10.2 Peptic Ulcer Disease, Helicobacter pylori & Zollinger-Ellison Syndrome

3. Peptic Ulcer Disease (PUD) & Helicobacter pylori

Gastric vs Duodenal Ulcers

Peptic ulcer disease arises when aggressive luminal factors (hydrochloric acid, pepsin, NSAIDs, H. pylori) overwhelm endogenous gastroduodenal mucosal protective mechanisms (mucus layer, bicarbonate secretion, prostaglandins, tight intercellular junctions, mucosal blood flow).

Helicobacter pylori Pathogenesis

Helicobacter pylori is a microaerophilic, flagellated, spiral Gram-negative bacillus adapted to colonize the human gastric mucosa:

1. Urease Activity: Synthesizes large amounts of the enzyme urease, which hydrolyses luminal urea into carbon dioxide and ammonia (NH3). Ammonia buffers ambient gastric hydrochloric acid, raising peri-bacterial pH and permitting survival within the acidic mucosal mucus layer.
2. Virulence Cytotoxins:
   • CagA (Cytotoxin-Associated Gene A): Translocated into gastric epithelial cells via a Type IV secretion system, inducing cellular cytoskeletal rearrangements, nuclear factor-kappa B (NF-kB) activation, and massive secretion of interleukin-8 (IL-8), provoking intense neutrophilic infiltration.
   • VacA (Vacuolating Cytotoxin A): Inserts into host cell membranes, forming pores that induce endosomal vacuolation, mitochondrial dysfunction, and epithelial apoptosis.
3. Phenotypic Patterns of Infection:
   • Antral-Predominant Gastritis: Localized inflammation in the gastric antrum leads to targeted destruction of somatostatin-producing D-cells. Loss of somatostatin's inhibitory tonic control causes uninhibited release of gastrin from G-cells. Hypergastrinaemia stimulates corpus parietal cells, resulting in marked gastric acid hypersecretion, delivering excess acid to the duodenal bulb, inducing gastric metaplasia, and driving duodenal ulceration.
   • Corpus-Predominant Gastritis / Pangastritis: Inflammation involves the acid-secreting corpus, leading to progressive destruction of parietal cells, loss of intrinsic factor, profound hypochlorhydria, and multifocal atrophic gastritis. This drives intestinal metaplasia, dysplasia, and significantly elevates the risk of gastric adenocarcinoma.
   • Gastric MALT Lymphoma: Chronic H. pylori antigen-driven B-cell stimulation within mucosa-associated lymphoid tissue induces clonal low-grade B-cell marginal zone lymphomas. Early-stage (Ann Arbor Stage IE) MALT lymphomas achieve complete histological regression in >75% of cases solely following successful H. pylori eradication.

Diagnostic Testing for Helicobacter pylori

Diagnostic modalities are categorized into non-invasive and invasive tests. Both urea-dependent non-invasive tests require strict patient preparation:

• Prerequisite Rules: Patients must stop proton pump inhibitors (PPIs) for at least 2 weeks and stop antibiotics and bismuth compounds for at least 4 weeks before testing. Failure to do so suppresses bacterial load and urease activity, generating false-negative results.

Eradication Regimens (NICE & BSG Guidelines)

• First-Line Standard Triple Therapy (Low Clarithromycin Resistance Areas):
  • Twice-daily PPI (e.g., omeprazole 20 mg BD or lansoprazole 30 mg BD) +
  • Amoxicillin 1 g BD +
  • Clarithromycin 500 mg BD (or Metronidazole 400 mg BD if penicillin-allergic) for 7 to 14 days.
• Bismuth Quadruple Therapy (High Clarithromycin Resistance Areas or Previous Macrolide Exposure):
  • Twice-daily PPI +
  • Bismuth subsalicylate / subcitrate (120–240 mg QDS) +
  • Metronidazole 400 mg TDS +
  • Tetracycline hydrochloride 500 mg QDS for 10 to 14 days.
• Salvage / Second-Line Therapy: In patients failing first-line triple therapy, switch to bismuth quadruple therapy or a levofloxacin-containing triple regimen (PPI + Amoxicillin 1 g BD + Levofloxacin 500 mg OD). Always confirm eradication with 13C-UBT or stool antigen >=4 weeks after treatment in complicated PUD, MALToma, or persistent symptoms.

