The significance of H. pylori eradication in NSAIDs ulcer

The significance of H. pylori eradication for NSAIDs induced gastroduodenal ulcer has not been clarified. NSAIDs and H. pylori infection are independent causal factors for gastroduodenal mucosal injuries. However, the interaction between these two factors is complicated. H. pylori eradication can reduce the risk of NSAIDs induced ulcer in NSAIDs naive patients. However, H. pylori eradication is not recommended in NSAIDs user because of no ulcer suppression and ulcer healing delay. In prevention of NSAIDs induced ulcer recurrence, H. pylori eradication plus PPI treatment is necessary.     

Current state and measures of NSAIDs induced ulcer

In recent years, the incidence of Helicobacter pylori (H. pylori) infection has been decreasing and the incidence of peptic ulcer and bleeding ulcer induced by NSAIDs, especially low-dose aspirin (LDA), have been increasing. PPI and PG are useful for treatment and prevention of ulcers in patients receiving continuous administration of NSAIDs and/or LDA. H. pylori eradication is effective if performed before the start of NSAIDs administration, but a beneficial effect of H. pylori eradication performed during NSAIDs treatment cannot be expected. The incidence of ulcers is lower when administering COX-2-selective inhibitor than when administering non-selective NSAIDs, but attention must be given to cardiovascular events as side effects when administering COX-2-selective inhibitor.     

Peptic ulcer recurrence after successful eradication of Helicobacter pylori--clinical characteristics and management

Peptic ulcer recurrence after successful eradication of Helicobacter pylori(H. pylori) is not rare. We evaluated the effect of H. pylori eradication on prevention of gastric ulcer recurrence. Ulcer recurrence had occurred in 20 of 256 H. pylori-eradicated patients, and most of ulcer recurrence were found within 1 year after eradication. NSAIDs and psychological stress, but not sex, smoking habit, drinking habit, and past history of ulcer, seem to be associated with ulcer recurrence. Intractable ulcers after the eradication of H. pylori frequently recurred. Some recurrent ulcers were refractory to treatment with H2-receptor antagonists or proton pump inhibitors. The mechanism(s) by which healed ulcers recur after successful eradication of H. pylori remains unclear.     

Guidelines for the management of Helicobacter pylori--Maastricht III-2005 and Japanese guidelines

The guidelines on the management of Helicobacter pylori were updated at the European Helicobacter study group third Maastricht consensus conference in March 2005. Especially, this conference emphasis on the management of non ulcer dyspepsia, GERD, and the patients who use non steroidal anti-inflammatory drug. Eradication of H. pylori is recommended in patients with peptic ulcer, low grade MALT lymphoma, atrophic gastritis, unexplained iron deficiency anemia, chronic idiopathic thrombocytopenic purpura and first degree relatives of patients with gastric cancer. H. pylori eradication is less effective than proton pomp inhibitor(PPI) treatment in preventing ulcer recurrence in long term NSAIDs users. This meeting also emphasized on the relationship between H. pylori and gastric cancer. The guideline concluded that H. pylori eradication has the potential to reduce the risk of gastric cancer development. Japanese guideline in 2003 does not mention the effect of eradication for prevention of gastric cancer. The H. pylori eradication and new strategy should be desirable for global strategy of gastric cancer prevention.     

Role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users

Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drug (NSAID) are independent risk factors for peptic ulcers and ulcer complications and they have additive or synergistic effects. A meta-analysis showed that the OR for the incidence of peptic ulcer was 61.1 in patients infected with H. pylori and also taking NSAID when compared to patients uninfected with H. pylori and not taking NSAID. H. pylori eradication may prevent NSAID-induced ulcers in NSAID naive patients. In patients receiving long-term NSAID, proton pump inhibitor(PPI) is more effective in the prevention of ulcer recurrence and bleeding. However, H. pylori eradication should be considered in patients receiving long -term PPI maintenance treatment to prevent the development of corpus gastritis and gastric atrophy.     

