H. Pylori

Overview

• Gram-negative bacillus
  • Spiral or helical shaped
  • 4-6 flagella
• Colonizes gastric type mucosa within or beneath the mucus layer
  • Only found in gastric mucosa
    • Needs specific adherence receptors in gastric epithelium
  • Can cause metaplasia in duodenum & hence be present in duodenum
  • Can be present in heterotopic gastric mucosa (Meckel’s)
• Transmission
  • ? Faecal-oral, oral-oral
  • Most people infected during childhood
  • Leads to life-long chronic gastritis
  • Acquisition as an adult is rare
• Primary causative factor in pathogenesis of peptic ulcer disease

Incidence

• 25% of general population infected (higher in developing countries)
  • NB: Only ≈ 10% of people with H pylori develop ulcers - reasons unclear
• M = F

Clinical problems

Gastritis

• Antral gastritis ≈ 100% H.pylori +ve
• Associated with pan-gastritis / chronic atrophic gastritis
• Due to long-term H.pylori

Ulcers

• DU – present in 90%
• GU – present in 75%
  • Other 20-30% are NSAID related
• Small role in non-ulcer dyspepsia

Pathology

• Binding of H. pylori to gastric epithelium is enhanced in pts with blood group O antigen
• Predominates in Gastric Antrum
  • Only in duodenum if gastric metaplasia
  • Can spread more proximal, to the cardia, in patients with low acid output
• Virulence factors
  • Motility due to flagella
  • Release of toxic products causing local tissue injury
  • Induction of local immune response
  • Increased gastrin levels, resulting in increased acid secretion
  • Gastric metaplasia in the duodenum

Virulence Factors

• H.pylori has many factors that enable survival in acidic environments, immune evasion, and host tissue damage
• Bacteria cell surface factors
  • Flagella
    • H. pylori is motile due to 4-6 flagella
    • Can bury itself into mucous layer - protects itself from acid and protects itself from antibiotic contact
  • Adhesins
    • Mediated by adhesins and outer membrane proteins which are specific for gastric mucosa
    • BabA, SabA and OipA
  • Lipopolysaccharide
    • Modified to mimic host antigens, helping evade immune detection and delaying host immune responses.
  • Outer membrane proteins (OMPs)
    • Some OMPs reduce immune recognition and contribute to antibiotic resistance.
• Enzyme production
  • Urease:
    • Breaks down Urea to Ammonia + Bicarbonate
    • Neutralises acid locally causing alkaline micro-environment
    • Allows H. pylori to survive & also ↓acid → ↑ Gastrin secretion
    • Ammonia causes cell damage
  • α Protease
    • Breaks down glycoproteins → Degradation of mucus
  • Mucinase
    • Degrades mucus
  • Phospholipase + Glycoproteins
    • Damage epithelial and mucus cells
• Local cellular
  • CagA (Cytotoxin-associated gene A)
    • Injected into the cytoplasm of gastric epithelial cells via the type IV secretion system.
      • Disrupts cell junctions
      • Induces cytoskeletal changes
      • Promotes inflammation by increasing the production of IL-8
      • Interfers with normal cell proliferation and there contributed to carcinogenesis
  • VacA(Vacuolating cytotoxin A)
    • Function: Forms pores in host cell membranes, leading to:
    • Apoptosis (via mitochondrial dysfunction).
    • Immune suppression (disrupting T-cell function)
    • Effect: Contributes to tissue damage and chronic infection
  • Increased Gastrin
    • Increased gastrin (therefore ↑ acid secretion)
      • Due to
        • Neutralized acid
          • → ↓ Acid in antrum
          • → ↑ Gastrin secreted
        • H. Pylori-induced stimulation of Antral G-cells
          • Due to inflammation
        • Damage to Delta-cells
          • Decreased somatostatin produced

Duodenal Metaplasia

• Two mechanisms of development of DU
• H. pylori migrates from antrum to duodenal cap
  • Associated with high acid output
  • Causes gastric metaplasia of the duodenum
    • Protective
    • Now H. pylori can colonise this area
    • Breakdown of mucosa → Ulcer
• Increased Gastrin
  • Increased acid produced in stomach
  • Increased acid received in duodenum
    • DUs can occur when H pylori is limited to the stomach

H. Pylori and Cancer

• Increased risk 6 x
• See Correa Model
• Probably risk exacerbated by prolonged PPI
  • Enables bacteria to colonize the gastric body and results in atrophic gastritis (more common in pts with H. pylori on prolonged PPI)
  • No study has shown definite increased risk but likely as atrophic gastritis definitely increases risk of gastric cancer
• Related to H. pylori virulence factors:
  • Vaculating cytotoxin antigen (VacA)
  • Cytotoxin-associated gene A antigen (CagA)
• Promote bacteria that produce N-nitroso carcinogens in stomach from nitrite containing foods

MALT

• 85% due to H. pylori
• 75% regress with Rx of H. pylori
  • Thus eradicate before considering chemo
• T-cells are driven by H. pylori antigens
  • Stimulate B cells ⇒ Lymphoma

Testing

• Invasive
  • Histological biopsy – sens 95%- Gold Standard
  • Rapid urease assay (CLO) – detects urease in gastric biopsy – sens 90%/spec 98%
    • Urea (orange) in membrane is converted to ammonia (red) by urease and changes pH which is detected by reagent similar to litmus paper (orange to red)
    • Rapid result in 1 hour but may take up to 24 hours
  • Culture – sens 80%. 3-5 days till dx & expensive
• Non-invasive
  • Serology (ELISA) to detect IgG antibody
    • 90% sensitivity/spec but titre can remain high for up to 12 months after eradication therefore not good to test eradication
  • Carbon-13 Urea breath test
    • Carbon labeled urea is hydrolyzed by H. pylori to CO2 and exhaled – sens/spec = 95%
      • Best performed 4 weeks after eradication as can give false –ve if too early
• Stool antigen testing
  • Monoclonal immunoassay to detect H. pylori antigens. Sens 95%
  • Can test eradication early but false neg may occur so recommended to wait 4 weeks and off PPI for at least 2 weeks

H pylori eradication

• Reduces recurrence to < 2%
• Healing in > 90%
• Can follow local guidelines (BPAC)
• Initially triple therapy for one week
  • PPI, Clarithromycin and either Amoxicillin or metronidazole
    • If has had metronidazole recently, don’t use that
    • If has had macrolide recently, uses PPI, Amoxil and metronidazole
  • If penicillin allergic use PPI, Clarithromycin and Amoxil
  • Consider Bismuth for refractory disease
    • Bismuth quadruple therapy: Bismuth subsalicylate, Metronidazole, Tetracycline and PPI for 14 days
• Retest to ensure eradication if the patient has had a peptic ulcer

Prognosis and Follow-up

• Without eradication
  • Likelihood of DU relapse after 1 month ≈ 45%
  • < 2% if H. pylori eradicated
• Follow-up
  • Need to check eradication
  • Do triple therapy then continue PPI for 2/12 then stop
  • Do faecal Ag test to see if cleared (after 2/52 off PPI)
  • Re-infectivity rate low - 1%