Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

The stomach in health and disease.

The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.

Expression of neutrophil gelatinase-associated lipocalin in colorectal neoplastic progression: a marker of malignant potential?

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has a diverse functional repertoire, involved in the innate immune response as well as cell growth and differentiation. Expression has been linked to malignant disease development and progression. METHODS: Neutrophil gelatinase-associated lipocalin expression was assessed immunohistochemically in 98 colorectal neoplastic lesions (52 cancer polyps (CaPs) and 46 sporadic adenoma/adjacent normal mucosa paired specimens) to investigate association with adenoma progression and early colorectal carcinogenesis. RESULTS: Within CaPs, all adenomatous and carcinomatous epithelium expressed NGAL, with 92% (43 out of 47) and 58% (19 out of 33) epithelial positivity, respectively, as well as positive stromal cell expression. This was significantly increased compared with normal mucosal epithelium (P=0.0001). Neutrophil gelatinase-associated lipocalin positivity was also identified in sporadic low-grade adenomas, in both the epithelial and stromal compartments as compared with adjacent normal mucosa (P=0.0001 and 0.0002), and this increased along with adenoma size >1 cm (P=0.03). CONCLUSION: Neutrophil gelatinase-associated lipocalin is expressed by the majority of human neoplastic colorectal lesions. This phenotypic switch occurs at an early stage in neoplastic progression with clear differential expression between normal mucosa and adenomatous polyps, rather than further downstream in disease progression at the adenoma-carcinoma transformation. Thus, NGAL expression is not a useful biomarker for determining disease progression from adenomatous to malignant colorectal neoplasia.

Interobserver reliability in the endoscopic diagnosis and grading of Barrett's esophagus: an Asian multinational study.

BACKGROUND AND STUDY AIM: The establishment of precise and valid diagnostic criteria is important for any disease. We determined the interobserver reliability in the endoscopic diagnosis and grading of Barrett's esophagus. PATIENTS AND METHODS: Video clips of endoscopy in 21 patients with/without Barrett's esophagus were used for training (n = 3) and for diagnosis/grading (n = 18) of Barrett's esophagus by endoscopists from seven hospitals in Asia. Barrett's esophagus was graded using the Prague C & M Criteria whereby the circumferential extent of the Barrett's segment (C value), maximum extent of Barrett's segment (M value), location of the gastroesophageal junction, and location of the diaphragmatic hiatus were scored. The intraclass correlation coefficients (ICC) were calculated as a measure of interobserver reliability. RESULTS: A total of 34 endoscopists participated. ICC values for the scores of the C value, M value, location of the gastroesophageal junction, and location of the diaphragmatic hiatus were: 0.92 (95 % confidence interval [CI] 0.88 - 0.97), 0.94 (95 %CI 0.90 - 0.98), 0.86 (95 %CI 0.78 - 0.94), and 0.81 (95 %CI 0.71 - 0.92), respectively, indicating excellent interobserver agreement. The differences in region/country, endoscopists' experience, case volume of participating centers, or primary practice type had no significant effect on the reliability. The ICC values for recognition of Barrett's esophagus of > or = 1 cm were 0.90 (95 %CI 0.80 - 1.00) and 0.92 (95 %CI 0.87 - 0.98) for the C and M values, respectively, whereas the corresponding ICC values for Barrett's segment of < 1 cm were 0.18 (95 %CI 0.03 - 0.32) and 0.21 (95 %CI 0.00 - 0.51), respectively. CONCLUSIONS: Despite the uncommon occurrence of Barrett's esophagus in Asia, our endoscopists exhibited excellent agreement in the endoscopic diagnosis and grading of Barrett's esophagus using the Prague C & M Criteria. However, in view of the low interobserver reliability in recognizing Barrett's segments of < 1 cm, future studies in Asia should take this into account when selecting the study population.

COX-2 expression in sporadic colorectal adenomatous polyps is linked to adenoma characteristics.

