H.pylori peptic ulcer disease pathophysiology
Jump to navigation
Jump to search
For more information on peptic ulcer disease click here.
|
Helicobacter pylori infection Microchapters |
|
Differentiating Helicobacter pylori infection from other Diseases |
|---|
|
Diagnosis |
|
Guideline Recommendation |
|
Treatment |
|
Case Studies |
|
H.pylori peptic ulcer disease pathophysiology On the Web |
|
American Roentgen Ray Society Images of H.pylori peptic ulcer disease pathophysiology |
|
Directions to Hospitals Treating Helicobacter pylori infection |
|
Risk calculators and risk factors for H.pylori peptic ulcer disease pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Yamuna Kondapally, M.B.B.S[3]
Overview
H. pylori and NSAIDs/aspirin remain the two dominant causes of peptic ulcer disease. Although more than half of the world's population is chronically infected, only about 5–20% of infected persons develop an ulcer. Ulcer risk therefore depends on the topography of the chronic gastritis that the organism induces, the host acid-secretory and immune response, and bacterial strain virulence, not on infection alone.[1][2] Antral-predominant gastritis causes acid hypersecretion and duodenal ulcer. Corpus-involving pangastritis causes normal or reduced acid output, mucosal atrophy, and gastric ulcer, and it carries a gastric cancer risk.[3] Among ulcers not caused by NSAIDs, more than 95% of duodenal ulcers and more than 80% of gastric ulcers have historically been H. pylori-associated. Eradication reduces annual ulcer recurrence from 60–100% to under 15%.[4]
Pathophysiology
Mucosal balance
Peptic ulceration reflects an imbalance between aggressive factors and protective factors.
- Aggressive factors are acid and pepsin.
- Protective factors are the mucus–bicarbonate layer, epithelial tight junctions, and prostaglandin-dependent mucosal blood flow and repair.
H. pylori shifts this balance mainly through the pattern of chronic gastritis it induces.[5][3]
Colonization of the gastric niche
- Motility: The organism uses its spiral shape and flagella to penetrate the mucus layer. It resides at the near-neutral epithelial surface, away from luminal acid.
- Urease: Membrane-bound urease hydrolyzes urea to ammonia and bicarbonate. This buffers the bacterial periplasm and lowers local mucus viscosity, which aids motility.
- Adhesins: Three adhesins anchor the organism to gastric epithelium and amplify inflammation:
- BabA, which binds Lewis b antigen
- SabA, which binds sialyl-Lewis x
- OipA
Gastritis topography determines ulcer phenotype
The location and intensity of chronic gastritis dictate whether a duodenal ulcer, a gastric ulcer, or neither develops. The mere presence of the organism does not.[3][2]
| Feature | Antral-predominant gastritis | Pangastritis (corpus involvement) |
|---|---|---|
| Ulcer phenotype | Duodenal ulcer | Gastric ulcer |
| Frequency among infected persons | About 10–15%[1] | |
| Acid output | Increased basal and stimulated acid output | Normal or reduced; some acid secretion is always preserved |
| Key mechanism | Antral somatostatin falls, causing hypergastrinemia, increased histamine release, and acid hypersecretion. Excess acid in the duodenal bulb induces gastric metaplasia, which H. pylori then colonizes. | Corpus inflammation damages acid-secreting mucosa. Ulcers arise at sites of mucosal injury, atrophy, and intestinal metaplasia. |
| Typical site | Duodenal bulb | Lesser curve near the antral–corpus transitional zone |
| Long-term implication | Recurrent duodenal ulcer if the infection is not eradicated | The same atrophy/metaplasia pathway underlies non-cardia gastric cancer |
Antral-predominant gastritis and duodenal ulcer
- Inflammation concentrated in the antrum, with relative sparing of the corpus, disrupts acid regulation.[1][2]
- Antral D-cell number and somatostatin output fall. The G-cell:D-cell and gastrin:somatostatin ratios rise, producing hypergastrinemia.[1][2]
- Without the somatostatin brake, enterochromaffin-like (ECL) cells release more histamine. This drives increased basal and stimulated acid output.[2]
- Patients with duodenal ulcer also have greater parietal cell mass and exaggerated acid responses to gastrin.[2]
- Excess acid delivered to the duodenal bulb promotes gastric metaplasia. H. pylori colonizes these metaplastic islands but not native duodenal epithelium, which produces local active duodenitis and ulceration.[7][3]
- Eradication reverses the gastritis. In duodenal ulcer disease, it restores somatostatin and lowers gastrin expression.[3][1]
Pangastritis and gastric ulcer
- When inflammation involves both corpus and antrum, acid-secreting mucosa is damaged and acid output is normal or reduced.[5][3]
- Gastric ulcers arise where injury, atrophy, and intestinal metaplasia are maximal. This is classically the antral–corpus transitional zone along the lesser curve.[3][2]
- H. pylori also directly impairs epithelial tight junctions. This increases paracellular leak of luminal contents and perpetuates inflammation.[3]
Bacterial virulence factors
Strain virulence helps explain why only a minority of infected persons ulcerate.