Prostaglandin derivatives--indication and critical points

After discovery of H. pylori, management of peptic ulcer disease (PUD) is getting much easier. However, four thousands a year still died caused by this disease in Japan. Ten to twenty percent of the non-NSAIDs ulcer could be expected to remain after complete eradication of H. pylori; The number could be still 100,000-200,000 a year in Japan. Furthermore, NSAIDs ulcer would not decrease in number in the post-H. pylori era. Recurrence of ulcer is related to the quality of ulcer healing. Deficiency of prostaglandins(PG) in the mucosa is another main reason than H. pylori infection of poor quality of ulcer healing. Therefore, a PG analogue may be a most reasonable tool for treatment of H. pylori-negative PUD including NSAIDs ulcer, but is often poorly tolerated because of diarrhea and abdominal pain. The mucosal damage caused by NSAIDs is also gastric acid-dependent and so, an H2-receptor antagonist is to some extent effective although the efficacy is far behind of that with a PG-analogue. Recently, a proton-pump inhibitor has been reported to exert the same effect as a PG-analogue in healing of gastroduodenal mucosal damage caused by NSAIDs and the superior effect in preventing recurrence of the damage with better tolerance. This results suggest that strong acid inhibition is highly effective for such damage. Whether such strong acid inhibition causes disturbance of absorption of NSAIDs is not clear, which might result in poor antiinflammatory effect. Elderly patients often have tendency of constipation and less possibility of pregnancy. Therefore, a PG-analogue may be not only safe but also more favorable for such patients.     

Influence of H. pylori infection on upper gastrointestinal damage

H. pylori infection and low-dose aspirin (LDA) are not only independent causal factors of peptic ulcer and gastrointestinal bleeding, they also have synergistic and additive effects. H. pylori infection rate has drastically decreased over the past decade to 34.3% amongst people in their 40's, 28.0% amongst those in their 30's, and 15.7% amongst those in their 20's. Therefore, LDA are expected to become more important factor of peptic ulcer in the near future. The incidence of peptic ulcer induced by LDA was 15.8% (16/101) in authors' hospital. Deep ulcers(more than proper muscularis layer) were only 4 cases, shallow ulcers(submucosal layer) were 12 cases. All deep ulcers were gastric ulcers (3 H. pylori positive, 1 negative), on the other hand shallow ulcers were 8 gastric ulcers (3 H. pylori positive, 5 negative), and 4 duodenal ulcers (1 H. pylori positive, 3 negative). Majority of peptic ulcers induced by LDA were shallow, and independent on H. pylori infection.     

Japanese epidemiologic investigation for non-steroidal anti-inflammatory drugs-induced ulcers

This review summaried epidemiologic investigation for non-steroidal anti-inflammatory drugs (NSAIDs)-induced ulcers to focus on the Japanese evidence. In Japan, national health insurance does not cover procedures that prevent or lower the risk for NSAIDs-induced ulcer. In NSAIDs treatment to patients with risk factors, it is desirable to administer antiulcer agents. However, in Japan, there are no large-scale studies on the efficacy of co-medication such as proton pump inhibitors, prostaglandin analogs (misoprostol) or histamine-H2 receptor antagonists or on the effectiveness of H. pylori eradication or selective COX-2 antagonists. In the future, large-scale clinical studies should be conducted to accumulate high quality evidence including cost-effectiveness and overall safety including cardiovascular events, because Japanese differ from Westerners in several genetical or acquired factors.     

Ulcers and gastritis

This article reviews recently published reports on ulcers and gastritis. Helicobacter pylori is known to be an important pathogen involved in gastroduodenal inflammation and peptic ulcers. Conventional endoscopy is of limited usefulness in the evaluation of gastritis, but magnifying endoscopy is evidently helpful in the diagnosis of chronic atrophic gastritis, intestinal metaplasia, and H. pylori infection. A significant reduction in the incidence of refractory ulcers and the prevalence of H. pylori infection in patients with peptic ulcer disease followed the introduction of H. pylori eradication treatment. Chronic H. pylori infection is associated with gastric cancer, and the effect of H. pylori eradication on the prevention of gastric cancer is an important issue that is still a matter of controversy. Endoscopic hemostasis and intravenous proton-pump inhibitor (PPI) infusion represent a widely accepted approach to the treatment of peptic ulcer bleeding. In clinical practice, it is important to prevent recurrent bleeding and to treat patients who do not respond to endoscopic therapy or PPI treatment. Laparoscopic repair for peptic ulcer perforations, with postoperative eradication treatment, has gradually met with acceptance in patients with H. pylori infection. H. pylori infection and its treatment continue to be interesting problems in this field.     

