrophic gastritis, intestinal metaplasia, dysplasia, and eventually gastric cancer. Screening, treatment, and prevention of H. pylori colonization can reduce the incidence of gastric cancer. Other interventions that may yield a similar effect, although of smaller magnitude, include promotion of a healthy lifestyle including dietary measures, non-smoking, low alcohol intake, and sufficient physical activity. This chapter reviews interventions that can lead to a decline in gastric cancer incidence in high and low incidence countries.

The societal gain of medical development and innovation in gastroenterology.

Background Gastroenterology has over the past 30 years evolved very rapidly. The societal benefits to which this has led are incompletely determined, yet form a mandate to determine the need for future innovations and further development of the field. A more thorough understanding of societal benefits may help to determine future goals and improve decision making. Aims The objective of this article is to determine the societal gains of medical innovations in the field of gastroenterology in the past and future, using peptic ulcer disease as an example of past innovation and the implementation of colorectal cancer screening as an illustration of future gains. Methods Literature searches were performed for data on peptic ulcer and colorectal cancer epidemiology, treatment outcomes, and costs. National and governmental databases in the Netherlands were searched to obtain the input for calculations of quality-adjusted life years (QALYs), health-adjusted life expectancy (HALE), and the corresponding societal benefit. Results Since 1980 the improvements in peptic ulcer treatment have had a limited impact on life expectancy, rising from 83.6 years to 83.7 years, but have led to a yearly gain of 46,000 QALYs, caused by improved quality of life. These developments in the field of peptic ulcer translated into a yearly gain of 1.8 billion to 7.8 billion euros in 2008 compared with the 1980s. Mortality due to colorectal cancer is high, with 21.6 deaths per 100,000 per year in the Netherlands (European Standardized Rate (ESR)). The future implementation of a nationwide call-recall colorectal cancer screening by means of biennial fecal immunochemical testing (FIT) is expected to result in a 50%–80% mortality reduction and thus a gain of an estimated 35,000 life years per year, corresponding to 26,000 QALYs per year. The effects of the implementation of FIT screening can be translated to a future societal gain of 1.0 billion to 4.4 billion euro. Conclusions The innovations and developments in the field of gastroenterology have led to significant societal gains in the past three decades. This process will continue in the near future as a result of further developments. These calculations provide a template for calculations on the need for specialist training as well as research and implementation of new developments in our field.

Premalignant gastric lesions in patients with gastric mucosa-associated lymphoid tissue lymphoma and metachronous gastric adenocarcinoma: a case-control study.

Background Patients with gastric mucosa-associated lymphoid tissue lymphoma or diffuse large B-cell lymphoma have an increased risk of developing gastric carcinoma (GC). Identifying patients at high GC risk may lead to improved survival and prognosis. The aim of this case–control study was to evaluate whether premalignant gastric lesions are more prevalent and severe in gastric lymphoma (GL) patients with a subsequent diagnosis of GC than in those without GC. Methods Patients with a first GL diagnosis from 1991–2008 were identified in the Dutch histopathology registry (PALGA). Cases were patients with a diagnosis of GL and a subsequent diagnosis of GC. Controls were patients with a diagnosis of GL without GC development. Results In total, eight cases (mean follow-up 5.5 years) and 31 controls (mean follow-up 5.3 years) were included (mean age 60 years). At lymphoma diagnosis, six (75%) cases were diagnosed with premalignant lesions, whereas in the control group, 21 (68%) had histological evidence for premalignant lesions (P=0.69). At GC diagnosis, five (63%) cases showed intestinal metaplasia in the surrounding gastric mucosa. In 22 (71%) controls premalignant lesions were present at the end of follow-up (P=0.47). Conclusion No differences were demonstrated in the prevalence of premalignant lesions of cases and controls at GL diagnosis or the end of follow-up. As the prevalence of premalignant lesions is substantial in both the groups of patients, careful endoscopic surveillance of GL patients is warranted not only for recurrence of lymphoma, but also for progression to adenocarcinoma.

Helicobacter pylori colonization and obesity – a Mendelian randomization study

Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and continues to rise worldwide. While etiological understanding is needed for prevention, epidemiological studies indicated that colonization with Helicobacter pylori (H. pylori) may affect body mass index (BMI), but with inconsistent results. Here, we examine the relationship between H. pylori colonization and BMI/obesity. Cross-sectional analyses were performed in two independent population-based cohorts of elderly from the Netherlands and Germany (n = 13,044). Genetic risk scores were conducted based on genetic loci associated with either H. pylori colonization or BMI/obesity. We performed a bi-directional Mendelian randomization. Meta-analysis of cross-sectional data revealed no association between anti-H. pylori IgG titer and BMI, nor of H. pylori positivity and BMI. Anti-H. pylori IgG titer was negatively associated with obesity (OR 0.99972; 95% CI 0.99946-0.99997, p = 0.03) and with obesity classes (Beta −6.91 •10−5; 95% CI −1.38•10−4, −5.49•10−7, p = 0.048), but the magnitude of these effects was limited. Mendelian randomization showed no causal relation between H. pylori genetic risk score and BMI/obesity, nor between BMI or obesity genetic risk scores and H. pylori positivity. This study provides no evidence for a clinically relevant association between H. pylori and BMI/obesity.

The Birth Cohort Effect and Helicobacter pylori: Evidence for Stabilized Colonization Rates in Childhood in a Developed Country

impaction (90% vs. 79%; p=0.007). Conclusions: The majority of patients with EFBI at our institution between 2005 and 2009 presented to the ED. Medical management was largely ineffective, and a therapeutic procedure was required to clear the EFBI in most patients. Time of ED arrival made no difference in time-to-procedure, indicating that GI and ENT specialists recognize and address the urgency of treating EFBI regardless of time of day.

Esomeprazole for the treatment of peptic ulcer bleeding

Peptic ulcer bleeding is the most common cause of acute bleeding in the upper GI tract. The incidence of peptic ulcer bleeding has slowly decreased and endoscopic treatment options have improved; nevertheless, it remains a very common condition with a 7–15% mortality. Acidic environments have a negative effect on hemostasis. Therefore, acid inhibitors have been applied in the adjuvant treatment of peptic ulcer bleeding, both in preventing rebleeding and in treating the underlying cause. This requires profound acid suppressive therapy aiming for a rapid onset of effect and a persistent intragastric pH above 6. This can only be achieved by proton pump inhibitors (PPIs). Esomeprazole is the S-isomer of omeprazole, and the first PPI to consist of only the active isomer. A number of studies have compared esomeprazole with other PPIs, demonstrating a faster and more persistent increase in intragastric pH with the use of esomeprazole than with other agents. Continuous high-dose intravenous treatment with esomeprazole decreases rebleeding, surgery, transfusion rates and hospital days in peptic ulcer bleeding.