This Month in Gastroenterology

Article Outline

• Helicobacter pylori Eradication and the Risk of Gastric Cancer
• Long-Acting Somatostatin Analog for Polycystic Liver Disease
• Diet, Not Obesity, Dictates Gut Microbiome
• Acid-Triggered, Immune-Mediated Injury in the Submucosa Initiates Esophagitis That Progresses to the Epithelial Surface
• Copyright

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Helicobacter pylori Eradication and the Risk of Gastric Cancer 

Helicobacter pylori infection is a well-established risk factor for gastric carcinogenesis. In animal models, H pylori infection induces a sequence of atrophic gastritis, intestinal metaplasia, dysplasia, and cancer. In some animal models, early eradication of H pylori decreases the incidence of gastric cancer. Whether eradication of H pylori prevents future development of gastric cancer in man remains to be proven.

In this issue of Gastroenterology, Wu et al report on a population-based, retrospective cohort study of hospitalized patients with peptic ulcer disease in Taiwan who received H pylori eradication therapy over a 10-year period. Using a national health insurance database, the authors identified patients who were hospitalized for the first time between January 1997 and December 2004 with a primary diagnosis of peptic ulcer who received H pylori eradication therapy after the index hospitalization. Patients <20 years old, those who underwent (partial) gastrectomy or vagotomy, and those with a previous diagnosis of gastric cancer or a diagnosis of gastric cancer within the first 2 years of follow-up were excluded. Comorbidities and use of nonsteroidal anti-inflammatory agents (NSAIDs) were registered. Patients who received H pylori eradication therapy within the first year of the index admission were included in the “early eradication cohort.” Patients included in the “late eradication cohort” were given H pylori eradication therapy ≥1 year after the index hospitalization. The 2 cohorts were followed until the development of gastric cancer, death, or the end of 2006. The risk of gastric cancer was compared with the corresponding age- and gender-specific incidence rates for the entire Taiwan population based on a population census and cancer registry data from 2001.

A total of 80,255 hospitalized patients who were admitted for the first time with a primary diagnosis of peptic ulcer diseases and received H pylori eradication therapy after the index hospitalization were recruited. Among these subjects, 54,576 received early H pylori and 25,679 received late eradication therapy. There were small but significant differences between both cohorts in age, gender distribution, index hospitalization year, ulcer characteristics, NSAID use, and comorbidities.

Early H pylori eradication conferred no significant difference in gastric cancer risk compared with the general population (standardized incidence ratio, 1.05; 95% confidence interval (CI), 0.96–1.14), but late eradication was associated with an increased risk compared with the general population (standardized incidence ratio, 1.36; 95% CI, 1.24–1.49). Kaplan–Meier estimates of cumulative incidences of gastric cancer for early and late eradication cohorts are shown in Figure 1. The increased risk was most prominent in patients who were younger, and only present in those with gastric peptic ulcer. In fact, duodenal peptic ulcer was associated with a lower risk of gastric cancer. On multivariate analysis, older age, male gender, gastric ulcer, peptic ulcer with complications, and a number of endoscopic examinations were independent risk factors of gastric cancer, whereas frequent aspirin or NSAID use and early H pylori eradication were independent protective factors.

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• Figure 1. 

  Cumulative incidences of gastric cancer for early and late H pylori eradication cohorts.

This long-term cohort study confirms the potential of H pylori eradication to prevent gastric cancer in patients with peptic ulcer. Limitations of the study are the patient selection (hospitalized with peptic ulcer); potential influences of social, economic, and historical issues, the lack of confirmation of successful eradication, and the lack of a noneradicated control group. It remains to be established whether the beneficial effect of early eradication is also true for H pylori-infected subjects without peptic ulcer.

See page 1641.

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Long-Acting Somatostatin Analog for Polycystic Liver Disease 

Polycystic liver disease is an autosomal-dominant, hereditary disorder characterized by a progressive increase in volume with age of the affected liver. Depending on the underlying gene mutation, polycystic kidneys may or may not also be present. The age-dependent increase in liver volume is caused by a growing number of liver cysts as well as an increase of the individual cyst volume. Symptoms occur through the increasing liver volume (abdominal distension, early satiety, dyspnea, and pain) or through complications like bleeding, infection, or rupture of cysts. Current therapeutic options are limited. When massive liver volume underlies major symptom generation, surgery (fenestration or partial liver resection) is advocated, but these procedures are associated with only partial effectiveness and are not devoid of morbidity or mortality. Studies in animal models and uncontrolled observations in patients suggest a potential for somatostatin analogs to decrease liver volume, probably through inhibition of cholangiocyte secretion.

In this issue of Gastroenterology, Van Keimpema et al report on a randomized, placebo-controlled, 24-week clinical trial that evaluated the efficacy of a long-acting somatostatin analog in polycystic liver disease. Patients were recruited from 2 centers (in The Netherlands and Belgium) and were randomized to receive lanreotide autosolution 120 mg or placebo SC every 4 weeks. The primary endpoint was change in liver volume measured on computed tomography at baseline and after 24 weeks of treatment. Secondary end points were change in polycystic kidney volume, change in abdominal symptoms, and health-related quality of life.

A total of 54 patients were recruited for the study. Both treatment groups were balanced, except for a higher prevalence of kidney involvement in the lanreotide group. The mean liver volume decreased by 2.9% in the lanreotide group while it increased by 1.6% in the placebo group (P < .01) (Figure 2). A decrease in liver volume occurred in 85% of patients on lanreotide compared with 27% on placebo. In addition, the polycystic kidney volume decreased by 1.5% in lanreotide treated patients compared with a 3.4% volume increase in the placebo group (P = .02). No significant changes in gastrointestinal symptoms or quality of life occurred. No major adverse events occurred, but lanreotide treatment was associated with fatty diarrhea in 19 patients, 6 of whom were treated with pancreatic enzymes. Thirteen lanreotide-treated patients noted nodules at the injection sites.