AIMS: To assess cyclooxygenase-2 (COX-2) expression in sporadic colonic adenomas and to explore the association of COX-2 positivity with adenoma characteristics linked to increased risk of malignant transformation. METHODS AND RESULTS: COX-2 expression and localization were assessed in 64 colorectal adenomas and 35 paired adjacent normal colonic mucosal biopsy specimens. The number of adenoma specimens was then extended to include polyps exhibiting an increasing degree of epithelial dysplasia. Forty colonic hyperplastic polyps were also identified from the pathology diagnostic database and included in the analysis. Immunohistochemistry was performed with the Envision+ peroxidase-linked biotin-free system incorporating a signal amplification step. There was a statistically significant increase in COX-2 expression in colonic polyps compared with paired adjacent normal mucosa, chi(2) = 40.1, P = 0.001. The probability of COX-2 expression increased along with increasing adenoma size and increasing degree of epithelial dysplasia. Fifty-five per cent of the hyperplastic polyp specimens expressed COX-2. CONCLUSIONS: This study associates COX-2 epithelial expression with a number of adenoma characteristics that convey an increased risk of malignant transformation. This is in keeping with a positive role for COX-2 in early colorectal carcinogenesis.

The fungal microbiota of de-novo paediatric inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterised by an inappropriate chronic immune response against resident gut microbes. This may be on account of distinct changes in the gut microbiota termed as dysbiosis. The role of fungi in this altered luminal environment has been scarcely reported. We studied the fungal microbiome in de-novo paediatric IBD patients utilising next generation sequencing and compared with adult disease and normal controls. We report a distinct difference in fungal species with Ascomycota predominating in control subjects compared to Basidiomycota dominance in children with IBD, which could be as a result of altered tolerance in these patients.

The Glasgow Dyspepsia Severity Score--a tool for the global measurement of dyspepsia.

OBJECTIVE: There is currently no reliable tool for providing a global measurement of the severity of dyspepsia in patients with a variety of upper gastrointestinal disorders. We have designed a questionnaire which records frequency of symptoms, effect on routine activities, time off work, frequency of medical consultations, clinical investigations and use of over-the-counter and prescribed medications. The objective of the paper was to assess this questionnaire with respect to reproducibility, validity, responsiveness and performance time. METHODS AND RESULTS: For intra-observer variation, one author interviewed 50 subjects (25 males) including 20 healthy volunteers and 30 with a variety of upper gastrointestinal pathologies. The interview was repeated one week later by the same author who was blinded to the dyspepsia score for the first interview. The second author, who was blinded to the diagnoses and subject identity, scored all the questionnaires. The mean dyspepsia score was 6.78 on Day 1 and was similar at 6.80 on Day 2. The coefficient of variation between Days 1 and 2 was 2%. For inter-observer variation, 30 patients with non-ulcer dyspepsia (NUD) were interviewed by one author and the interview was repeated on a separate occasion within 24 h by a second author who was blinded to the score from the first interview. The mean dyspepsia score for the first author was 10.7 and for the second author 10.9 with a coefficient of variation between the two authors of 8%. Validity was assessed by comparing the dyspepsia scores in healthy volunteers and patients with upper gastrointestinal diseases. The mean score in 80 healthy volunteers was 1.16 (range: 0-7) and was significantly higher in 70 duodenal ulcer (DU) patients (mean score 11.1, range: 6-16) and 80 NUD patients (mean score 10.5, range: 6-17) (P < 0.001 for both vs. healthy volunteers). Responsiveness was assessed by comparing dyspepsia scores before and one year after eradication of Helicobacter pylori infection in 42 DU patients. The mean dyspepsia score before eradication was 11.4 (range: 6-16) and fell to 1.33 (range: 0-11) one year after eradication (P < 0.001). The mean time taken to complete 150 questionnaires was 4 min (range: 3-5.5 min). CONCLUSION: This new questionnaire for assessing the severity of dyspepsia is highly reproducible and has high validity and responsiveness. In addition, it is simple and rapid to perform. It provides a valuable tool for assessing the response to treatment in patients with dyspepsia.

The role of H. pylori infection in the pathophysiology of duodenal ulcer disease.

