A bacterium now known to be the cause of most peptic ulcers as well as a factor in stomach cancer. The infection is probably acquired during childhood through person-to-person spread. There is an extremely high worldwide incidence of Helicobacter Pylori infection, with higher rates in developing countries. Of those infected, only about 15 per cent develop peptic ulcer disease, although 95 per cent of people with duodenal ulcers are found to be infected with Helicobacter Pylori. The bacterium is thought to damage the mucus-producing layer of the stomach and duodenum, bringing gastric acid into contact with the linings of these structures and cause ulceration.
Peptic Ulcers and Helicobacter Pylori in more detail
Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin are the most important causes of peptic ulcer disease. Cigarette smoking also increases the risk, but—although often alleged—there is little evidence to implicate psychological stress. Zollinger–Ellison syndrome, which consists of a gastrin-secreting islet cell tumour (gastrinoma) leading to marked hypergastrinemia, is a rare cause of recurrent peptic ulceration.
Peptic ulcer disease is characterized by a history of waxing and waning symptoms of localized, dull, aching pain in the upper abdomen. Bleeding is the most common complication. Free perforation of the stomach or duodenum into the peritoneal cavity is an uncommon but serious complication.
The diagnosis of peptic ulcer disease is made by endoscopy, which can (1) confirm the diagnosis of peptic ulcer; (2) offer an opportunity for biopsy of gastric ulcers, which may be malignant; and (3) reveal important prognostic indicators in patients with bleeding ulcers (Forrest classification: grade I ulcers are those with active bleeding; grade II have signs of recent bleeding; grade III have a clean base).
A single daily dose of a proton pump inhibitor gives quick relief of symptom and effective healing of peptic ulcers in 4 to 6 weeks. These drugs are more effective than misoprostol and H2-receptor antagonists in healing ulcers, as well as in preventing further peptic ulcerations and erosions.
The management of patients with upper gastrointestinal haemorrhage requires a multidisciplinary medical and surgical approach. Upper gastrointestinal bleeding stops spontaneously in about 80 to 85% of patients, but the remaining 15 to 20% continue to bleed or develop recurrent bleeding, and these patients constitute a high-risk group with substantially increased morbidity and mortality. Early risk stratification based on clinical and endoscopic criteria allows delivery of appropriate care, with endoscopic intervention (endoscopic injection, thermal coagulation, or mechanical haemostasis, i.e. clipping or banding) now widely accepted as the first line of therapy. This should be applied to actively bleeding ulcers or ulcers covered with an adherent clot to reduce both recurrent bleeding and the need for surgical intervention, and be followed by administration of a high dose of intravenous proton pump inhibitor to further reduce recurrent bleeding.
Treatment of H. pylori is a cure for peptic ulcer disease in most patients with the condition. Many antimicrobials can be effective, but successful cure usually requires at least two antimicrobial agents, with the most popular triple therapy combining a proton pump inhibitor with any two of amoxicillin, metronidazole, and clarithromycin for 7 to 14 days. Eradication of H. pylori can be confirmed by either urea breath test, stool antigen test, or biopsy urease test, which should be done at least 4 weeks after finishing the anti-helicobacter regimen and discontinuation of the proton pump inhibitor for at least 2 weeks.
Eradication of H. pylori infection, avoidance of high-dose NSAIDs or aspirin, and the maintenance use of proton pump inhibitors in high-risk individuals are the best ways to prevent recurrence of ulcer and ulcer complications.
Helicobacter Pylori in great detail
Duodenal bicarbonate secretion
Patients with duodenal ulcer are found to have impaired bicarbonate secretion in the proximal duodenum in face of influx of gastric acid. This impaired response is reversed by the eradication of H. pylori. The mechanism by which H. pylori hampers duodenal bicarbonate secretion is not understood. One proposed mechanism is that nitric oxide synthase activity in the duodenum interferes with bicarbonate secretion.
Since the discovery of H. pylori in the stomach of patients with gastritis and peptic ulcer, this bacteria has been reported in approximately 90% of cases of duodenal ulcer and 60% of cases of gastric ulcer. H. pylori is a slow-growing, microaerophilic, highly motile, Gram-negative spiral organism aetiologically linked to gastritis, peptic ulcer disease, gastric lymphoma, and adenocarcinoma of the stomach. H. pylori infection has a long latent period before symptomatic disease appears. H. pylori is tropic for gastric epithelium (i.e. stomach and areas of gastric metaplasia outside the stomach) and is found either attaching to the surface epithelium through a pedestal or dwelling within the mucous coating on the surface of gastric epithelium. A very small proportion of organisms can be found intracellularly, but the significance of this in relation to the inflammatory response and evasion of antimicrobial therapy is still under investigation. H. pylori infection elicits robust chronic active inflammatory and immune responses that continue throughout life. H. pylori produces abundant amount of urease, which is important for its colonization and survival in the stomach.
