Helicobacter pylori in Peptic Ulcer: Have Koch's Postulates Been Fulfilled?

This brief review considers whether or not Koch's postulates have been fulfilled for Helicobacter pylori and peptic ulceration. The histological features of peptic ulcer disease in man are active chronic gastritis with antral predominance, duodenal gastric metaplasia and active duodenitis. Other features are hyperpepsinogenaemia, relative postprandial hypergastrinaemia and basal acid hypersecretion. The macroscopic features are duodenal bulb ulceration or lesser curve and antral gastric ulceration.

At present, gastric colonization with H. pylori has been produced in small animal species (rats and mice), but the infection is difficult to establish in immunocompetent animals, and histological gastritis is unconvincing. In larger animals the germ-free pig has been the most reliable model but the gastritis tends to be chronic with little activity.

The best examples of acute infection are in three ‘self-administration’ experiments in humans. In these cases acute gastritis with hypochlorhydria developed which, when it converted to active chronic gastritis, tended to be asymptomatic. Either the circumstances were incompatible with ulceration, or the experiments were not continued for the many years necessary to develop peptic ulceration. It is concluded that only one of the many steps required for the development of peptic ulceration has so far been fulfilled, i.e. the ability of H. pylori to produce histological gastritis in a susceptible host.     

Geographical Pathology of Helicobacter pylori Infection: Is There More than One Gastritis?

Helicobacter pylori is the aetiological agent of chronic gastritis and a major causative factor in duodenal and gastric peptic ulcer disease; a strong association also exists with gastric cancer and primary gastric lymphoma. The prevalence of infection in adults ranges from less than 15% in developed countries to virtually 100% in less developed areas. If H. pylori infection alone was responsible for the development of gastritis, peptic ulcer disease, gastric carcinoma and primary gastric lymphoma, one would expect the frequency of all these conditions to parallel closely the prevalence of H. pylori infection. This is clearly not the case: therefore, genetic, environmental and cultural factors must act in concert with H. pylori to induce different outcomes of the infection.

This paper outlines the geographic approach to the study of disease and discusses the possible application of this methodology to the inquiry into the relationship between H. pylori, atrophic gastritis and gastric cancer. Preliminary results of a study showing great variation in the prevalence of intestinal metaplasia in duodenal ulcer patients from different geographic origin are presented and briefly discussed.     

Helicobacter pylori infection in Finland

Helicobacter pylori causes chronic gastritis worldwide and it is the most important single factor in peptic ulcer disease. Up to half of H. pylori infected individuals develop atrophic gastritis over years and decades. H. pylori infection has also been classified as a class I carcinogen in human gastric cancer. Most infections are obtained in childhood, in Finland mainly before the age of 7 years but the exact transmission routes are not known. The infection shows an age‐dependent pattern, the infection being rare among children but gradually becoming more prevalent among older age groups. As new infections are few in adults and the infection only rarely disappears without effective antimicrobial therapy, the occurrence of the infection in the old actually reflects the prevalence of the infection in their childhood. In developed countries, such as Finland, a rapid decline of H. pylori prevalence rate has been demonstrated. In order to speed up this natural decline of the infection, a unique population based ‘screen and treat’ project was started in Vammala, a semiurban south‐western community in Finland. In this survey, young inhabitants were offered diagnosis and treatment for H. pylori.     

Guidelines for treatment of Helicobacter pylori in the East and West

Infection with Helicobacter pylori remains a major healthcare burden, with persistently high prevalence rates, especially in less-developed countries. H. pylori infection is causally related to non-malignant and malignant gastroduodenal diseases, such as peptic ulcer diseases, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. Current international guidelines recommend a standard triple therapy as first-line therapy, including a proton pump inhibitor and a combination of amoxicillin and clarithromycin. Standard triple therapy has shown a decreasing efficacy over the years. The main reason is the increasing antibiotic resistance, particular to clarithromycin of H. pylori strains. Several new treatment options or modifications of already established regimens have been introduced to overcome treatment failure. In this article, we intend to report the reasons for treatment failure, and furthermore we give an overview of new treatment options as alternatives to the current treatment regimens. Finally, the strategy for the future is considered.     

