Peptic Ulcer Disease

Overview & Definition

Peptic ulcer disease (PUD) is a break in the mucosal lining of the stomach (gastric ulcer) or proximal duodenum (duodenal ulcer) that extends through the muscularis mucosae. It results from an imbalance between aggressive factors (acid, pepsin, H. pylori, NSAIDs) and defensive factors (mucus-bicarbonate barrier, prostaglandins, mucosal blood flow, rapid cell turnover).^[1][1]

The discovery of H. pylori (Marshall and Warren, 1982) revolutionised PUD management — what was once a surgical disease (vagotomy, antrectomy, gastrectomy) is now primarily medical (eradication therapy + PPI). Surgery is now reserved for complications: perforation, haemorrhage, and gastric outlet obstruction.^[1][2]

Classification

By anatomical site:^[1]

• Duodenal ulcer (DU) — occurs in the proximal duodenum (usually the first part, the duodenal bulb). More common than gastric ulcer. Almost never malignant. Associated with H. pylori (approximately 95% in the Cochrane association figures) and acid hypersecretion.^[15]
• Gastric ulcer (GU) — occurs in the stomach (commonly along the lesser curvature at the antrum-body junction). Can be malignant — an estimated 2 to 5% of ulcers with a benign appearance prove malignant; perforated gastric-ulcer series quote malignancy in 4 to 14%, while contemporary estimates are generally below 5%.^[20][19] Classified by location (Johnson types I to V — classic surgical convention).
  • Type I — along lesser curvature (most common).
  • Type II — gastric + duodenal ulcer (combined).
  • Type III — prepyloric.
  • Type IV — near the gastro-oesophageal junction (cardia).
  • Type V — anywhere (NSAID-induced). ^[1]

By cause:

• H. pylori-associated — duodenal (approximately 95% H. pylori-positive) and gastric (approximately 70% H. pylori-positive) in the Cochrane association figures.^[15]
• NSAID-induced — direct mucosal injury + inhibition of protective prostaglandins.
• Stress-related mucosal disease (ICU patients, burns [Curling's ulcer], CNS injury [Cushing's ulcer]).^[23][24]
• Zollinger-Ellison syndrome (gastrinoma) — multiple, recurrent, atypical ulcers.
• Idiopathic (no H. pylori, no NSAIDs) — increasing proportion. ^[1]

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Epidemiology & Risk Factors

Lifetime prevalence approximately 5 to 10%, incidence 0.1 to 0.3% per year (declining due to H. pylori eradication).^[6]

Risk factors:

• H. pylori infection — associated with approximately 95% of DU and 70% of GU. Transmitted mainly via the faecal-oral and oral-oral routes; it infects over 43% of the global population.^[15][27] Although H. pylori infects a large fraction of the world's population, only a minority of infected individuals ever develop PUD (about 10% in the VNAGE consensus statement).^[28]
• NSAIDs and aspirin — inhibit cyclo-oxygenase (COX), reducing protective mucosal prostaglandins. Risk rises with dose, duration, older age and concurrent corticosteroid use. COX-2 selective inhibitors (celecoxib) carry a lower GI risk but an increased myocardial-infarction risk (class effect; MI OR 2.26 vs placebo).^[30]
• Smoking — impairs mucosal healing; synergises with H. pylori.
• Alcohol — direct mucosal irritant (but no proven causal link at moderate intake).
• Stress — psychological stress may worsen but does not directly cause PUD.
• Diet — spicy food does NOT cause PUD (a myth); coffee/caffeine may increase acid secretion.
• Genetics — family history and familial clustering; ABO-locus variants (the blood group O association) are duodenal-ulcer susceptibility alleles (GWAS OR 1.32).^[29]
• Zollinger-Ellison syndrome — gastrinoma (duodenum 70%, pancreas 25%) causing massive acid hypersecretion and multiple/recurrent ulcers.^[8]
• Comorbidity — COPD, cirrhosis, chronic renal failure (increased PUD risk).

Pathophysiology

H. pylori pathogenesis:^[1]

• H. pylori is a spiral, microaerophilic, urease-producing Gram-negative bacterium that colonises the gastric mucus layer.
• Urease converts urea to ammonia, creating an alkaline microenvironment that protects the bacterium from gastric acid.
• CagA and VacA virulence factors cause epithelial cell damage, inflammation, and ulceration.
• In the antrum, H. pylori causes gastritis with reduced somatostatin (normally inhibits gastrin) → hypergastrinaemia → increased acid secretion → duodenal ulcer (acid overload overwhelms the duodenal mucosal defence).
• In the body/fundus, H. pylori causes atrophic gastritis → reduced acid → gastric ulcer (and increased gastric cancer risk).

NSAID pathogenesis:

• NSAIDs inhibit COX-1 (constitutive, produces protective prostaglandins in gastric mucosa) and COX-2 (inducible, inflammation).
• Loss of prostaglandin E2 and I2 reduces mucus and bicarbonate secretion, reduces mucosal blood flow, and impairs healing — making the mucosa vulnerable to acid injury.
• NSAIDs may also cause direct topical injury to the mucosa (especially acidic NSAIDs like aspirin). ^[1]

Duodenal vs gastric ulcer key differences (exam table): ^[1]

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Clinical Presentation

Typical presentation:^[1]

• Epigastric pain — burning or gnawing; the hallmark symptom.
  • DU: pain 2 to 3 hours after meals, relieved by food, milk, or antacids, often nocturnal (wakes the patient — pain causing night-waking or occurring between meals is the classical pattern).^[31]
  • GU: pain worsened by food, nausea, vomiting, weight loss.^[31]
• Water brash (excess salivation), heartburn (acid reflux).
• Nausea, bloating, early satiety.
• Periodicity — episodes of pain lasting days to weeks with symptom-free intervals.