The discovery of H. pylori infection and the recognition of its effects on gastric physiology has significantly advanced our understanding of the pathophysiology of ulcer disease, In DU patients H. pylori gastritis is mainly confined to the antral mucosa. It stimulates increased release of gastrin by the antral mucosa and this is accompanied by high acid output by the oxyntic mucosa. This high acid response to gastrin stimulation by the oxyntic mucosa in DU patients is due to the combination of a high parietal cell mass and the fact that the function of these parietal cells is not impaired by any body gastritis. The increased acid secretion results in an increased duodenal acid load with the development of gastric metaplasia within the duodenal bulb and then actual ulceration. The reason why only some subjects develop this antral predominant pattern of H. pylori gastritis and associated acid hypersecretion is unclear but may be explained by a premorbid high acid output protecting the oxyntic mucosa form H. pylori gastritis.

Loss of sensory and noradrenergic innervation in benign colorectal adenomatous polyps--a putative role of semaphorins 3F and 3A.

BACKGROUND: Nerve fibers can exert trophic/anti-trophic effects on epithelial cells. Substance P (SP) is a pro-proliferative neuropeptide, whereas sympathetic noradrenaline is anti-proliferative at high concentrations. METHODS: Density of noradrenergic and sensory nerve fibers and presence of nerve repellent factors specific for noradrenergic (semaphorin 3F) and sensory nerve fibers (semaphorin 3A) were investigated in colorectal adenomas. KEY RESULTS: The pedunculus was innervated by noradrenergic fibers, whereas the mucosa was sparsely innervated. The control submucosa compared with control mucosa demonstrated increased density of noradrenergic fibers. Control tissue was much better innervated than the polyp. This was accompanied by strong expression of semaphorin 3F in epithelial cells. Density of sensory SP+ nerve fibers was higher in control colon mucosa compared with polyp mucosa, and SP+ cell clusters and semaphorin 3A-positive cells appeared in the intercrypt space in polyps, but not in control tissue. CONCLUSIONS & INFERENCES: This study demonstrated a marked loss of noradrenergic and sensory nerve fibers in polyp mucosa, which was associated with a strong increase of semaphorin 3F and 3A. Up-regulation of the sympathetic repellent semaphorin 3F in the polyps possibly triggers sympathetic repulsion and polyp growth due to the loss of anti-proliferative noradrenaline and presence of SP from local SP+ cells.

Role of endoscopic ultrasonography in predicting the response to cyclosporin A in ulcerative colitis refractory to steroids.

BACKGROUND AND AIMS: Although cyclosporin A has been reported to be effective in the treatment of severe ulcerative colitis, factors predicting its therapeutic efficacy remain unclear. Technical progress in endoscopic ultrasonography has improved visualisation of the structure of the colon wall. Here, to assess the value of endoscopic ultrasonography in predicting the response to cyclosporin A treatment, we evaluated the therapeutic effect of cyclosporin A by determining the pre- and post-cyclosporin A thickness of the mucosal layer in the rectum using endoscopic ultrasonography with an ultrasonic catheter probe. PATIENTS AND METHODS: Fifteen ulcerative colitis patients who did not respond to high-doses of corticosteroids were treated with cyclosporin A by continuous intravenous infusion at 4mg/kg/day for 20 days. Before and 20 days after cyclosporin A therapy, clinical disease activity was assessed using clinical activity index scores. Colonoscopy and endoscopic ultrasonography were undertaken before and 20 days after cyclosporin A therapy. RESULTS: Following treatment with cyclosporin A, nine patients showed a decrease in clinical activity index score by six points or more and were defined as responders, while the other six were defined as non-responders. Endoscopic ultrasonography measurement using an ultrasonic catheter probe showed that thickness of the rectal mucosal layer before cyclosporin A was significantly greater in responders than in non-responders (p<0.05). Further, thickness after cyclosporin A was statistically decreased (p<0.01) in the responders but not in the non-responders. CONCLUSIONS: The ultrasonic catheter probe may represent a useful means of predicting and evaluating the efficacy of cyclosporin A treatment in severely ill ulcerative colitis patients.