H. pylori infection is primarily acquired in childhood, such that the prevalence at the age of 20 approximates the prevalence of that birth cohort throughout life. Acquisition during adulthood is rare, with estimates ranging from 0.3 to 0.5% per year, and recurrence of infection after successful eradication is therefore uncommon. The primary mode of transmission is person to person, probably via a gastro-oral route (through vomitus) or oro-oral route (through contamination of saliva). There are links between the bacterial genotype, its virulence factor, and the development of gastroduodenal disease. CagA, a 120- to 140-kDa highly antigenic protein, is encoded by the cagA gene as part of the cag pathogenicity island. In Western countries 60 to 80% of H. pylori express CagA, compared to 90% of isolates from Asian patients. The presence of the cag pathogenicity island is associated with a more prominent inflammatory tissue response than is seen with strains lacking this virulence factor. This increase in inflammation is associated with an increased risk of developing of peptic ulcer disease and adenocarcinoma of the stomach. The cag pathogenicity island encodes a type IV secretory apparatus that injects CagA and possibly other bacterial proteins into mammalian cells. CagA undergoes phosphorylation in the cell and is responsible for the changes in actin polymerization seen in the infected cell, resulting in conformational change. Besides cytoskeletal changes, CagA also enhances inflammatory response which is mediated through NF-κB. Attachment of H. pylori to the cell is required for cagA-positive H. pylori to elicit an interleukin-8 (IL-8) response in the gastrointestinal epithelium triggering gastritis. Beside CagA, approximately 50% of H. pylori strains produce a protein that induces vacuole formation in eukaryotic cells. This protein, which is called VacA, has been purified and the gene vacA has bee cloned. The vacA gene has two families of alleles of the middle region (m1, m2) and at least three families of alleles of the signal sequence (s1a, s1b, s2). The vacA genotype s1 is strongly, but not exclusively, associated with the cagA gene. So far, studies have not found an important role for VacA in relation to histological findings, or risk of H. pylori-related disease. The function of VacA remains unclear.
Despite the establishment of a strong association between H. pylori infection and peptic ulcer disease, it is still unclear why some patients develop duodenal ulcer and others gastric ulcer. McColl and El-Omar proposed an intriguing paradigm . In patients with duodenal ulcer, H. pylori colonizes mainly the antrum. The antral-predominant gastritis stimulates production of gastrin-releasing peptide, triggering secretion of gastrin leading to excessive output of gastric acid. Profuse amount of acid flooding in the duodenum leads to gastric metaplasia, which allows colonization of H. pylori in the duodenum. This sets up an intense inflammation in the duodenum, further weakening mucosal protection and eventually developing into duodenal ulcer. On the other hand, in patients with gastric ulcer, H. pylori is often found throughout the entire body of the stomach, leading to diffuse gastritis. The intense inflammation in the body of stomach tends to reduce gastric acid secretion as a result of glandular atrophy. In these patients other bacterial virulence factors come into play, leading to development of either gastric ulcer or adenocarcinoma in the distal stomach. Although this schema is probably oversimplified, it provides a broad-brush picture explaining how an infection can induce two distinctly different diseases.
The ultimate proof of causal relationship between H. pylori and peptic ulcer disease comes from interventional studies. If peptic ulcer disease is merely a result of altered gastric physiology in bacterial infection, eradication of H. pylori in the stomach and duodenum should rectify the physiological change and cure the disease. And, if re-infection with H. pylori is rare, peptic ulcer disease should not recur. Indeed, this has been proved in clinical trials. In a study that randomized duodenal ulcer patients to receive either 1-week bismuth triple therapy or bismuth triple therapy plus 4-week therapy with proton pump inhibitor, ulcers healed in 90 to 95% of cases with or without acid suppressive therapy. Similarly, when non-NSAID-related gastric ulcer was treated by 1-week bismuth triple therapy or 4-weeks proton pump inhibitor therapy, ulcer healing was higher with anti-Helicobacter therapy. More importantly, ulcer recurrence was much lower after patients received anti-Helicobacter therapy with successful eradication than with a full course of proton pump inhibitor. Studies have also shown that peptic ulcer bleeding and bowel perforation does not recur, obviating the need for acid-reduction surgery.