Enhanced systemic matrix metalloproteinase response in Helicobacter pylori gastritis

Background. Helicobacter pylori causes chronic gastritis, peptic ulcer disease, and is the most important risk factor for non-cardia gastric cancer, and has been shown to upregulate matrix metalloproteinases (MMPs) in infected gastric mucosa. MMPs are proteolytic enzymes regulated by tissue inhibitors of metalloproteinases (TIMPs).

Aims. We set up this study to find out whether H. pylori gastritis induces systemic MMP response.

Methods. Serum samples were collected from patients undergoing gastroscopy; 26 patients had H. pylori gastritis and 18 were H. pylori-negative controls with normal gastric mucosa. Serum MMP levels were analysed by enzyme-linked immunosorbent assay.

Results. Significantly elevated serum levels of collagenase-2 (MMP-8), gelatinase B (MMP-9), neutrophil elastase (NE), and myeloperoxidase (MPO), and reduced serum levels of gelatinase A (MMP-2) and TIMP-1 were demonstrated in patients with H. pylori gastritis as compared to H. pylori-negative controls. No significant differences were shown in serum matrilysin-1 (MMP-7) levels.

Conclusions. For the first time, we show enhanced MMP-8 response in H. pylori infection together with other neutrophil degranulation products (MMP-9, MPO, NE). Elevated circulating neutrophil degranulation product levels in serum of H. pylori-positive patients reflect accelerated proteolysis and oxidative stress, and may contribute to extraintestinal sequelae, such as cardiovascular diseases.     

Helicobacter pylori-infected Japanese monkeys

Conclusion It is possible to establish persistentH. pylori infection in the gastric mucosa of Japanese monkeys and create acute and chronic gastritis similar to that found in humans; persistent infection causes atrophic changes in the gastric mucosa. Japanese monkeys, which age approximately flve times faster than humans, provide a valuable model for investigating the long-term effects ofH. pylori infection on the gastric mucosa and for the study of stages in the development of gastric cancer. H. pylori produces gastritis resulting in both local inflammation and a systemic immune response. Genes have been isolated that code for cytotoxic proteins such as CagA, VacA, and for heat-shock protein. A number of points remain unresolved concerning the pathology ofH. pylori infection, known to be closely related to the recurrence of peptic ulcers. Routes of infection are fecaloral and oral-oral, and humans can be infected from pets.⁵³ Gastroendoscopy can be a source of nosocomial infections. The natural habitat ofH. pylori in humans is limited almost exclusively to the surface layer of the gastric mucosa; it is rarely found in other locations. In the future, we should develop chemotherapeutic methods for curingH. pylori infections and a vaccine for their prevention. The present study was conducted in accordance with Oita Medical University guidelines for animal experimentation.     

HELICOBACTER PYLORI PREVALENCE IN A ROUTINE UPPER GASTROINTESTINAL ENDOSCOPY POPULATION

SUMMARY The presence of Helicobacter pylori (HP) in gastric biopsy specimens of 500 patients referred for routine upper gastrointestinal endoscopy for various abdominal complaints was investigated histologically and microbiologically. HP was detected in 429 of the 500 patients (86%). Antral biopsy specimens revealed gastritis in 457 out of 500 cases (91.4%). In the 43 patients who had normal histological findings, only 3 had HP infection (7%). The prevalence of HP in the patients with gastric and duodenal ulcers was 91%. In 95.6% of the ulcer patients, biopsy specimens showed gastritis. There was a statistically significant rise in the prevalence of HP with age. The correlation between histologic and microbiologic diagnostic methods was good. This study shows that HP positivity and gastritis are common in a routine endoscopy population and that there is a strong association between H. pylori, gastritis and peptic ulcer disease.     