Polymorphisms in Toll-like receptor genes and risk of cancer.

Host genetic factors are emerging as key determinants of disease risk for many cancers. Identifying candidate genes is a major challenge that has to stem from a profound understanding of the pathophysiology of the disease. The Toll-like receptors are important members of the host's innate immune response and their genes have been found to be polymorphic. This genetic variation allows for a more intricate repertoire that enables the host to withstand microbial challenges. While this may be advantageous on a population level, there may be less favourable outcomes for individuals that harbour certain genotypes associated with excessive immune activation and inflammatory drive. The damage is often collateral and is manifest in organs where this chronic inflammation alters normal physiology. A classic example of this paradigm is the Helicobacter pylori-induced gastric cancer model. Another emerging model is prostate cancer where Toll-like receptor polymorphisms have also been found to play a role. In this review, we discuss polymorphisms in Toll-like receptors and give an insight into how they may influence risk of cancer.

Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer.

Helicobacter pylori infection, the dominant risk factor for gastric cancers, has been shown to elicit T helper type 1 (Th1) polarized immunological responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqMan(TM) assays to determine TNFA (-308 G>A, -417 G>A, -555 G>A, -1036 C>T, -1042 C>A, -1210 T>C), IL1A (-889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G and Ex2-16 A>G) and IL12A (IVS2-798 T>A, IVS2-701 C>A and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for sex, age, education and smoking status. Out of six single nucleotide polymorphisms (SNPs) tested in TNFA, gastric cancer risk was significantly associated with the TNFA (-308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0-2.0) for the G/A and 2.5 (95% CI: 1.3-4.9) for the A/A genotype carriers, when compared with the more frequent genotype (G/G) (P-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95% CI: 1.0-2.3) for T/C and 1.7 (95% CI: 1.1-2.7) for C/C carriers when compared with T/T carriers (P-trend = 0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA -308 A/A genotypes had the highest risk (OR = 5.5, 95% CI: 1.5-19.4), although the interaction was not statistically significant. IL1A (-889 C>T) and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA -308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.

Mechanisms of increased acid secretion after eradication of Helicobacter pylori infection.

Eradication of Helicobacter pylori infection leads to recovery of gastric acid secretion in some individuals but the mechanism is not fully understood. In the short term, there is an impressive increase in expression of H+/K+-ATPase pumps without an increase in the number of parietal cells. Longer follow up studies are needed to see if the parietal cell mass eventually recovers.

Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy.

BACKGROUND AND AIMS: The relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease (GORD) is controversial but it is accepted that GORD is associated with increased exposure to gastric acidity. The proinflammatory interleukin (IL)-1B polymorphisms increase the risk of hypochlorhydria and gastric atrophy. We examined the association between proinflammatory cytokine gene polymorphisms, presence of gastric atrophy, and risk of GORD in H pylori positive and negative subjects in Japan. METHODS: We studied 320 consecutive dyspeptic patients without peptic ulcers or cancers. GORD symptoms were scored using the Carlsson-Dent questionnaire and erosive oesophagitis was assessed endoscopically. H pylori infection was diagnosed by urea breath test, histological examination, and serology. Gastric atrophy was assessed histologically, and polymorphisms in the IL-1B, IL-10, and tumour necrosis factor alpha (TNF-A) genes were genotyped. RESULTS: Two hundred and eight patients were H pylori positive and 112 were negative. One hundred and eight (34%) were found to have erosive oesophagitis by endoscopic criteria (grade A: 78; grade B: 23; grade C: 6; grade D: 1). Erosive oesophagitis and GORD symptoms were significantly more common in H pylori negative compared with H pylori positive subjects (p<0.05). H pylori positive subjects were more likely to have corpus gastric atrophy than H pylori negative subjects (p<0.001). Among H pylori positive patients, those without erosive oesophagitis or GORD symptoms were significantly more likely to have corpus atrophy than subjects with erosive oesophagitis or GORD symptoms (p<0.05). Among H pylori positive patients, subjects homozygous for the proinflammatory allele IL-1B-511T had a significantly lower risk of erosive oesophagitis (odds ratio (OR) 0.06 (95% confidence interval (CI) 0.006-0.51); p=0.01) and GORD symptoms (OR 0.10 (95% CI 0.01-0.85); p=0.04) compared with those homozygous for the -511C allele, while none of the two other proinflammatory cytokine gene polymorphisms had significant correlations with erosive oesophagitis or GORD symptoms. CONCLUSIONS: A proinflammatory IL-1B genotype is associated with increased risk of atrophy and decreased risk of GORD in H pylori infected subjects in Japan. These data indicate that in some genetically predisposed subjects, H pylori infection may protect against GORD through induction of gastric atrophy.