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• Figure 2. 

  Absolute change in liver volume in all patients. Each bar represents 1 patient.

This 24-week, controlled study demonstrates that lanreotide is able to change the natural disease course of polycystic liver disease. Liver volume decreases, although this was not associated with differences in symptoms or quality of life. Longer term studies are required to establish whether this benefit translates into clinically relevant outcome parameters.

See page 1661.

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Diet, Not Obesity, Dictates Gut Microbiome 

The composition of the microflora in the gut seems to be influenced in obesity. However, it is not clear if it is the obese state or the diet that causes alteration of the intestinal microbiome.

In the study by Hildebrandt et al, wild-type and RELMb knockout mice had gut microflora assessed from fecal pellets after changing standard chow to a high-fat diet for 21 weeks. RELMb knockout mice show no overt phenotype; RELMb is a colonic goblet cell-specific gene whose expression is dependent on the presence of the gut microbiome. Upon switching wild-type mice to a high-fat diet, RELMb expression increased, which was muted with antibiotics, consistent with its expression being dependent on the gut microbiome. Compared with wild-type mice, RELMb knockout mice exhibited less weight gain and were relatively lean on a high-fat diet, caused by an increase in mice energy expenditure and not alteration in food intake or fat absorption or physical activity, and allowing observation of diet separate from obesity on the microbiome. Microflora from both wild-type and RELMb knockout mice were relatively similar on standard chow, with Bacteroides followed by Firmicutes as the dominant phyla. After ingesting a high-fat diet, both wild-type and RELMb knockout mice experienced a dramatic change in microbiota, with Firmicutes and Proteobacteria greatly expanding at the expense of Bacteroides (Figure 3). Metagenomic analysis revealed a percentage shift from predominant bacteria sequences on standard chow to murine sequences on the high-fat diet, possibly owing to greater shedding of intestinal epithelial cells. With institution of the high-fat diet (and reduction in carbohydrates), bacteria lineages altered their metabolic gene profile by changing nutrient transporter expression, presumably owing to nutrient stress and to adjust to the local intestinal environment.

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• Figure 3. 

  Analysis of gut bacterial communities by 16S rDNA analysis from mice on the standard chow and high-fat diets. The figure shows percentages of each community contributed by the indicated Phyla. KO, RELMb knockout mice; WT, wild-type mice.

The study indicates that diet, not the state of obesity, is the greater determinant of gut microflora alterations. This finding suggests that dietary variation and intervention, at least based on mouse experiments, could modify the intestinal microbiome.

See page 1716.

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Acid-Triggered, Immune-Mediated Injury in the Submucosa Initiates Esophagitis That Progresses to the Epithelial Surface 

Gastroesophageal reflux disease (GERD) is thought to be caused by exposure of the distal esophagus to stomach acid and bile together with activated pepsin, causing caustic injury to the esophageal epithelium and manifested clinically by erosions and ulcerations. In some animal models, however, direct caustic injury is only seen with extremely low pH (ie, <2.0), which is not typical of human GERD, and esophagitis may take some time (weeks) to develop histologically, arguing against direct caustic injury as a mode for erosions and ulcerations.

In the study by Souza et al, male Sprague-Dawley rats that had undergone esophagoduodenostomy (keeping intact the vagal nerve branches to the stomach) to allow the esophagus exposure to acid and bile acids as a model for esophagitis were used to study the timing of histologic changes after the acid/bile exposure for up to 8 weeks after esophagoduodenostomy. Additionally, acid/bile-exposed immortalized but not transformed esophageal squamous cells were utilized to examine cytokine release and the recruitment of immune cells. In the rat model after esophagoduodenostomy, inflammation consisted of T lymphocytes in the submucosa as the initial histologic lesion, occurring on day 3 after exposure, with lymphocytic infiltrate reaching significant levels in the lamina propria and epithelium around week 3 after surgery. Neutrophils first appeared at day 7. Basal cell and papillary hyperplasia were observed peaking at week 4, which preceded the development of esophageal erosions (Figure 4). In esophageal squamous cell lines exposed to acidic bile, the cytokines interleukin (IL)-8 secretion from the epithelial cells occurred starting on day 2 after exposure and continued to increase through day 5. IL-1b increased on days 4 and 5 after acidic bile exposure. Conditioned media containing cytokines from the exposed cells induced migration of T cells and neutrophils, and blocking antibodies to IL-8 reduced the migration of neutrophils, suggestive of IL-8 being at least 1 cytokine involved in the inflammatory response. Rat esophagus histology after esophagoduodenostomy showed IL-8 immunoreactivity by week 2 in the submucosa, lamina propria, and squamous epithelium that increased through week 7 in the mature epithelial cells.

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• Figure 4. 

  Degree of basal cell hyperplasia, papillary hyperplasia and surface erosions in the distal esophagus at various time points after esophagoduodenostomy in rats. The bar graphs depict the mean + SEM.

This study challenges the belief that esophagitis is caused by direct caustic chemical injury by stomach acid and bile. Instead, the authors lay out a new hypothesis of an acid-triggered, immune-mediated injury that begins in the submucosa which progresses to epithelial injury. This cytokine-mediated hypothesis could lend itself to new approaches to prevent esophagitis caused by GERD.

See page 1776.