Signs — usually normal between episodes. Epigastric tenderness on deep palpation. May have iron-deficiency anaemia (chronic occult blood loss). ^[1]

Presentation with complications:

• Perforation — sudden, severe, generalised abdominal pain (like being "stabbed"); rigid, board-like abdomen; guarding and rebound; free gas under the diaphragm on erect CXR. Classical: "mummified" patient lying still (any movement worsens pain).
• Haemorrhage — haematemesis (coffee-ground or fresh blood) and/or melaena (black, tarry, foul-smelling stool). May cause hypovolaemic shock.
• Gastric outlet obstruction — non-bilious vomiting of undigested food eaten hours/days earlier; succussion splash on examination (splashing sound on shaking the abdomen); visible gastric peristalsis; hypokalaemic, hypochloraemic metabolic alkalosis (loss of HCl and K+ from vomiting). ^[1]

Differential Diagnosis

Clinical & Bedside Assessment

History is key — the pain-food relationship, nocturnal symptoms, NSAID/aspirin use, corticosteroids, anticoagulants/antiplatelets, smoking, alcohol, prior ulcer or H. pylori treatment, and red-flag systemic symptoms. Ask specifically about over-the-counter ibuprofen/diclofenac — patients often omit them unless prompted. ^[1]

Examination:

• Epigastric tenderness — often the only sign between uncomplicated episodes.
• Complications: board-like rigidity and silence of bowel sounds (perforation); tachycardia, postural hypotension, melaena on DRE, haematemesis (bleeding); succussion splash, visible gastric peristalsis, dehydration (GOO).
• Chronic disease: pallor (iron-deficiency anaemia), cachexia (think malignancy if GU phenotype), lymphadenopathy (Virchow node if gastric cancer on differential). ^[1]

Alarm features requiring urgent OGD (do not treat empirically alone): new dyspepsia in older patients (the audit age varies by region and gastric-cancer risk — for example ≥40 years for men and ≥35 for women in the VNAGE consensus),^[28] unintentional weight loss, dysphagia/odynophagia, GI bleeding, persistent vomiting, palpable epigastric mass, iron-deficiency anaemia, progressive symptoms on PPI, family history of upper GI cancer. ^[1]

Worked bedside vignette — "is this still medical?"
A 60-year-old on aspirin for stents develops melaena without free air. This is a bleed pathway (resuscitate → risk score → OGD), not Graham-patch theatre. Conversely, sudden rigidity with free gas is a surgical perforation pathway even if the patient later needs H. pylori eradication after repair. ^[1]

Investigations

Diagnostic:

• OGD (oesophagogastroduodenoscopy) — the gold standard. Directly visualises the ulcer, assesses location, size, depth, and signs of malignancy (irregular borders, heaped-up edges). Gastric ulcers are ALWAYS biopsied (multiple biopsies from the edge and base) to exclude carcinoma — even if they look benign. Duodenal ulcers are rarely biopsied (almost never malignant).^[1]
• H. pylori testing:
  • CLO test (rapid urease test) — biopsy placed in urea-containing medium; colour change indicates urease (H. pylori). Done at OGD. Highly sensitive and specific.
  • Urea breath test (13C or 14C) — non-invasive; patient ingests labelled urea; if H. pylori urease is present, labelled CO2 is exhaled. Used for confirmation of eradication (4 weeks after completing therapy). False-negative if on PPI or antibiotics.
  • Stool antigen test — non-invasive; detects H. pylori antigen in stool. Also used for eradication confirmation.
  • Serology — detects anti-H. pylori antibodies; cannot distinguish current vs past infection; not useful for eradication confirmation.
  • Histology — biopsy stained (Giemsa or immunohistochemistry) shows H. pylori; gold standard but slower.

Risk scores for bleeding (reproduce purpose, not every rare variant):

• Glasgow-Blatchford score (pre-endoscopy): urea, haemoglobin, systolic BP, pulse, melaena, syncope, hepatic disease, cardiac failure — predicts need for transfusion or intervention;^[11] a score of 0 to 1 identifies very-low-risk patients who may be discharged with outpatient follow-up (ACG).^[3]
• Rockall score (post-endoscopy): age, shock, comorbidity, diagnosis, major SRH — predicts mortality/rebleed risk.^[12]

For complications:

• Erect CXR — free gas under the diaphragm (perforation); reported sensitivity is highly variable across studies (30 to 85%) — a negative film does not exclude perforation. If clinical perforation but CXR negative → CT abdomen (more sensitive for free air/fluid).^[6]
• CT abdomen — for perforation (free gas/fluid) or exclusion of other pathology; up to 12% of perforations still have a normal CT, and oral water-soluble contrast can improve accuracy. Do not delay theatre for CT when peritonitis is clear and patient is unstable.^[6]
• FBC, U&Es, group & save/crossmatch, coagulation, lactate, ABG as indicated — anaemia (bleeding), hypokalaemia/hypochloraemia/alkalosis (GOO from vomiting), raised urea out of proportion to creatinine (UGI bleed digestion of blood). ^[1]