Alterations in gastric physiology in Helicobacter pylori infection: causes of different diseases or all epiphenomena?

Helicobacter pylori infection exerts variable effects on gastric acid secretion. It may increase acid secretion, decrease acid secretion or produce no overall change. The effect of the infection on acid secretion depends upon the relative extent to which the Helicobacter pylori gastritis affects the antral and body mucosa of the stomach. When there is antral predominant, body-sparing gastritis, there is increased gastrin release and this is accompanied by increased acid secretion. When there is a significant body gastritis, acid secretion is reduced and subjects may be completely achlorhydric. The majority of subjects have both antral gastritis and body gastritis and this results in no overall change in gastric acid secretion. There is now increasing evidence that the alteration which Helicobacter pylori infection exerts upon gastric acid secretion is a pivotal factor in determining the clinical outcome of the infection. Subjects in whom the infection produces acid hypersecretion develop duodenal ulcer disease due to the increased duodenal acid load. In subjects in whom the infection induces marked hypochlorhydria, there is an increased risk of gastric cancer. The hypochlorhydria probably plays an important role in the carcinogenic process as high intragastric pH markedly raises intragastric nitrite levels, profoundly lowers gastric juice ascorbic acid and allows colonization by nitrosating bacteria. The reason for the different functional responses to Helicobacter pylori infection is unclear but may be related to the host's pre-morbid acid secretory status.

Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease.

BACKGROUND & AIMS: The mechanism by which Helicobacter pylori predisposes to duodenal ulcers (DUs) remains unclear. The aim of this study was to investigate the effect of the infection on acid secretion. METHODS: Acid output was examined basally and in response to gastrin-releasing peptide (GRP) and gastrin in healthy volunteers with and without H. pylori infection and in patients with DUs before and after eradication of the infection. RESULTS: Compared with H. pylori-negative healthy volunteers, patients with DUs with H. pylori had the following abnormalities of acid secretion: (1) threefold increase in basal acid output, (2) sixfold increase in acid response to GRP, (3) increased maximal acid response to exogenous gastrin, (4) increased ratio of basal acid output to maximal gastrin-stimulated output, and (5) increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output. All of these abnormalities resolved fully after H. pylori eradication except for increased maximal acid output to gastrin, which was unchanged. Infected healthy volunteers showed a threefold increase in acid response to GRP that resolved after eradication of H. pylori infection. CONCLUSIONS: These disturbances in acid secretion caused by H. pylori infection are consistent with impaired inhibitory control and are likely to be relevant to the mechanism by which the infection predisposes to DU.

The acid response to gastrin distinguishes duodenal ulcer patients from Helicobacter pylori-infected healthy subjects.