Treatment of Helicobacter pylori infection
Treatment of H. pylori is a cure for peptic ulcer disease in most patients. H. pylori is susceptible to many different antimicrobials and a variety of combinations have been used successfully. Antimicrobials that have proved effective include amoxicillin, metronidazole, tetracycline, clarithromycin, and furazolidone. Other less commonly used antimicrobials include rifabutin and several fluoroquinolones. Successful cure of infection usually requires two antimicrobial agents. Cure rates with single antimicrobial agents are poor, ranging from 0 to 35%, and monotherapy is also associated with the rapid development of antibiotic resistance. It is therefore not recommended for H. pylori infections. In principle, only those regimens that give high cure rates (>90%) should be used as first line therapy. Generally, higher doses and longer durations provide better results. Antibiotic resistance leads to reduced efficacy of therapy. The antimicrobial resistance pattern of H. pylori should be monitored and made known in each locality. The patient’s compliance with therapy is very important for successful cure of the infection, so regimens should be simple and with few side effects that might affect compliance.
Treatment regimens for H. pylori infection are classified by the number of antibiotics and adjunctive agents employed. Dual therapies were the first therapies to be introduced for H. pylori. Because of low cure rates and a high frequency of clarithromycin resistance among the treatment failures, dual therapies with a proton pump inhibitor and clarithromycin or amoxicillin, or ranitidine and bismuth citrate with clarithromycin, are no longer recommended. Triple therapy with either bismuth or a proton pump inhibitor combined with two antibiotics is now the most widely used regimen. Ranitidine bismuth citrate may be substituted for bismuth or a proton pump inhibitor, but in many countries this drug is not available. Therapy with metronidazole, tetracycline, and bismuth (‘traditional’ triple therapy) produces very good cure rates, especially with organisms sensitive to metronidazole. However, the side effects of metronidazole may be prohibitive in some patients. Substitution of clarithromycin for metronidazole gives similar results. Amoxicillin should be substituted for tetracycline in children to avoid staining of teeth. The most popular triple therapy combines a proton pump inhibitor with any two of these three antimicrobials: amoxicillin, metronidazole, and clarithromycin. The triple therapy described above is often enough unless the organism being treated is resistant to clarithromycin or metronidazole.
The most effective regimens to cure H. pylori infection are combinations of two antibiotics and adjunctive agents taken for 7 to 14 days. See table below:
|Table 1 Recommended first-line regimens to treat Helicobacter pylori|
|Adjuvant||Antimicrobial 1||Antimicrobial 2||Duration of therapy (days)|
|Proton pump inhibitor twice daily||Clarithromycin twice daily||Amoxicillin twice daily or metronidazole twice daily||7–14|
|Ranitidine bismuth citrate twice daily||Clarithromycin twice daily||Amoxicillin twice daily or metronidazole twice daily||7–14|
|Bismuth four times daily||Tetracycline four times daily||Metronidazole three times daily||7–14|
Although regimens composed of two antibiotics with a proton pump inhibitor are expensive, they are easy to take and have few major side effects. Unless a patient has taken clarithromycin previously, one of the two regimens containing this antibiotic, with an additional antimicrobial plus a proton pump inhibitor, is recommended. The most effective and best-tolerated combination seems to be a twice daily combination of a proton pump inhibitor with clarithromycin 500 mg twice daily plus 1000 mg of amoxicillin (PPI +AC) or 500 mg of metronidazole (PPI +MC). The choice of antibiotic should be determined by the local antibiotic resistance pattern and the history of treatment received by the patient.
Eradication of H. pylori can be confirmed by urea breath test, stool antigen test, or biopsy urease test. In order to differentiate temporary suppression of H. pylori from successful eradication, these tests should be done at least 4 weeks after finishing the anti-Helicobacter regimens and discontinuation of proton pump inhibitor for at least 2 weeks.
Patients who fail to respond to these first line therapies should be considered for repeat proton pump inhibitor-based therapy switching between clarithromycin and metronidazole. As clarithromycin resistance readily developed after exposure, repeating the same regimen with clarithromycin is usually futile. A longer treatment duration such as 2 to 4 weeks is desirable to ensure optimal antimicrobial activity. The other option is to use a quadruple therapy combining proton pump inhibitors twice daily, bismuth salt four times daily, tetracycline 500 mg four times daily and metronidzole 500 mg three times daily. This is a more complicated regimen, with significant side effects. Patient compliance is a main determining factor for the success of therapy. In recent years, levofloxacin 250 mg twice daily and rifabutin 150 to 300 mg daily in combination with a proton pump inhibitor and amoxicillin has been advocated for multidrug resistant H. pylori.