Screening for Zollinger-Ellison syndrome — if multiple, recurrent, jejunal, or atypical ulcers, or ulcers with diarrhoea: fasting serum gastrin (markedly elevated) and gastric pH (hyperchlorhydria, pH under 2). Interpreting gastrin on PPI is complex — involve gastroenterology; seek MEN1 features (hyperparathyroidism, pituitary). ^[1]

Management — Resuscitation

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Perforated peptic ulcer (emergency):^[6]

• The WSES pillars for complicated peptic ulcer: prompt recognition, resuscitation when required, appropriate antibiotic therapy, and timely surgical/radiological treatment.^[6]
• Broad-spectrum IV antibiotics started as soon as possible, covering Gram-negative, Gram-positive and anaerobic organisms, chosen per local policy and severity — WSES suggests short courses (3 to 5 days or until inflammatory markers normalise) and its pathway spans ED arrival through post-discharge antimicrobial therapy.^[6]
• Urgent surgical review once resuscitated — in perforation, simple closure is sufficient in the large majority of cases; definitive acid-reducing ulcer surgery is no longer justified in these patients.^[2] WSES notes that an omental patch does not add benefit to a simple suture repair but increases operating time; Graham omentopexy remains the exam-standard described technique. A 2020 meta-analysis found laparoscopic repair reduced early postoperative pain and wound infection with no mortality difference — reasonable for stable patients where skills allow (WSES).^[6]

Acute upper GI bleeding:^[3]

• Restrictive transfusion — red blood cell transfusion at a threshold of 7 g/dL for hospitalised patients with upper GI bleeding (ACG suggestion).^[3]
• Erythromycin infusion before endoscopy, and endoscopy within 24 hours of presentation.^[3]
• Endoscopic therapy is recommended for ulcers with active spurting or oozing and for non-bleeding visible vessels — in the landmark trial these were treated with epinephrine injection followed by thermocoagulation.^[3][4]
• After endoscopic haemostasis: IV omeprazole 80 mg bolus followed by 8 mg/h for 72 h (rebleeding 6.7% vs 22.5% with placebo), then oral omeprazole 20 mg daily for 8 weeks; ACG recommends high-dose PPI for 3 days then twice-daily oral PPI for the first 2 weeks.^[4][3]
• If endoscopic therapy fails: transcatheter embolisation; repeat endoscopy is suggested for recurrent bleeding.^[3]

Gastric outlet obstruction:^[7]

• Peptic ulcer disease is the most common cause of benign GOO; with H. pylori eradication and PPI use the predominant causes have shifted towards malignant disease (gastric cancer, lymphoma, GIST), so the underlying cause must be established.^[7]
• Treatment depends on the cause: proton pump inhibitors, H. pylori eradication, endoscopic balloon dilatation or self-expandable metal stents, or surgery.^[7]

Management — Definitive & Stepwise

Medical (first-line for uncomplicated PUD)

H. pylori eradication:^[5]

• First-line choice depends on antibiotic history and local resistance — ask about previous antibiotic exposure and incorporate it into decision-making.^[5]
• Clarithromycin triple therapy should be confined to patients with no previous macrolide exposure who live where clarithromycin resistance amongst H. pylori isolates is known to be low.^[5]
• Most patients are better served by first-line bismuth quadruple therapy or concomitant therapy (PPI + clarithromycin + amoxicillin + metronidazole).^[5]
• Salvage after failure must avoid previously used antibiotics: after a clarithromycin-containing first line, bismuth quadruple or levofloxacin regimens are preferred; after first-line bismuth quadruple, clarithromycin- or levofloxacin-containing salvage is preferred.^[5]

Acid suppression and healing: (when H. pylori is diagnosed, eradicate and give antisecretory therapy — preferably a PPI — for four weeks)^[31]

• Eradication itself heals most duodenal ulcers — in one prospective study (with historical controls) ulcers healed in 98% of patients in whom H. pylori was eradicated versus 73% with persistent infection, and acid suppression following successful eradication therapy was not required for duodenal ulcer treatment.^[10]
• When acid suppression is used, doubling the PPI dose adds nothing — omeprazole 20 mg and 40 mg once daily gave identical eradication, healing and symptom outcomes in that trial.^[10]
• Stop the NSAID — patients at risk for ulcer disease who need arthritis treatment should receive a COX-2 selective NSAID or a non-selective NSAID with a PPI rather than an unprotected NSAID.^[9]

NSAID ulcer prevention:

• Co-prescribe PPI with NSAIDs in high-risk patients (age over 60, previous PUD, concurrent corticosteroid/anticoagulant).
• Use COX-2 selective inhibitor (celecoxib) instead of non-selective NSAID in patients at high GI risk (but beware the increased myocardial-infarction risk — class effect).^[30]
• Consider H. pylori eradication before starting long-term NSAIDs. ^[1]

Surgical (for complications)

Perforated peptic ulcer:^[1][2]

• Graham omental patch (omentopexy) — the standard emergency procedure for a perforated DU. The perforation is closed by suturing a piece of omentum (Graham patch) over the hole. Can be done laparoscopically or open.
• Perforated GU: if small and clean — patch repair; if large or malignant-looking — biopsy (frozen section) and consider resection (wedge excision or partial gastrectomy) if malignancy suspected.
• Post-op: IV PPI, H. pylori eradication (if positive), analgesia, DVT prophylaxis.