Pathologic condition and prognosis of NSAids ulcer

Recently, H. pylori infection rate has decreased and non-steroidal anti-inflammatory drugs(NSAIDs including aspirin) induced ulcers have increased more and more with aging in Japan. Pathological and clinical conditions of NSAIDs ulcer are different from that of H. pylori-related peptic ulcer. In other words, main pathologic condition of NSAIDs ulcer is not only gastric acid secretion but also destruction of defense mechanisms of upper gastrointestinal mucosa, because NSAIDs inhibit both cyclooxygenase (COX)-1 and COX-2 which block production of prostaglandins, consequently resulting in impairing gastroduodenal protective factors. Moreover, it is not rare that NSAIDs ulcer has serious complications such as bleeding and/or perforation. These should be paid attention in NSAIDs users in routine practice.     

Prevention and treatment of gastro-duodenal ulcers in elderly--from theory-based toward evidence-based

Aging is one of the major risk factors for development of gastroduodenal ulcers, probably reflecting increased incidence of H. pylori infection and age-dependent decreases in mucosal blood flow, prostaglandin synthesis, etc. Increased risks for other systemic disorders such as cardiovascular attacks and increased use of drugs such as NSAIDs also play important roles in ulcer susceptibility in the elderly. Recent clinical evidences clearly show that certain anti-ulcer agents(misoprostol, proton pump inhibitors and an H2-receptor antagonist in a high-dose) are effective in prevention and treatment of NSAIDs-ulcers. Interestingly, efficiency of these anti-ulcer drugs significantly changes depending on age and history of NSAIDs ulcers and cardiovascular disorders. For an example, prevention with misoprostol is significantly efficient in the elderly with ulcer history. Thus, ulcer prevention and treatment should be planned in a tailor-made manner in future clinical practice in the elderly.     

Position of NSAIDs in causal factors of peptic ulcer

The cause of peptic ulcer is classified into five categories; infectious, drug-induced, hyperacidic, secondary, and idiopathic. Among these factors, H. pylori infection and non-steroidal anti-inflammatory drugs including aspirin (NSAIDs) are most important for development of gastroduodenal ulcer. More than 95 percent of gastroduodenal ulcers are associated with H. pylori or NSAIDs. Therefore, the frequency of non-H. pylori non-NSAIDs ulcer is very low. NSAIDs have the effect to inhibit synthesis of cyclooxygenase-1 (COX 1) and COX-2. This inhibitory action induces analgesic and anti-inflammatory effects. On the other hand, inhibitory action for COX-1 reduces the production of prostaglandin that is related to protective effect for gastrointestinal mucosa. Its mechanism is able to induce gastroduodenal ulcer. Since the elderly population in Japan is rising, the number of patients who need NSAIDs treatment is expected to increase in near future.     

Helicobacter pylori eradication: role of individual therapy constituents and therapy duration

Treatment of Helicobacter pylori ( H. pylori ) infection has become a key factor in the management of dyspepsia and is the treatment of choice for peptic ulcer disease. First-line eradication regimens combining a proton pump inhibitor (PPI) with clarithromycin and amoxicillin or metronidazole are considered most effective when given for a minimum period of 1 week. Eradication regimens of shorter duration have shown promising results but clinical experience remains limited. Pharmacological properties such as bioavailability and plasma concentrations of individual PPIs differ between individuals but it remains unclear whether these differences impact on the efficacy of eradication therapy and are influenced by renal or hepatic impairment. Bioavailability of PPIs also differs and is impacted on by factors including intragastric pH, metabolic pathways, potency on an mg-for-mg basis and intrinsic antibacterial activity. Several significant pharmacokinetic differences between the PPIs do not seem to influence overall H. pylori eradication rates for first-line triple therapy. However, comparison of factors including pharmacokinetics and treatment duration may prove important in achieving successful eradication with second- and third-line treatments. Based on the factors which influence therapy outcome, we suggest an algorithm for the use of H. pylori eradication therapies.     

Anti-ulcer therapy after eradication of Helicobacter pylori

Helicobacter pylori (H. pylori) infection is the cause of the frequent relapse of peptic ulcer disease. Successful eradication therapy of H. pylori is associated with a decline in the recurrence of peptic ulcer. In this paper, we discussed the significance of anti-ulcer therapy after H. pylori eradication therapy. In patients with duodenal ulcer, maintenance therapy for preventing ulcer recurrence is not necessary because the rate of ulcer recurrence after eradication therapy is very low. However, in patients with gastric ulcer, the rate of ulcer relapse and reflux esophagitis ranges between 5-10% in the Japanese population even after successful eradication therapy; therefore, maintenance therapy for 1 year may be permissible in patients with gastric ulcer even after successful eradication therapy.     