| Factor | Mechanism | Clinical association |
|---|---|---|
| cag pathogenicity island / CagA | Encodes a type IV secretion system that injects the oncoprotein CagA into epithelial cells. CagA perturbs cytoskeletal and proinflammatory signaling (including SHP-2). Translocated peptidoglycan activates the NOD1 and ALPK1–TIFA innate pathways. | cag-positive strains cause more intense inflammation, higher mucosal IL-8, and greater ulcer and cancer risk than cag-negative strains.[6][8] |
| Vacuolating cytotoxin (VacA) | vacA is present in nearly all strains. Toxin activity depends on allelic variation in the signal (s), intermediate (i), and middle (m) regions. The s1, i1, and m1 alleles encode more active pore-forming toxin; s2/i2/m2 strains are comparatively avirulent. | In a matched case-control study of a Belgian population, vacA s1 and i1 were the strongest markers of duodenal-ulcer strains. They were associated with duodenal ulcer, whereas cagA status was not.[9] |
| Adhesins (BabA, SabA, OipA) | Mediate epithelial attachment and intensify the inflammatory response. | Associations with ulcer disease vary by population.[6][8] |
- Virulence-genotype associations are geographically inconsistent. cagA-positive strains dominate in many Asian populations; in a large Thai cohort, cagA rather than vacA was the principal marker associated with peptic ulcer.[10][8]
- Routine cagA/vacA genotyping is not standard of care. It remains a research and risk-stratification tool.[8]
Host immune response
- Infection triggers an initial innate neutrophilic influx. This is followed by a Th1/Th17-polarized adaptive response with IL-8, IL-6, IL-1β, IL-12, TNF, and IFN-γ, counterbalanced by regulatory T cells.[6][1]
- The response is vigorous but fails to clear the organism, so chronic inflammation persists and drives mucosal injury.[6]
- Functional cytokine-gene polymorphisms modulate the gastritis pattern and disease risk. They are not yet clinically actionable.[6][1]
Clinical implications of the pathophysiology
- Phenotype mapping: Antral-predominant gastritis with acid hypersecretion produces duodenal ulcer. Pangastritis with atrophy and normal or low acid produces gastric ulcer and carries gastric cancer risk.[3]
- Disease modification by eradication: Eradication reverses the inflammatory and secretory lesion, which is why it collapses ulcer recurrence rates.[4] See the treatment microchapter for regimens.
- Hypergastrinemia: In duodenal ulcer disease, hypergastrinemia reflects loss of antral somatostatin restraint. Atypical, refractory, or multiple ulcers with marked hypergastrinemia warrant consideration of Zollinger-Ellison syndrome.[3]
- Gastric ulcers: Gastric ulcers arise on a background of atrophy and intestinal metaplasia. Biopsy and follow-up for malignancy are indicated as clinically appropriate.[3]
- Concurrent NSAID/aspirin use: NSAID-induced prostaglandin depletion and H. pylori inflammation are additive mechanisms. Assess concurrent use in every patient.[1]
Areas of uncertainty
- Why only a minority of infected persons ulcerate remains incompletely explained.[4][1]
- The independent pathogenic contribution of VacA alleles versus cag status is still debated, and associations vary by geography.[9][10]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 Lanas A, Chan FKL (2017). "Peptic ulcer disease". Lancet. 390 (10094): 613–624. doi:10.1016/S0140-6736(16)32404-7. PMID 28242110.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Malfertheiner P, Chan FK, McColl KE (2009). "Peptic ulcer disease". Lancet. 374 (9699): 1449–1461. doi:10.1016/S0140-6736(09)60938-7. PMID 19683340.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Vakil N (2024). "Peptic Ulcer Disease: A Review". JAMA. 332 (21): 1832–1842. doi:10.1001/jama.2024.19094. PMID 39466269 Check
|pmid=value (help). - ↑ 4.0 4.1 4.2 Walsh JH, Peterson WL (1995). "The treatment of Helicobacter pylori infection in the management of peptic ulcer disease". N Engl J Med. 333 (15): 984–991. doi:10.1056/NEJM199510123331508. PMID 7666920.
- ↑ 5.0 5.1 5.2 Almadi MA, Lu Y, Alali AA, Barkun AN (2024). "Peptic ulcer disease". Lancet. 404 (10447): 68–81. doi:10.1016/S0140-6736(24)00155-7. PMID 38885678 Check
|pmid=value (help). - ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek R, Schulz C, Smith SI, Suerbaum S (2023). "Helicobacter pylori infection". Nat Rev Dis Primers. 9 (1): 19. doi:10.1038/s41572-023-00431-8. PMC 11558793 Check
|pmc=value (help). PMID 37081005 Check|pmid=value (help). - ↑ Walker MM, Dixon MF (1996). "Gastric metaplasia: its role in duodenal ulceration". Aliment Pharmacol Ther. 10 (Suppl 1): 119–128. PMID 8730266.
- ↑ 8.0 8.1 8.2 8.3 Chan FK, Leung WK (2002). "Peptic-ulcer disease". Lancet. 360 (9337): 933–941. PMID 12354485.
- ↑ 9.0 9.1 Memon AA, Hussein NR, Miendje Deyi VY, Burette A, Atherton JC (2014). "Vacuolating cytotoxin genotypes are strong markers of gastric cancer and duodenal ulcer-associated Helicobacter pylori strains: a matched case-control study". J Clin Microbiol. 52 (8): 2984–2989. doi:10.1128/JCM.00551-14. PMC 4136171. PMID 24920772.
- ↑ 10.0 10.1 Wattanawongdon W, Simawaranon Bartpho T, Tongtawee T (2023). "Relationship between Helicobacter pylori virulence genes and gastroduodenal disease". J Int Med Res. 51. doi:10.1177/03000605231161465.