Prevention of NSAID-associated ulcer
NSAID-associated ulcer and ulcer complications are more commonly reported in high-risk individuals, i.e. older people and those with history of peptic ulcer disease or chronic medical illness. Concomitant use of NSAIDs with aspirin, anticoagulants or corticosteroid also increases the risk of bleeding from peptic ulcers. Special caution has to be exercised before prescribing NSAIDs to these patients.
Various prophylactic strategies to reduce gastroduodenal injury by NSIADs have been investigated. These include concurrent treatment with H2-receptor antagonist, misoprostol, proton pump inhibitor, and substitution of conventional NSAIDs by COX-2 selective inhibitors. Systematic review pooling over 30 randomized controlled clinical trials of misoprostol, H2-receptor antagonist, or proton pump inhibitor for the prevention of gastroduodenal ulcer showed that these drugs have different efficacy. H2-Receptor antagonists reduce the risk of duodenal ulcer, but not not of gastric ulcer, except at very high dose. Misoprostol at 80 µg per day can reduce ulcer and ulcer complication but its side effects are significant. Proton pump inhibitors can reduce the risk of both duodenal and gastric ulcers associated with NSAIDs and they are much better tolerated than misoprostol.
The interaction between H. pylori and NSAIDs in the development of peptic ulcer disease is a complex. Clinical studies reported by different investigators have yielded conflicting results. Part of the confusion stems from the recruitment of different patient groups and use of different outcome measurement. Meta-analysis of 16 studies showed that H. pylori infection and NSAID use increase the risk of ulcer bleeding by 1.8-fold and 4.8-fold respectively. The risk of ulcer bleeding increases to around sixfold when both factors are present. This implies that NSAIDs and H. pylori are independent but additive risk factors for ulcer development. H. pylori-infected individuals taking NSAIDs will have an increased risk of peptic ulcer and ulcer complications. If a patient known to have H. pylori infection requires an NSAIDs, eradicating H. pylori before using the NSAID may substantially reduce the risk of peptic ulcer disease. However, simply curing H. pylori infection may not be sufficient to protect the stomach and duodenum from ulcer formation in high-risk individuals. In elderly patients with history of ulcer complication, concomitant use of a proton pump inhibitor is warranted. In these patients, even the use of COX-2 selective inhibitors is not entirely safe. The risk of recurrent bleeding with celecoxib is comparable to the use of diclofenac combined with omeprazole, according to one study. In patients with a history of ulcer bleeding, a combination of COX-2 selective inhibitors with a proton pump inhibitor offers the best safety profile for the gastrointestinal tract. See table below:
|Table 2 Recommendations for reducing the risk of ulcer and ulcer complications in high-risk patients (NSAID and aspirin users)|
|Strategies||NSAID users||Aspirin users|
|Choice of medication||Choose less ulcerogenic NSIAD (e.g. ibuprofen) or short-term COX-2 selective inhibitors||Use low-dose aspirin (80–100 mg/day)|
|H. pylori infection||Eradicate H. pylori infection with proton pump inhibitor triple therapy||Eradicate H. pylori infection with proton pump inhibitor triple therapy|
|Concomitant medication||Avoid combining with aspirin, anticoagulants, and steroid||Avoid combining with NSAID, clopidogrel, COX-2 selective inhibitors, anticoagulant, and steroid|
|Ulcer-preventing drugs||Proton pump inhibitor or high-dose H2-receptor antagonist in high-risk individuals||Proton pump inhibitors in high-risk individuals|
Areas of uncertainty and future development
We have come a long way in the last two decades in the understanding of pathogenesis of peptic ulcer disease and its management. Substantial improvements have been made in preventing recurrent disease and in the treatment of its associated complications. There are, however, areas of uncertainty and room for future improvement.
Although H. pylori has been identified as the major cause of peptic ulcer disease in individuals who do note use NSAIDs or aspirin, it is still not clear why only a relatively small proportion of infected subjects develop peptic ulcer disease. Bacterial factors (other than the cag pathogenesity island) and host factors (other than IL-1b polymorphism) need further studies to elucidate the difference in outcome. With rapid emergence of antimicrobial resistance in H. pylori, cure cannot be assumed without confirmation. An effective second-line therapy is still much needed.