Bleeding peptic ulcer (surgical management when endoscopy fails):

• Indications for surgery after failed endoscopic haemostasis: WSES suggests surgical haemostasis (or angiographic embolisation if immediately available) after failure of repeated endoscopy, and for hypotension/haemodynamic instability or ulcer larger than 2 cm at first endoscopy, surgery without repeating endoscopy.^[6]
• DU: under-running (oversewing) the bleeding vessel (usually the gastroduodenal artery at the posterior duodenal bulb) with non-absorbable sutures. May require duodenotomy to access.
• GU: under-running the bleeding vessel or wedge excision of the ulcer.
• Alternative: interventional radiology — angiographic embolisation of the bleeding vessel (e.g., GDA); increasingly used as an alternative to surgery in unstable patients.

Gastric outlet obstruction:

• Endoscopic balloon dilatation — for fibrotic strictures from chronic DU (may need repeat dilatations).
• Surgical: Gastrojejunostomy (bypass the obstruction) ± truncal vagotomy (reduce acid). Pyloplasty for pyloric stenosis. Rarely needed now with endoscopic techniques and H. pylori eradication.^[2]

Elective ulcer surgery (now rare):

• Before H. pylori eradication, elective surgery included truncal vagotomy + antrectomy (Billroth I or II), highly selective vagotomy (HSV), and total gastrectomy. These are now historical for uncomplicated PUD but may appear in exams.^[2]

Specific Subtypes & Scenarios

H. pylori eradication regimens in detail

The choice of regimen is dictated by local antibiotic resistance patterns, prior exposure, and penicillin allergy. The Toronto consensus strongly recommends that all eradication regimens be given for 14 days,^[16] and the Maastricht consensus reports advise against clarithromycin triple therapy where resistance exceeds 15%.^[25]

First-line: clarithromycin-based triple therapy (PPI–AC)

The ACG confines this regimen to selected patients:^[5]

• Use only with no previous macrolide exposure AND where clarithromycin resistance amongst H. pylori isolates is known to be low — prior antibiotic exposure must be asked about and folded into the regimen decision.^[5]
• The regimen is PPI + clarithromycin + amoxicillin; drug, dose and duration details per the guideline and local formulary.^[5]
• Most patients are better served by first-line bismuth quadruple therapy or concomitant therapy because macrolide resistance keeps rising.^[5]

Regimen choice after penicillin allergy or treatment failure follows the same principle: ask about previous antibiotic exposure, and make the salvage regimen avoid antibiotics that were previously used — after clarithromycin-containing first-line failure, bismuth quadruple or levofloxacin salvage regimens are the preferred options.^[5]

Bismuth quadruple therapy (BQT)

Preferred as first-line for most patients (ACG), and the go-to option after clarithromycin failure:^[5]

• A PPI + bismuth + tetracycline + metronidazole regimen — chosen where clarithromycin resistance or prior macrolide exposure makes triple therapy unreliable. Drug, dose and duration details per the guideline and local protocols.^[5]

Levofloxacin rescue / sequential / concomitant therapy

Salvage principles after failed eradication:^[5]

• Avoid antibiotics that were previously used — the salvage regimen must not repeat first-line agents.^[5]
• After a clarithromycin-containing first line: bismuth quadruple therapy or levofloxacin salvage regimens are the preferred options.^[5]
• After first-line bismuth quadruple therapy: clarithromycin- or levofloxacin-containing salvage regimens are the preferred options.^[5]
• Concomitant therapy (PPI + clarithromycin + amoxicillin + metronidazole) is a first-line alternative, not a repeat-salvage of the same antibiotics.^[5]

Eradication verification and troubleshooting

Always confirm eradication with a urea breath test or stool antigen test at least 4 weeks after completing therapy (and after ≥4 weeks off antibiotics/bismuth) and at least 2 weeks after stopping PPIs (PPI suppression causes false-negatives).^[28][27] Serology is unsuitable for confirmation because IgG antibodies persist for months to years after eradication. If eradication fails after second-line therapy, endoscopic culture and antibiotic-susceptibility testing should be performed to tailor the third-line regimen.^[1]

Zollinger-Ellison syndrome (gastrinoma) — in detail

Zollinger-Ellison syndrome (ZES) is the constellation of severe acid hypersecretion caused by a gastrin-secreting neuroendocrine tumour (gastrinoma), producing multiple, recurrent, atypical peptic ulcers and often chronic secretory diarrhoea. Its incidence is 1 to 1.5 cases per million per year — rare, but a critical reversible cause of refractory PUD.^[8]

Pathophysiology: Gastrinomas most commonly arise within the “gastrinoma triangle” — the junction of the cystic and common bile ducts, the second/third parts of the duodenum, and the neck/body of the pancreas.^[26] They arise in the duodenum (70%) or pancreas (25%); nodal metastases are present in almost half of patients at surgery, and MEN1 coexists in about 25% of ZES.^[8] Secreted gastrin drives parietal cell hyperplasia and unrestrained acid output, producing ulcers that are unusually multiple, distal, and refractory to standard therapy.

