GIS20 Helicobacter Pylori

Question 1

H. pylori bacteriology

Answer 1

• Gram -ve
• Spiral-shaped
• 4-6 unipolar flagella
• ***Microaerophilic (5% oxygen)
• strongly ***Urease +ve (others: Phospholipase, Catalase, Mucinase etc. —> weakens mucosa)
• survives in acid pH only in presence of ***urea
• interface between mucus and gastric epithelial surface
• human: only significant natural reservoir
• infection mainly acquired during ***childhood
• ***Silver stain: Warthin-starry stain
• class 1 carcinogen

Question 2

Transmission

Answer 2

• Person-to-person via Faeco-oral route
• Contaminated endoscope —> nosocomial transmission
• Drinking water / food (milk)

Question 3

Epidemiology

Answer 3

• World-wide, 50-60%
• prevalence in low-income countries higher
• socio-economic status associated

Question 4

Pathology

Answer 4

1. Gastritis always present +/- symptoms
   - mononuclear inflammatory cells (i.e. lymphocytes)
   - neutrophil infiltration
   - variable degree of inflammation: minimal change —> severe dense inflammation / micro-abscess
   - most active in **body (corpus) and **antrum
   - may develop ***Atrophic gastritis

Question 5

Foci of infection

Answer 5

1. Natural niche: Gastric ***antra epithelium
2. Other parts (fundus, body) may also be involved
3. May occur in other foci of peptic ulceration: ***Gastric metaplasia in duodenum
4. Bacteria mainly found in ***Mucus gel layer over gastric epithelium (small no. of bacteria attach to surface of epithelial cells)
   —> invasion of bacteria intracellularly into epithelial cells + lamina propria observed

Question 6

***Virulence factor

Answer 6

1. Colonisation:
   - **Urease
   - **Flagella
   - Adherence
2. Persistence: inaccessibility to immune attack
3. Altered gastric physiology (result of infection and inflammation)
   - **Antral gastritis
   —> ↓ gastric somatostatin levels (less D cells) + ↑ gastrin secretion (inflammation stimulate G cells + ↓ inhibition by D cells)
   —> **high gastric acid secretion from body of stomach
   —> Duodenitis
4. Vacuolating cytotoxin (vacA gene), cytotoxin-associated gene A protein (cagA gene)
   —> tissue injury and carcinogenesis

Question 7

Diseases

Answer 7

1. Chronic Superficial gastritis
   - often asymptomatic
2. Peptic ulcer disease
   - either **Duodenal ulcer / **Gastric ulcer
   - duodenal ulcer:
   —> ***Antral-predominant gastritis
   —> ↑ gastrin, ↓ somatostatin
   —> ↑ acid secretion
3. Chronic Atrophic gastritis —> **Gastric adenocarcinoma
   - body and antrum (non-cardia)
   - **Pan-gastritis + ***Atrophic gastritis (usually chronic)
   - ↓ acid secretion (hypo/achlorhydria) (∵ inflamed body —> cannot produce enough acid) —> ∴ NOT develop duodenal ulcer
   - H. pylori group 1 carcinogen
4. Gastric MALT lymphoma
   - mucosa-associated lymphoid tissue (MALT)-type low grade ***B-cell lymphoma
5. Extra-gastric diseases
   - cardiovascular, respiratory, etc
   - etiology to be established

Question 8

Diagnosis

Answer 8

1. Bacteriological diagnosis
   - Endoscopic gastric mucosal biopsies (transported in sterile saline)
   - ***Microaerophilic culture
   - 50-95% sensitivity
   - problem of sampling error
   * **- essential for Antibiotic susceptibility testing (esp. in patients had treatment failure due to antibiotic resistance)
2. Histopathological diagnosis
   - Endoscopy-based
   - **multiple biopsy samples required (>=2)
   - recognised by characteristic morphology, position, diffuse distribution, presence of inflammation
   - Stains: H+E, **Warthin-Starry, Immunostaining
   * **- essential to Exclude other upper GI pathology
3. Antibody detection (serology)
   - ELISA: chronic infection: elevated IgG, IgA
   - antibody level tends to decrease (to half pre-treatment level by 6 months) after eradication of H. pylori
   - urine / saliva antibody test available
   * **- NOT commonly used for diagnosis, NOT useful for monitoring after therapy
   * **- useful for Epidemiological studies
4. Stool antigen detection tests
   - Enzyme immunoassay (EIA) / immunochromatographic assays (ICA)
   - ICA performed more rapidly in-office, but lower sensitivity
   - EIA: use monoclonal Ab —> better accuracy (comparable to urea breath tests) —> ***Post-treatment monitoring
5. Urease-based tests
   - urease: Urea —> CO2 + NH3
   - **Rapid urease test: use biopsy specimens of gastric mucosa, requires endoscopy
   —> broth containing urea and pH indicator
   —> rapid diagnosis (within 24 hrs)
   —> potential **false-positive reaction from other urease +ve bacteria
   —> detects pH change due to NH3 production