BACKGROUND & AIMS: Helicobacter pylori-induced hypergastrinemia is accompanied by increased acid secretion in patients with duodenal ulcer (DU) but not in infected healthy volunteers. The aim of this study was to investigate the mechanism underlying this difference. METHODS: Thirty-four H. pylori-negative and 20 H. pylori-positive healthy volunteers and 15 H. pylori-positive patients with DU were studied. Maximal acid output and sensitivity to gastrin (gastrin concentration required to achieve 50% maximal acid output) were assessed by examining the dose response to gastrin 17. Inhibitory control was tested by comparing the maximal acid response to cholecystokinin octapeptide with that for gastrin 17. RESULTS: Sensitivity to gastrin was similar in patients with DU (median, 69.5 ng.L-1; range, 26.2-142) and H. pylori-negative healthy volunteers (median, 82.2 ng.L-1; range, 17.7-410); H. pylori-positive healthy volunteers were less sensitive than either (164.5 ng.L-1; range, 44.8 to > 3360 ng.L-1). Patients with DU had higher maximal acid output (51.2 mmol.h-1; range, 30.8-73.7 mmol.h-1) than either infected healthy volunteers (37.8 mmol.h-1; range, 0.0-65.0 mmol.h-1; P < 0.04) or uninfected healthy volunteers (35.3 mmol.h-1; range, 21.3-67.3 mmol.h-1; P < 0.002). The maximal acid output in both groups of healthy subjects was similar. The proportion of maximal acid output to gastrin 17 achieved by cholecystokinin was similar in patients with DU (36.6%; range, 21.5%-58.2%) and H. pylori-negative healthy volunteers (28.7%; range, 5.9%-85.8%). CONCLUSIONS: A combination of decreased sensitivity to gastrin in infected healthy volunteers and increased maximal acid secretory capacity in patients with DU underlies their different acid response to H. pylori-induced hypergastrinemia.

Helicobacter pylori infection and chronic gastric acid hyposecretion.

BACKGROUND & AIMS: We have identified a subgroup of Helicobacter pylori-infected subjects with low or absent gastric acid output. The aim of this study was to document the morphological and functional abnormalities in these subjects and to assess the effect of eradicating the infection. METHODS: The 16 hypochlorhydric subjects (6 men) had a mean age of 55 years (range, 36-79 years). They underwent a 14C-urea breath test, H. pylori serology, fasting gastrin, gastric autoantibodies, gastroscopy with antral and body biopsies, and measurement of peak acid output to pentagastrin (PAO(PG)). Their histology was compared with that of age- and sex-matched duodenal ulcer and nonulcer dyspepsia patients (16 each). H. pylori infection was eradicated in the hypochlorhydric subjects, and the investigations were repeated 6 months later. RESULTS: Compared with controls, the hypochlorhydric subjects had less dense H. pylori colonization, body-predominant colonization and gastritis, and increased prevalence of body atrophy and intestinal metaplasia. Median PAO(PG) before eradication in the hypochlorhydric subjects was 1.1 mmol/h and increased to 12.6 mmol/h after eradication (P < 0.001), with no significant change in body atrophy or intestinal metaplasia. CONCLUSIONS: In some subjects, chronic H. pylori infection produces a body-predominant gastritis and profound suppression of gastric acid secretion that is partially reversible with eradication therapy.

Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori.

BACKGROUND & AIMS: Helicobacter pylori is believed to predispose to gastric cancer by inducing gastric atrophy and hypochlorhydria. First-degree relatives of patients with gastric cancer have an increased risk of developing gastric cancer. The aim of this study was to determine the prevalence of atrophy and hypochlorhydria and their association with H. pylori infection in first-degree relatives of patients with gastric cancer. METHODS: H. pylori status, gastric secretory function, and gastric histology were studied in 100 first-degree relatives of patients with noncardia gastric cancer and compared with those of controls with no family history of this cancer. RESULTS: Compared with healthy controls, relatives of patients with gastric cancer had a higher prevalence of hypochlorhydria (27% vs. 3%) but a similar prevalence of H. pylori infection (63% vs. 64%). Relatives of cancer patients also had a higher prevalence of atrophy (34%) than patients with nonulcer dyspepsia (5%) matched for H. pylori prevalence. Among the relatives of cancer patients, the prevalence of atrophy and hypochlorhydria was increased only in those with evidence of H. pylori infection, was greater in relatives of patients with familial cancer than in relatives of sporadic cancer index patients, and increased with age. Eradication of H. pylori infection produced resolution of the gastric inflammation in each subject and resolution of hypochlorhydria and atrophy in 50% of the subjects. CONCLUSIONS: Relatives of patients with gastric cancer have an increased prevalence of precancerous gastric abnormalities, but this increase is confined to those with H. pylori infection. Consequently, prophylactic eradication of the infection should be offered to such subjects.