Clinical clues:

• Multiple ulcers in unusual locations (second part of duodenum, jejunum).
• PUD refractory to standard 8 to 12 weeks of therapy, or recurrent ulceration within months of completing eradication.
• Prominent chronic secretory diarrhoea with steatorrhoea — one arm of the classic triad with GERD and recurrent peptic ulceration.^[8]
• Markedly thickened gastric rugae on OGD (gastrin-driven parietal cell hyperplasia — Menetrier-like appearance).
• Personal or family history suggestive of MEN1 (parathyroid hyperplasia → hypercalcaemia; pituitary adenoma → galactorrhoea, acromegaly). ^[1]

Diagnostic workup:

• Fasting serum gastrin — gastrin levels over 1000 pg/mL with a gastric pH under 2 are considered diagnostic for gastrinoma; stop PPIs before testing where safe because they elevate gastrin.^[8]
• Secretin stimulation test — the gold standard where fasting gastrin is borderline (100 to 1000 pg/mL). IV secretin paradoxically raises gastrin in gastrinoma patients (rather than suppressing it as in normal physiology); a rise of ≥120 pg/mL is positive (sensitivity 94%, specificity 100%).^[8]
• Localisation: CT/MRI pancreas, somatostatin receptor scintigraphy (Octreoscan: sensitivity 77 to 78%, specificity 93 to 94%) or 68Ga-DOTATATE PET/CT where available, EUS of the duodenal wall and pancreas for small primaries, and intra-operative palpation/ultrasound at surgical exploration.^[8]
• MEN1 screening: serum calcium, PTH, prolactin, IGF-1 in any young ZES patient (under 40) or with suggestive family history.^[1]

Management:^[8]

• Localised disease: proton pump inhibitor therapy, which usually resolves symptoms, combined with surgery whenever feasible, with curative intent — the hallmark of gastrinoma treatment.^[8]
• Somatostatin analogues: gastrinomas highly express somatostatin receptors and are highly responsive to somatostatin analogs, supporting their use as anti-proliferative agents in patients not amenable to surgical cure.^[8]
• Advanced disease: medical options are superimposable to other neuroendocrine neoplasms; the multidisciplinary approach remains the cornerstone of management.^[8]

NSAID-induced ulcers — prevention and management

NSAIDs and aspirin are the other major cause of PUD worldwide — NSAID use alone raises ulcer-bleeding risk nearly 5-fold (OR 4.85) — and H. pylori-negative non-NSAID takers rarely develop PUD.^[14] Damage is mediated by both topical mucosal injury and systemic loss of COX-1–derived prostaglandins (PGE2, PGI2) that maintain mucus, bicarbonate, and mucosal blood flow.^[1]

Risk stratification (CV risk–balanced):

• High GI risk — age over 60, previous peptic ulcer, H. pylori co-infection, concurrent corticosteroid, anticoagulant (warfarin, DOAC) or antiplatelet (aspirin, clopidogrel) therapy, or high-dose/multiple NSAIDs.
• High CV risk — established coronary, cerebrovascular, or peripheral arterial disease; diabetes with end-organ damage; chronic kidney disease.
• The H. pylori + NSAID interaction is synergistic: concurrent infection and NSAID use raise ulcer-bleeding risk to OR 6.13 versus neither factor (H. pylori alone OR 1.79; NSAID alone OR 4.85); eradication before starting chronic NSAID therapy is advised where feasible.^[14]

Prevention strategy:^[9]

• Patients at risk for ulcer disease who require treatment for arthritis should receive an NSAID selective for cyclooxygenase-2 (celecoxib 200 mg twice daily) or the combination of a non-selective NSAID with a proton-pump inhibitor (diclofenac 75 mg twice daily plus omeprazole 20 mg daily) — the guideline-endorsed strategies.^[9]
• The two strategies are equivalent for recurrent ulcer bleeding in patients with a recent bleed: 6-month probability 4.9% (celecoxib) vs 6.4% (diclofenac + omeprazole) — but renal adverse events are common in high-risk patients on either (24.3% vs 30.8% in the trial).^[9]
• Test and treat H. pylori — it has a recognised role in ulcer risk in patients taking low-dose aspirin or starting NSAID therapy.^[5]

Management of an established NSAID ulcer:^[9]

• Stop the NSAID wherever possible.
• If arthritis treatment must continue after an ulcer bleed, use a COX-2 selective inhibitor or a non-selective NSAID with a PPI — equally effective at preventing recurrent bleeding over 6 months.^[9]
• Eradicate H. pylori if positive — cure of the infection and metronidazole susceptibility enhance duodenal ulcer healing and symptom relief.^[10]

Refractory peptic ulcer — diagnostic algorithm

An ulcer that has failed to heal after 8 to 12 weeks of optimised therapy, or recurs within 6 months, is refractory and must be investigated deliberately rather than re-treated empirically. Common aetiologies are listed below in approximate order of frequency.^[1][1]

Causes to exclude:^[5]

• Ongoing NSAID or aspirin use — the history must cover prescribed, over-the-counter and low-dose cardioprotective aspirin use.^[9]
• Persistent H. pylori infection — failed eradication is usually regimen- or resistance-related; ask about prior antibiotic exposure and move to a salvage regimen that avoids previously used antibiotics.^[5]
• Gastric adenocarcinoma or lymphoma — every non-healing gastric ulcer needs repeat biopsy.
• Zollinger-Ellison syndrome — think of it early: diagnosis is delayed by more than 5 years on average because symptoms are nonspecific; gastrin over 1000 pg/mL with gastric pH under 2 is diagnostic.^[8]

Stepwise work-up:

1. Re-take history focused on NSAID use (prescribed, OTC, topical), compliance, smoking, family history of MEN1.
2. Repeat OGD with multiple biopsies from ulcer edge and base + CLO test / histology + CMV / TB immunohistochemistry if atypical.
3. Fasting serum gastrin and gastric pH — to exclude ZES (off PPI for 1 to 2 weeks where safe).
4. H. pylori retest (urea breath / stool antigen); consider endoscopy with culture if two prior eradications have failed.
5. Cross-sectional imaging (CT pancreas protocol) + somatostatin receptor imaging if ZES suspected.
6. Treat the underlying cause: PPI high-dose, H. pylori rescue regimen, surgical resection for gastrinoma, chemotherapy/radiotherapy for malignancy, immunomodulation for Crohn's. ^[1]