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4. Zollinger-Ellison Syndrome (ZES)

Pathophysiology & Clinical Features

Zollinger-Ellison syndrome is caused by a gastrinoma—a functional neuroendocrine tumour that hypersecretes the peptide hormone gastrin. Approximately 70–80% of gastrinomas arise within the anatomical boundaries of the "gastrinoma triangle" (defined by the junction of the cystic and common bile duct superiorly, the junction of the second and third parts of the duodenum inferiorly, and the neck and body of the pancreas medially). Up to 60% of gastrinomas are malignant, metastasizing predominantly to regional lymph nodes and the liver.

• Multiple Endocrine Neoplasia Type 1 (MEN1): Approximately 20–25% of ZES cases occur in association with MEN1, an autosomal dominant disorder caused by germline inactivating mutations in the MEN1 tumour suppressor gene on chromosome 11q13. MEN1 is defined by the triad of parathyroid hyperplasia/adenomas (95%, hypercalcaemia), pituitary adenomas (prolactinoma, GH-secreting), and pancreatic/duodenal neuroendocrine tumours (gastrinoma, insulinoma). Gastrinomas in MEN1 are typically multifocal, duodenal, and diagnosed at an earlier age.
• Clinical Presentation:
  • Severe, Recurrent, or Atypical Peptic Ulceration: Peptic ulcers occur in >90% of patients; classic red flags include ulcers refractory to standard PPI therapy, multiple synchronous ulcers, ulcers occurring in atypical anatomical locations (distal duodenum or jejunum), or ulcer perforation.
  • Severe Chronic Diarrhoea & Steatorrhoea: Present in ~50% of cases and can precede ulcer symptoms. Massive volumes of gastric acid delivered to the proximal small bowel overwhelm pancreatic bicarbonate reserves, acidifying the duodenal lumen (pH <3). This denatures pancreatic digestive enzymes (particularly pancreatic lipase) and precipitates conjugated bile acids, inducing fat malabsorption and osmotic/secretory diarrhoea.
  • Severe GORD and Oesophagitis: Acid hypersecretion provokes extensive erosive oesophagitis and peptic strictures.

Diagnostic Algorithm & Localization

1. Fasting Serum Gastrin (FSG): Initial screening test of choice. The patient must discontinue PPIs for at least 1–2 weeks (withholding acid suppression leads to physiological hypergastrinaemia in normal individuals). A fasting serum gastrin >1000 pg/mL (normal <100 pg/mL) accompanied by a gastric pH <=2.0 is virtually diagnostic of ZES.
2. Secretin Stimulation Test: Indicated when fasting serum gastrin is moderately elevated (150–1000 pg/mL) and gastric pH is <=2.0, to definitively differentiate a gastrinoma from other causes of hypergastrinaemia (such as antral G-cell hyperplasia, atrophic gastritis, or gastric outlet obstruction):
   • Mechanism: Intravenous administration of secretin (2 clinical units/kg). In healthy subjects or atrophic gastritis, secretin inhibits antral G-cells, causing gastrin levels to fall or remain unchanged. In gastrinomas, secretin binds directly to abnormal receptors on neoplastic gastrinoma cells, triggering a paradoxical, rapid surge in serum gastrin.
   • Positive Diagnostic Criterion: A rise in serum gastrin of >120 pg/mL (or >200 ng/L) above baseline drawn at 10 to 15 minutes confirms Zollinger-Ellison syndrome.
3. Tumour Localization:
   • 68Ga-DOTATATE / DOTATOC PET-CT: Somatostatin receptor scintigraphy utilizing positron emission tomography; exhibits superior sensitivity (>90%) for identifying primary tumours and distant hepatic metastases.
   • Endoscopic Ultrasound (EUS): Outstanding sensitivity for small duodenal and pancreatic head lesions.

• Management: High-dose oral PPI therapy (e.g., omeprazole 60–120 mg daily) to control acid hypersecretion; surgical exploratory laparotomy with curative lymphadenectomy and enucleation/resection in sporadic, non-metastatic gastrinomas. Patients with MEN1 require medical acid suppression and management of concurrent hyperparathyroidism.