• ***Urea breath tests: use 14C (radioactive) / 13C (non-radioactive)
  —> detects labelled CO2 molecules using mass spectrometry from exhaled air
  —> most current breath tests use 13C

6. Nucleic acid amplification tests
   - PCR of faecal sample, not routinely used

Question 9

Management of H. pylori infection:

Clearance vs Eradication

Answer 9

Clearance: absence of detectable organisms IMMEDIATELY after stopping therapy
Eradication: absence of detectable organisms >= 4 weeks after stopping therapy

In-vitro antibiotic sensitivity =/ clinical efficacy

Question 10

Management of H. pylori infection:

Key agents

Answer 10

1. Tetracycline (30s)
   - acid stable
   - high topical concentration
   - ***CI in children <8 and pregnant women
   - resistance uncommon
2. Amoxicillin (transpeptidase)
   - acid stable
   - more active at neutral pH
   - resistance relatively infrequent
3. Nitroimidazoles (Metronidazole, Tinidazole) (PFOR reduce nitro group: disrupt DNA helical structure —> inhibit DNA synthesis)
   - highly active against H. pylori
   - well absorbed but actively secreted into gastric juice and saliva
   - pH independent antibacterial activity
   - ***prevalence of resistance in HK: overall 29-39% in two local studies, over 70% in some years. Over 70-80% in some countries
4. Clarithromycin (50s)
   - highly active against H. pylori
   - more acid stable and more active than erythromycin
   - key component in many treatment regimens
   - success rates appear to be compromised in recent years due to growing prevalence of clarithromycin resistance
5. Bismuth compounds (promote mucosal defence)
   - ***Topical antimicrobial
   - Disrupts bacterial cell wall integrity —> prevent adhesion to gastric epithelium
   - Inhibit bacterial urease, phospholipase, protease
   - Bismuth subsalicylate, Tripotassium dicitrato bismuthate
   - similar clinical efficacy when used in combination therapy, some differences on in-vitro activity
   - Pylera (Bismuth subcitrate potassium, metronidazole, tetracycline) in the some countries
6. Proton-pump inhibitors
   - Similar efficacies for eradication
   - **Optimise intragastric pH for other antibiotics
   - some direct action on H. pylori
   - when give alone **suppresses but NOT eradicate
7. Potassium-competitive acid blocker
   - Vonoprazan
   - Inhibit proton pump H/K-ATPase
   - replace PPI in triple therapy, may have higher efficacy than PPI
   - not yet registered in HK

Question 11

Indication of eradication therapy

Answer 11

Every individual with evidence of H. pylori irrespective of symptoms and stage of disease

Question 12

Eradication regimens

Answer 12

1. PPI-based Triple therapy
   - PPI + Clarithromycin + Amoxicillin / Metronidazole
   - 10-14 days (higher efficacy than 7 days)
   - antibiotic resistance (esp. clarithromycin): lower eradication rate
2. Bismuth-based Triple therapy
   - Bismuth + Metronidazole + Amoxicillin / Tetracycline
   - most failures: metronidazole resistance —> replace with Clarithromycin / Azithromycin
3. Quadruple therapy / 2nd line / 3rd line therapy
   - PPI + Bismuth + 2 Antibiotics (Tetracycline, Metronidazole / Amoxicillin, Clarithromycin)
   - PPI + 3 Antibiotics (Amoxicillin + Nitroimidazole + Clarithromycin)
   - Levofloxacin / Moxifloxacin-based regimens (when there is resistance to other antibiotics)
   - antibiotic susceptibility testing essential for patients who failed the initial 1st line regimens
4. Sequential therapy
   - 5 days of PPI + Amoxicillin
   —> 5 days of PPI + Clarithromycin + Nitroimidazole
5. Hybrid therapy
   - 14 days of PPI + Amoxicillin
   —> last 7 days addition of Clarithromycin + Nitroimidazole

Question 13

Selection of eradication regimen

Answer 13

1. Efficacy
2. SE
3. Cost
4. Compliance
5. Antibiotic resistance
6. Adverse drug interactions
   —> Optimal 1st line regimen may vary in different countries due to differences in antibiotic resistance prevalence

Question 14

Follow-up after eradication

Answer 14

1. Urea breath test
2. Lab-based, validated, stool antigen detection assay
3. Serology: NOT useful

Question 15

Recurrence after eradication

Answer 15

Uncommon in developed countries. <1% to >10%