^{[20] [19]}

Complications & Pitfalls

Complications of PUD (four major — surgical):^[1]

1. Perforation — 2 to 10% of ulcers; acute peritonitis; emergency surgery.^[19]
2. Haemorrhage — the most common complication by far (perforation:bleeding ratio ≈ 1:6) and the most common cause of upper GI bleeding; managed endoscopically.^[6]
3. Gastric outlet obstruction — now rare (modern medical management made obstruction from chronic fibrotic disease a rare event); from scarring/oedema of chronic DU or prepyloric GU.^[6]
4. Penetration (not perforation) — posterior DU erodes into the pancreas (causing pancreatitis) or the liver; causes intractable pain radiating to the back.

Complications of ulcer surgery (historical, but exam-yield):

• Dumping syndrome — early (10 to 30 min after eating: vasomotor — dizziness, sweating, palpitations, nausea, from rapid gastric emptying causing fluid shift) and late (1 to 3 h: hypoglycaemia from exaggerated insulin response).^[22] Managed with small, frequent, low-carbohydrate meals; octreotide for severe cases.
• Post-vagotomy diarrhoea — a recognised complication of truncal vagotomy (largely avoided by highly selective vagotomy).
• Afferent loop syndrome — after Billroth II; obstruction of the afferent limb causing bilious vomiting that relieves pain.
• Alkaline reflux gastritis — bile reflux into the stomach remnant; causes pain, nausea, bilious vomiting.
• Marginal (anastomotic) ulcer — ulcer at the gastrojejunal anastomosis; may perforate or bleed.
• Anaemia — iron deficiency (reduced acid impairs iron absorption), B12 deficiency (loss of intrinsic factor after gastrectomy).
• Osteoporosis — reduced calcium absorption after gastrectomy.
• Stump carcinoma — gastric cancer developing in the gastric remnant years after partial gastrectomy (alkaline reflux and bacterial overgrowth are carcinogenic). ^[1]

Classic pitfalls:

• Not biopsying a gastric ulcer — missing gastric carcinoma (2 to 5% of benign-appearing GUs prove malignant).^[20]
• Not confirming H. pylori eradication — recurrent ulceration.
• Not doing a repeat OGD to confirm gastric ulcer healing — missing non-healing malignancy.
• Not testing for H. pylori before starting long-term PPI — missing curable disease.
• Assuming a perforated ulcer is appendicitis — epigastric pain with free gas vs RLQ pain without gas.
• Forgetting Zollinger-Ellison in patients with multiple, recurrent, or atypical ulcers. ^[1]

Prognosis & Disposition

Uncomplicated PUD — excellent prognosis with H. pylori eradication + PPI. Healing of duodenal ulcer was 90% (69/77) on intention-to-treat in one eradication study, and 98% when H. pylori was cured versus 73% with persistent infection.^[10] Recurrence after successful H. pylori eradication: approximately 13% for duodenal ulcer versus 64% without eradication (RR 0.20), and approximately 16% versus 52% for gastric ulcer (Cochrane).^[15]

Complicated PUD — prognosis depends on the complication:

• Perforation: sample size-weighted average 30-day mortality 23.5%; perforation causes about 40% of all ulcer-related deaths (higher with delayed surgery, shock on admission, age over 70, comorbidity).^[6]
• Haemorrhage: weighted average 30-day mortality 8.6%; rebleeding 15 to 20% after endoscopic therapy alone, cut to under 7% by 72-h high-dose IV PPI (higher with visible vessel or clot on OGD).^[6][4]
• GOO: good with endoscopic dilatation or surgery; may recur. ^[1]

Follow-up: confirm H. pylori eradication (urea breath test at 4 weeks). Repeat OGD at 8 to 12 weeks for gastric ulcers to confirm healing and exclude malignancy. Duodenal ulcers do not require follow-up OGD (not malignant). ^[1]

Special Populations

• NSAID users — patients at risk for ulcer disease who require NSAID therapy should receive a COX-2 selective agent or a non-selective NSAID plus a PPI.^[9] H. pylori has a role in ulcer risk in patients taking low-dose aspirin or starting NSAID therapy — test and treat.^[5] Never restart an NSAID after a complicated ulcer without a documented gastroprotection plan and indication review.
• Elderly — higher perforation and bleed mortality; NSAID/aspirin ulcers predominate; pain may be muted; lower threshold for OGD and admission; careful PPI long-term risk–benefit (fracture/C. diff signals debated — still use when indicated after bleed/perforation).
• Anticoagulated / dual antiplatelet patients — early gastroenterology + cardiology input after bleed; do not casually stop stents’ essential antiplatelets without plan; reverse life-threatening coagulopathy per protocol; early OGD after resus.^[3]
• Pregnancy — PUD uncommon (progesterone reduces acid). Prefer antacids, H2-blockers, and PPIs with the best pregnancy safety data (omeprazole/pantoprazole commonly used). Avoid elective surgery; operate for free perforation/uncontrolled bleed. H. pylori eradication timing individualised (prefer postpartum if mild symptoms).
• ICU / burns / head injury — stress-related mucosal disease: Cook identified two strong independent risk factors — respiratory failure (OR 15.6) and coagulopathy (OR 4.3) — and concluded prophylaxis can be safely withheld unless coagulopathy or mechanical ventilation is present.^[13] Add major burns (Curling ulcer — typically >20% TBSA)^[23] and intracranial injury (Cushing ulcer — acid hypersecretion driven)^[24]. Prefer PPI or H2-blocker per unit protocol; early enteral nutrition protects mucosa (Curling-ulcer bleeding fell from ~15% to ~3% with prophylaxis and early feeding).^[23]
• Children — duodenal disease more than gastric; H. pylori family clustering; weight-based PPI and antibiotic dosing; exclude other causes of abdominal pain; paediatric gastroenterology for refractory disease.
• CKD / transplant / immunosuppressed — higher bleed risk on antiplatelets/steroids; drug interactions with eradication regimens; lower threshold to scope anaemia or melaena.