Current management of Helicobacter pylori infections in the elderly

Helicobacter pylori infection is a chronic gastric Gram-negative infection that increases with age worldwide. However, the percentage age of H. pylori-positive elderly patients who are tested and treated for their infection remains very low. It is now demonstrated that H. pylori infection induces a whole cascade of events leading to gastric pathologies, such as peptic ulcer diseases, gastric precancerous lesions and gastric cancer. Recent data also demonstrated that H. pylori chronic infection can play a role in gastric aging, appetite regulation and extradigestive diseases, such as Alzheimer’s disease, in the elderly. The diagnosis of H. pylori infection remains difficult to realize in the very old population, and the urea breath test obtains the best performance in this population. 1-week proton pump inhibitor-based triple therapy regimens are highly effective and well tolerated in elderly patients, and antibiotic resistance remains very low. Low compliance is the main factor related to treatment failure in this population.     

Quantitative detection of secretory immunoglobulin A to Helicobacter pylori in gastric juice: Antibody capture enzyme-linked immunosorbent assay

Helicobacter pylori is a major etiologic agent in gastroduodenal disorders. In this study, immunoglobulin A (IgA) antibodies to H. pylori were estimated in serum and gastric juice specimens from patients with gastritis and peptic ulcers using antibody capture enzyme-linked immunosorbent assays (ACELISAs). The antibody titers of the ACELISAs are independent of the antibody concentration and reflect the ratio of H. pylori-specific IgA to total IgA. The ratio is stable, although the antibody concentration fluctuates in gastric juice. Using the ACELISAs it was possible to evaluate quantitatively not only serum IgA (SR-IgA) antibodies but also secretory IgA (SC-IgA) antibodies in gastric juice. There were significant differences between the patients and control group in the SR-IgA and SC-IgA ACELISAs. Furthermore, the ACELISAs made it possible to compare between SR-IgA antibodies in serum and SC-IgA antibodies in gastric juice. In all patients, the ratios of H. pylori-specific IgA were higher in gastric juice than in serum. These results suggest that H. pylori SC-IgA antibodies are mainly produced by the local immune response in the gastric mucosa. Our studies indicate that ACELISA is well suited for the analysis of local immune response in mucosa. © 1996 Wiley-Liss, Inc.     

What Are the Specific Features of Helicobacter pylori Gastritis in Children?

Children with recurrent abdominal pain and dyspeptic symptoms often present histological gastritis and Helicobacter pylori infection. No specific symptomatology has been found, however, to discriminate H. pylori positive from negative subjects. Certain differences exist in gastritis in paediatric age groups, in comparison with adults. In terms of treatment, children also form a special entity because of the long exposure time of H. pylori infection. This article describes the typical findings of H. pylori gastritis in children and discusses their significance from a clinical point of view.     

Animal models for the study of <Emphasis Type="Italic">Helicobacter</Emphasis>-induced gastric carcinoma

Helicobacter pylori is considered to have a close association with gastric cancer. Many epidemiological studies have shown a strong association between chronic H. pylori infection and subsequent development of gastric carcinoma in humans. To clarify this link more clearly, it is necessary to use this bacterium in experimental studies to develop gastric carcinoma in suitable experimental animals. Persistent H. pylori infection was seen in the Japanese monkey model, and has recently been achieved in the Mongolian gerbil model. In these models, the sequential histopathological changes in the gastric mucosa are very similar to those in humans. The Japanese monkey model showed advances in atrophic change and p53 point mutations in the gastric mucosa during long-term observation. The Mongolian gerbil model demonstrated that H. pylori infection enhances gastric carcinogenesis in combination with known carcinogens such as N-methyl-N-nitrosourea (MNU) and N-methyl-N-nitro-N-nitrosoguanidine (MNNG), and also showed that H. pylori infection alone can result in the development of gastric carcinoma. These important results provide a starting point for further studies to clarify the mechanism of gastric carcinogenesis as a result of H. pylori infection and assist in the planning of eradication therapy to prevent gastric carcinoma.     

