Helicobacter Pylori Infection

A chronic infection of the gastric mucosa caused by Helicobacter pylori, a spiral shaped, urease producing Gram negative bacterium. It is one of the commonest chronic bacterial infections worldwide. It has a causal role in peptic ulcer disease, gastric mucosa associated lymphoid tissue lymphoma, and gastric adenocarcinoma, so identification and eradication of this organism has substantial implications extending well beyond symptomatic relief of dyspepsia.

Pathophysiology

• The organism colonises the gastric mucus layer. It produces urease, which hydrolyses urea to generate ammonia, neutralising local gastric acid and enabling survival in the otherwise hostile acidic gastric environment.
• It also produces a range of virulence factors. Notably, the cytotoxin associated gene A (CagA) protein in more virulent strains is injected directly into gastric epithelial cells and drives chronic inflammation, epithelial changes and an increased risk of the more severe downstream complications.
• Chronic infection produces a persistent gastritis. The pattern of inflammation, antral predominant versus corpus predominant, is influenced by host genetic factors, strain virulence and, importantly, gastric acid output.
• Antral predominant gastritis, with preserved or increased acid secretion, predisposes to duodenal ulceration.
• Corpus predominant gastritis, with reduced acid secretion, predisposes to gastric ulceration and, over a much longer timeframe, gastric atrophy, intestinal metaplasia and adenocarcinoma.

• The large majority of infected individuals remain entirely asymptomatic throughout life, with infection frequently acquired in childhood and persisting for decades without ever producing clinically apparent disease.
• Dyspepsia, including epigastric pain, bloating, early satiety and nausea, occurs in a proportion of infected individuals.
• The relationship between infection and dyspeptic symptoms in the absence of confirmed peptic ulcer disease remains an area of some clinical uncertainty. Symptomatic improvement following eradication is inconsistent in patients without demonstrable ulcer disease.
• Peptic ulcer disease is the most clinically significant direct consequence of infection in a proportion of colonised individuals.
• It presents with epigastric pain, classically food related, though the specific relationship to meals varies between gastric and duodenal ulceration.
• Complicated disease presents with upper gastrointestinal bleeding (haematemesis or melaena) or, less commonly, perforation.
• Gastric mucosa associated lymphoid tissue lymphoma and, over a much longer natural history, gastric adenocarcinoma are the most serious long term complications.
• The lymphoma is a low grade B cell lymphoma arising from the chronic lymphoid infiltration driven by persistent infection.
• Helicobacter pylori is formally classified as a definite (class one) human carcinogen.

• Urea breath testing, using either carbon 13 or carbon 14 labelled urea, is a highly sensitive and specific non invasive test.
• It relies on detection of labelled carbon dioxide in exhaled breath following hydrolysis of the labelled urea by bacterial urease.
• To avoid false negative results, it requires cessation of proton pump inhibitor therapy for at least two weeks and of antibiotics or bismuth containing compounds for at least four weeks before testing.
• Stool antigen testing offers similarly high sensitivity and specificity to breath testing, with the same requirement for prior cessation of proton pump inhibitors and antibiotics before testing, and is a practical and widely used alternative, particularly useful for confirming eradication following treatment.
• Endoscopic biopsy with histological assessment, rapid urease testing (CLO test) on biopsy material, or culture is used where endoscopy is being performed for another clinical indication, such as investigation of alarm symptoms or confirmed peptic ulcer disease.
• Culture is increasingly used specifically to guide antibiotic selection in areas of high resistance or following treatment failure, given rising rates of clarithromycin and metronidazole resistance in many regions.
• Serological antibody testing detects past or current exposure but cannot distinguish active from previously cleared infection.
• It is therefore of limited utility for confirming current infection status or for test of cure.
• It remains useful in specific circumstances, such as recent proton pump inhibitor or antibiotic use, where other test modalities would be unreliable.
• Test of cure uses urea breath testing or stool antigen testing performed at least four weeks after completion of eradication therapy, with the same proton pump inhibitor cessation requirement.
• It is recommended following treatment of confirmed peptic ulcer disease or gastric mucosa associated lymphoid tissue lymphoma, or where eradication failure would carry particular clinical significance.

• Indications for testing and treatment:
  • confirmed peptic ulcer disease (active or past history)
  • gastric mucosa associated lymphoid tissue lymphoma
  • uninvestigated dyspepsia in younger patients without alarm features (as part of a test and treat strategy)
  • long term nonsteroidal anti inflammatory drug or aspirin use, where eradication reduces subsequent ulcer risk
  • a family history of gastric cancer, or specific populations at elevated gastric cancer risk
• Standard triple therapy comprises a proton pump inhibitor (such as omeprazole 20 mg twice daily) combined with amoxicillin 1 g twice daily and clarithromycin 500 mg twice daily, given for seven to fourteen days.
• It has historically been first line treatment, though eradication rates have declined significantly in many regions given rising clarithromycin resistance.
• Local resistance patterns should inform regimen choice wherever data are available.
• Bismuth based quadruple therapy comprises a proton pump inhibitor, bismuth subsalicylate or subcitrate, tetracycline 500 mg four times daily and metronidazole 400 to 500 mg three or four times daily, given for ten to fourteen days.
• It is increasingly used as first line therapy in regions of high clarithromycin resistance, or as second line treatment following failure of clarithromycin based triple therapy.
• Efficacy is generally preserved despite rising resistance to individual component agents when used in this specific four drug combination.
• Concomitant (non bismuth quadruple) therapy, combining a proton pump inhibitor with amoxicillin, clarithromycin and metronidazole (or tinidazole) given together for ten to fourteen days, is a further effective first line alternative, particularly in regions of intermediate clarithromycin resistance.
• Levofloxacin based regimens (proton pump inhibitor with amoxicillin and levofloxacin 500 mg once daily) are generally reserved for second or third line treatment following failure of initial therapy, given concerns regarding fluoroquinolone resistance and the desire to preserve this antibiotic class where possible.
• Treatment failure warrants culture guided therapy where feasible given rising and geographically variable antimicrobial resistance, with careful attention to confirming genuine adherence to the prior treatment course before assuming true antimicrobial resistance as the explanation for failure.
• Proton pump inhibitor therapy is generally continued for a further period beyond completion of the eradication antibiotic course in patients with confirmed peptic ulcer disease, to support ongoing ulcer healing.
• The specific duration is guided by ulcer size, location and any associated complications such as bleeding.
• Screening and treatment of household or close contacts is not routinely recommended, given the generally low rate of person to person transmission in resource rich settings once established colonisation has occurred within an individual.
• Family based approaches to screening and treatment are used in some high prevalence settings, particularly relevant to gastric cancer prevention strategies at a population level.