Worked metabolic vignette — GOO alkalosis (exam favourite)

A patient with weeks of non-bilious vomiting of old food has Na 130, K 2.6, Cl 80, HCO3 38, urine paradoxically acidic. Mechanism: loss of HCl → hypochloraemic metabolic alkalosis; volume depletion + secondary hyperaldosteronism → renal Na retention with K and H secretion (paradoxical aciduria) until chloride is restored. Treatment: large-bore NG decompression, IV 0.9% sodium chloride with potassium chloride replacement, PPI, then OGD (biopsy any GU/stricture) and definitive dilatation or surgery once optimised. ^[1]

Evidence, Guidelines & Regional Differences

Duration and resistance thresholds (consensus guidance):

• Toronto consensus (2016): all H. pylori eradication regimens should be given for 14 days.^[16]
• Maastricht consensus (IV/V): avoid clarithromycin triple therapy where clarithromycin resistance exceeds 15% — use bismuth quadruple or concomitant therapy instead.^[25]
• Confirmation of eradication at least 4 weeks after completing therapy (and ≥2 weeks off PPI).^[28]
• Culture and sensitivity testing after two failed eradication attempts.^[5]

Regional differences:

• India — high H. pylori burden; clarithromycin resistance approximately 35% and metronidazole resistance approximately 78% in a 2024 two-decade systematic review — bismuth quadruple therapy is preferred; amoxicillin resistance approximately 38% and rising.^[17]
• West — declining H. pylori prevalence; NSAID-induced ulcers proportionally more common; PPI prophylaxis widely used. ^[1]

Historical note: The shift from surgery to medical management of PUD is one of the great triumphs of modern gastroenterology. Before H. pylori eradication, PUD was a chronic, recurrent condition treated with major surgery (vagotomy, antrectomy, gastrectomy). Today, uncomplicated PUD is cured by eradication therapy in the majority of patients.^[2]

Exam Pearls

• DU: pain relieved by food, nocturnal, weight gain. GU: pain worsened by food, weight loss. H. pylori ~95% of DU and ~70% of GU (Cochrane association figures).^[15]
• Gastric ulcers are ALWAYS biopsied (2 to 5% of benign-appearing ulcers are cancer). Duodenal ulcers are almost never malignant.^[20]
• H. pylori eradication is 14 days. Clarithromycin triple only if no prior macrolide and known low resistance; most patients need bismuth quadruple or concomitant therapy. Confirm eradication with urea breath test at ≥4 weeks (off PPI ≥2 weeks).^[5][16]
• Perforated DU: sudden severe epigastric pain, rigid abdomen, free gas under diaphragm on erect CXR. Graham omental patch repair.^[1]
• Posterior DU penetrates the pancreas (back pain) or erodes the gastroduodenal artery (massive GI bleed).^[1]
• Gastric outlet obstruction: non-bilious vomiting of old food, succussion splash, hypokalaemic hypochloraemic metabolic alkalosis.^[1]
• Curling's ulcer = burns. Cushing's ulcer = head injury. Zollinger-Ellison = gastrinoma, multiple ulcers, high fasting gastrin.^[23][24][8]
• Dumping syndrome: early (10 to 30 min, vasomotor) and late (1 to 3 h, hypoglycaemia). After gastrectomy/vagotomy.^[22]
• Billroth I = gastroduodenostomy (after distal gastrectomy). Billroth II = gastrojejunostomy; Roux-en-Y gastrojejunostomy is a distinct reconstruction.^[21]
• NSAIDs cause ulcers by inhibiting COX-1 (reducing protective prostaglandins). Co-prescribe PPI. COX-2 inhibitors have lower GI risk.^[1]

Operative and endoscopic detail (exam detail)

Anatomy examiners love:

• Anterior DU → free perforation into peritoneum → free gas under diaphragm.
• Posterior DU → penetration into pancreas (back pain) or erosion of gastroduodenal artery (GDA) → massive upper GI bleed.
• Lesser-curve GU → risk of malignancy higher than DU; always biopsy.
• Prepyloric / pyloric channel ulcers → scarring → gastric outlet obstruction (GOO). ^[1]

Bleeding ulcer — endoscopic haemostasis:

1. Resuscitate first; restrictive transfusion at a threshold of 7 g/dL for hospitalised upper GI bleeding.^[3]
2. Erythromycin infusion before endoscopy; OGD within 24 hours of presentation for diagnosis and therapy.^[3]
3. Endoscopic therapy for ulcers with active spurting or oozing and for non-bleeding visible vessels — recommended modalities include bipolar electrocoagulation, heater probe and absolute ethanol injection, with clips, argon plasma coagulation and soft monopolar electrocoagulation also supported; hemostatic powder TC-325 for actively bleeding ulcers and over-the-scope clips for recurrent bleeding.^[3]
4. After successful endoscopic haemostasis: IV omeprazole 80 mg bolus then 8 mg/h for 72 h, then oral omeprazole 20 mg daily for 8 weeks; ACG: high-dose PPI for 3 days, then twice-daily oral PPI for the first 2 weeks.^[4][3]
5. Failed endoscopic control → transcatheter embolisation; repeat endoscopy is suggested for recurrent bleeding.^[3]