Clinical features and diagnosis of non-steroidal anti-inflammatory drugs induced ulcers of the stomach

Helicobacter pylori (H. pylori) infection and non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin induce serious gastrointestinal ulcer and bleeding. Also both H. pylori infection and NSAIDs or aspirin use independently and significantly increase the risk of peptic ulcer and its complications. Interestingly, it has been reported that no evidence exists that reducing the dose or using modified release formulations such as enteric-coated of aspirin would reduce the incidence of ulcer bleeding. Selective COX-2 inhibitors use shows a low relative risk of ulcer bleeding than NSAIDs. However, when combined with aspirin, the differences between selective COX-2 inhibitors and NSAIDs tend to disappear. NSAIDs/aspirin dominantly develops multiple ulcers from the angulus to the antrum regardless of H. pylori infection. In contrast, the irregular shape of ulcer is more frequently detected in patients taking NSAIDs in comparison with H. pylori-associated ulcer, but the association was not seen in cases taking aspirin. This result indicates that the mechanism of ulcer formation may be different between NSAIDs and aspirin.     

The role of Helicobacter pylori in gastroduodenal disease.

Peptic ulcers are the result of a wide variety of factors, with H. pylori probably being one of the more significant. H. pylori has been most strongly associated with gastritis and duodenal ulcer disease. The relationship of H. pylori to gastric ulcers is less substantial. The eradication of H. pylori can be achieved in the majority of patients with triple antibiotic therapy. However, resistance to metronidazole occurs readily. Eradication of H. pylori can change the course of duodenal ulcer disease by decreasing recurrence rate from 80% to zero. Nonetheless, treatment for H. pylori should only be done in randomized trials at the current time because of the lack of completely effective therapy and the high risks of side effects. The mechanism by which H. pylori influences duodenal ulcer recurrence is unclear. Pathogenic mechanisms of the organism also need to be further elucidated.     

Guidelines in the management of Helicobacter pylori infection in Japan--in comparison with the guidelines published in other countries

Helicobacter pylori(H. pylori) is a causative agent for chronic gastritis and is an important risk factor for peptic ulcers, gastric carcinomas, and gastric MALT lymphomas. In 2000, the Japanese Society for Helicobacter Research published a guideline on the diagnosis and treatment of H. pylori infection for physicians in routine medical practice. In this guideline, H. pylori eradication therapy is recommended in gastric or duodenal ulcer patients. H. pylori eradication is also recommended in gastric MALT lymphoma patients but the guideline says it should be done at specialist institutions. Considering the high prevalence of gastric carcinomas in Japan. H. pylori eradication for the prevention of gastric carcinomas should be discussed urgently.     

Ulcers and gastritis

This article reviews recently published literature regarding ulcers and gastritis. Although endoscopy is the most useful procedure for diagnosis in the upper gastrointestinal tract, complications do occur, and procedure-related costs are significant. The appropriate indication for endoscopy has recently been debated. Helicobacter pylori is known to be an important pathogen involved in gastric and duodenal inflammation. Peptic ulcer disease and severe gastric mucosal injury are caused by virulent strains, and many reports have focused on CagA. Follow-up studies on surveillance endoscopy in patients with peptic ulcer or gastritis report that patients with atrophic gastritis and intestinal metaplasia are at significantly higher risk for gastric cancer. H. pylori eradication sometimes causes gastroduodenal erosion and reflux esophagitis, and the mechanisms involved have been revealed. Proton-pump inhibitors are useful in the treatment of ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), reflux esophagitis, and for preventing rebleeding after endoscopic hemostasis, but the effect of long-term acid suppression on the gastric mucosa is still a matter of debate. H. pylori infection and NSAID intake are both risk factors for peptic ulcer disease, and are important aspects in this field.     

Strategy for peptic ulcer therapy in the era of H. pylori eradication therapy

The Japanese guideline for gastric ulcer therapy published 2003 has adopted a policy that eradication therapy for H. pylori as the first line therapy on ulcer patients with positive H. pylori status. For NSAID-induced gastric ulcer patients, cessation should be considered. In patients who cannot stop NSAIDs, proton-pump inhibitors or prostaglandin drugs is recommended. Similar strategy can be applied for duodenal ulcer patients. Implementation of this basic strategy in daily clinical practice, however, require further efforts to wider recognition of the new guideline for gastric ulcer therapy as well as to solve several barriers caused by discrepant health reimbursement policy.