Management of Helicobacter pylori infection

Helicobacter pylori is the cause of peptic ulcer, gastric cancer and gastric lymphoma. Diagnosis of H. pylori infection can be made using invasive and noninvasive tests. Invasive tests based on endoscopy, such as histology, are recommended when a gastric malignancy is suspected. Alternatively, noninvasive tests, such as the urea breath test and stool tests are useful for H. pylori diagnosis and follow-up. Triple therapy with either amoxicillin or metronidazole, clarithromycin and proton pump inhibitor given twice daily for 7–14 days is the recommended first-line treatment, after having checked the individual clarithromycin antimicrobial susceptibility. A triple therapy with levofloxacin, amoxicillin and proton pump inhibitor for 10–14 days should be used as second-line treatment, where the strains are susceptible to fluoroquinolone. Alternatively, bismuth-based quadruple therapy is recommended.     

Assessment of systemic matrix metalloproteinase and their regulator response in children with Helicobacter pylori gastritis

Abstract

Background. Helicobacter pylori causes gastritis and is the most important risk factor of peptic ulcer disease and gastric cancer. In chronic adulthood H. pylori infection some matrix metalloproteinases (MMPs), which are proteolytic metalloendopeptidases regulated by tissue inhibitors of metalloproteinases (TIMPs), are upregulated. Our aim was to determine circulating levels of MMPs and their regulators TIMP-1, human neutrophil elastase (HNE) and myeloperoxidase (MPO) in childhood H. pylori infection. Design and methods. Twenty-six H. pylori positive and 34 H. pylori negative children whose H. pylori status was verified by histological examination of gastric biopsies were included. Serum samples were analysed by enzyme-linked immunosorbent assay. Results. Significantly decreased serum levels of TIMP-1 were detected in H. pylori-infected children (median, 97.50 ng/mL) as compared to H. pylori-negative children (median, 118.5 ng/mL, p = 0.003). However, there were no significant differences in serum levels of MMP?2, ?7, ?8, ?9, and their regulators HNE and MPO between H. pylori-positive and -negative children. Conclusions. Differing from the recent findings in adulthood H. pylori infection, only circulating TIMP-1 levels were significantly different between H. pylori-positive and -negative children. Whether this reflects the first sign of a proteolytic cascade later leading to increased levels of MMPs remains to be shown.     

Helicobacter pylori eradication and associated changes in the gastric mucosa

Persistent Helicobacter pylori infection contributes towards the development of chronic gastritis. To clarify the changes in chronic gastritis as a precursor of gastric cancer secondary to H. pylori eradication is an important issue, as it has significant implications for reducing the risk of gastric cancer. Studies published to date, however, are far from consistent with regard to the morphologic changes reported following H. pylori eradication. Of these, some papers reported improvement in gastric atrophy or intestinal metaplasia, versus others reporting no improvement, with the majority of papers published after 2000 reporting improvement in these end points. The inconsistent results concerning the impact of H. pylori eradication on gastric atrophy could be due to the inconsistency of the diagnostic criteria employed for evaluation of the morphology, confounded by the difficulties involved in evaluating atrophic changes in the gastric mucosa. While adherence to the Updated Sydney System available for evaluation of gastritis is primarily required worldwide to ensure consistency in evaluating gastritis, long-term research into the morphologic changes associated with H. pylori eradication is also required to explore strategies for the prevention of gastric cancer with H. pylori eradication.     