Perforated ulcer — operative repair:

1. Prompt recognition, resuscitation, appropriate antibiotic therapy, and timely surgical treatment — the WSES pillars for complicated peptic ulcer.^[6]
2. Laparoscopic or open washout; identify perforation (usually anterior DU).
3. Simple closure is sufficient in the large majority of cases — definitive ulcer surgery to reduce gastric acid secretion is no longer justified in perforation;^[2] laparoscopic repair reduces early pain and wound infection with no mortality difference (WSES meta-analysis).^[6]
4. Thorough lavage; the WSES pathway explicitly covers care through post-discharge antimicrobial therapy.^[6]

GOO from chronic DU scarring:

• Resuscitate, correct hypokalaemic hypochloraemic metabolic alkalosis (paradoxical aciduria teaching point).
• NG decompression, IV PPI, H. pylori eradication.
• Endoscopic dilatation for selected benign strictures; definitive surgery historically truncal vagotomy + gastrojejunostomy or antrectomy variants — now individualised; exclude malignant GOO. ^[1]

Historical acid-reducing operations (still examined):

• Truncal vagotomy + drainage (pyloroplasty/GJ).
• Highly selective (parietal cell) vagotomy — denervates acid-secreting corpus/fundus, preserves antral innervation (less dumping).
• Billroth I / II and Roux-en-Y reconstructions after partial gastrectomy — know dumping, bile reflux, B12 deficiency, stump carcinoma risk after Billroth II. ^[1]

Forrest classification of bleeding ulcers (reproduce)

Worked clinical stems (answer these without another book)

Stem A — Perforation. 45 M sudden epigastric pain, board-like rigidity, free gas under right hemidiaphragm.
Perforated peptic ulcer. ABC, IV access, fluids, NG, broad-spectrum IV antibiotics per local policy covering Gram-positive, Gram-negative and anaerobes (e.g. co-amoxiclav + metronidazole), IV PPI, urgent surgery for Graham patch, post-op H. pylori eradication. ^[6]

Stem B — Bleeding posterior DU. Melaena, HR 110, BP 95/60, Hb 78, on ibuprofen.
Ulcer bleed / GDA territory. Restrictive transfusion at a 7 g/dL threshold, IV PPI 80 mg then 8 mg/h for 72 h after endoscopic haemostasis, endoscopy within 24 h with epinephrine injection plus thermocoagulation; transcatheter embolisation if endoscopic therapy fails; stop the NSAID. ^[3][4]

Stem C — GOO. Recurrent vomiting of old food, succussion splash, metabolic alkalosis.
Pyloric stenosis from chronic DU (or malignancy). Correct electrolytes, NG, PPI, OGD with biopsy, dilatation or surgery. ^[1]

Stem D — Non-healing GU. GU still present at 12 weeks on PPI, biopsies "chronic gastritis" only once.
Re-biopsy extensively; exclude cancer, H. pylori, surreptitious NSAID, hypersecretory states; do not label "benign" without healing + adequate histology. ^[1]

Stem E — ZES suspicion. Multiple DU beyond D1, diarrhoea, recurrent despite PPI.
Measure fasting gastrin (off PPI if safe / with caution), gastric pH, seek gastrinoma (MEN1); high-dose PPI; oncology/endocrine pathway. ^[1]

Stem F — H. pylori after antibiotics. Completed triple therapy, still dyspeptic.
Urea breath test ≥4 weeks after antibiotics and ≥2 weeks off PPI; if positive → bismuth quadruple or susceptibility-guided therapy. ^[1]

OSCE / short-case performance script

1. ABCDE for acute abdomen or GI bleed; DRE for melaena.
2. Focused history: NSAIDs, steroids, anticoagulants, alcohol, prior ulcer, H. pylori treatment.
3. State Glasgow-Blatchford (pre-endoscopy intervention risk) vs Rockall (post-endoscopy mortality risk) roles.
4. Verbalise exact PPI infusion and triple therapy doses.
5. Consent themes: perforation repair, conversion, rebleed, need for IR/surgery if endoscopy fails.
6. Safety-net: return if melaena, syncope, severe pain; GU healing check OGD. ^[1]

Extended viva bank (model outlines)

1. DU vs GU pain patterns and malignancy risk.
2. Why biopsy every GU?
3. GDA anatomy and posterior DU bleed.
4. Lau PPI infusion evidence after endoscopic therapy.^[4]
5. Triple vs bismuth quadruple and clarithromycin resistance (India).
6. Graham patch technique and when to consider definitive ulcer surgery.
7. Dumping — early vs late.
8. H. pylori tests — which for diagnosis vs test of cure.
9. Stress ulcers (Curling/Cushing) in burns and head injury.
10. MEN1 / gastrinoma work-up outline.

Common exam traps (fail patterns)

• Single-agent adrenaline for high-risk bleed.
• Liberal transfusion without target.
• Testing H. pylori for cure while still on PPI.
• Calling free gas "medical" and delaying theatre.
• Forgetting NSAID cessation and gastroprotection plan.
• Missing alkalosis correction in GOO. ^[1]

Self-check coverage map

References31ShowHide

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