Helicobacter pylori in intensive care: why we should be interested

Helicobacter pylori is estimated to infect over 50% of the world's population, the majority of whom are asymptomatic. Although most research to date has focused on local gastroduodenal disease manifestations, the potential impact of H. pylori infection and the associated chronic active inflammation on systemic disease processes is now being explored. This review addresses three aspects of emerging importance regarding H. pylori in intensive care medicine: acute gastric stress ulceration, nosocomial infection, and the potential modulatory effect on the systemic stress response. The role of H. pylori in acute stress ulceration remains uncertain, but it is unlikely to have the same major aetiological role as in peptic ulcer disease. The pathogenesis of both acute stress ulceration and H. pylori gastritis suggest overlapping mechanisms of gastric mucosal damage and H. pylori may augment stress ulceration incidence and severity. Nosocomial infection of both staff and patients with H. pylori has been suggested by serological studies, and increased H. pylori infection has been reported in intensive care staff. This has significant short- and long-term health implications and also raises questions regarding the efficacy and implementation of routine infection control precautions in intensive care. Finally, H. pylori infection has been linked with the pathogenesis of many extra-intestinal diseases, but the evidence is weak and the relationship between H. pylori and systemic diseases remains controversial. However, the potential for H. pylori to modulate systemic disease processes, particularly the systemic stress response in critical illness, is both theoretically plausible and therapeutically tantalising and requires further investigation.     

Indication of H. pylori eradication therapy

In the guideline, for H. pylori the Japanese Society of Helicobacter published diagnosis and treatment in July 2000. Only peptic ulcers and low grade MALT lymphomas are recommended as an indication of H. pylori eradication and other diseases such as atrophic gastritis, post EMR state for early gastric cancer and post-operated stomach due to gastric cancer, hyperplastic polyps and non-ulcer dyspepsia, were not included. In addition, Japanese social security foundation approves only peptic ulcers for indication of H. pylori eradication treatment. However, eradication therapy for atrophic gastritis should be considered in aspect of decreasing gastric cancer risk. Since accumulated epidemiological, experimental and clinical data strongly support its positive correlation with cancer risk, patients in high risk group for gastric cancer should be included for a target eradication therapy. Indication of the treatment should be expanded to histological gastritis caused by H. pylori in our country, where prevalence of gastric cancer is very high.     

Helicobacter pylori Infection in Estonian Population: Is It a Health Problem?

The role of Helicobacter pylori infection In traditionally noncommunicable diseases as chronic gastritis, peptic ulcer and gastric carcinoma became more evident during the first decade of H. pylori studies. To analyse and evaluate the prevalence of H. pylori infection in Estonia as a population health problem, the data of three randomly selected samples of Estonian population aged over 15 years were used. The infection rate assessments in two representative samples of the population (Kambja 157 persons and Kuressaare 224 persons) were based on H. pylori colonization in the gastric mucosa, and in one sample (Karksi-Nula 1467 persons) on seroconversion of H. pylori IgG antibodies. The persons studied were divided into groups according to birth cohorts. The population studies in Estonia showed a high prevalence of H. pylori infection among Estonians: 73% in the Kuressaare sample, 78% in the Kambja sample, and 87% in the Karksi-Nuia sample. From the Kuressaare population sample 38 families with 290 persons were included in a family H. pylori infection study and 92.5% of the persons in these families were found to be H. pylori positive. H. pylori infection was frequent in persons who were born at the beginning of this century as well as in those born after World War II up to 30 years ago. It was concluded that H. pylori infection is common in Estonia, both in random persons and their families. It is probable that the infection rate of H. pylori depends to a great extent on the socioeconomic conditions of this country and that acquisition of H. pylori in Estonia starts at an early age.     

Phosphorylation of<Emphasis Type="Italic">Helicobacter pylori CagA</Emphasis> in patients with gastric ulcer and gastritis

The effects ofHelicobacter pylori infection are strongly associated with chronic gastritis, gastric and duodenal ulcer, gastric cancer, and MALT lymphoma. The microorganism has been classified as a type I carcinogen by the World Health Organization. Varying clinical results fromH. pylori infection are believed due, in part, to differences in virulence among species. Thecag pathogenicity island is a complex of virulent genes and a coding region for the type IV phosphorylated secretion system. Through this system, many virulent gene products or proteins are phosphorylated into the host cells. This study demonstrated the positiveCagA- phosphorylation effect ofH. pylori in patients with chronic gastritis and benign gastric ulcer and revealed significantly different rates ofCagA phosphorylation between these two diseases (P < .05).