Peptic ulcer disease

Peptic ulcer disease (PUD) is an umbrella term for the development of two different ulcers: gastric ulcers and duodenal ulcers.

PUD is a relatively common condition that frequently presents with dyspepsia, abdominal discomfort and nausea. It can be complicated by perforation, haemorrhage and gastric outlet obstruction.

It is important to understand the difference between ulcers and erosions:

• Erosion - superficial/partial break within the epithelium or mucosal surface.
• Ulcer - deep break through the full thickness of the epithelium or mucosal surface.

The most commonly identified aetiological factors are H.pylori infection and NSAID use. Upper GI endoscopy is used for diagnosis whilst management consists of H.pylori eradication therapy (when indicated), proton-pump inhibitors and lifestyle and risk-factor modification.

There is an estimated lifetime prevalence of 5-10%. 

The annual incidence is thought to be around 0.1-0.3%. The epidemiological pattern varies based on the affected location:

• Gastric ulcers: Incidence increases with age with equal gender distribution. 
• Duodenal ulcers: Appear to be more common in men with incidence that peaks between the ages of 45-64. 

The majority of peptic ulcers are related to H.pylori infection.

H.pylori is by far the most commonly implicated aetiological factor associated with approximately 95% of duodenal ulcers and 70-80% of gastric ulcers. Medications may predispose to PUD with NSAIDS the most important agents. Others include corticosteroids, bisphosphonates and SSRI's.

Smoking and alcohol are commonly discussed although their role is disputed. Ulcers may be seen following major physiological stressors - classically patients with significant burns.

Below we discuss some of the most important aetiological factors in more detail.

H. pylori is a gram negative spiral-shaped, flagellated, micro-aerophilic bacterium, which is thought to colonise up to 50% of the world’s population. 

The infection is more common in the developing world and usually acquired during childhood. It is estimated that up to 95% of patients with PUD are infected with H. pylori, yet only 15% of patients with H. pylori will develop PUD. H. pylori predominantly colonise the antrum of the stomach, which is the least acidic. Colonisation of the gastric antrum can lead to persistent low-grade inflammation.

This may damage the epithelial lining leading to the destruction of the normal gastric mucosal barrier. This promotes the development of ulcerations and other complications (e.g. upper GI bleeding, malignancy, gastritis, gastric outlet obstruction).

The enzymes it produces, ability to adhere and virulence factors are key to their ability to cause gastritis and PUD:

• Enzymes: H. pylori contain the enzyme urease, which is able to convert urea into water and ammonia. The resultant ammonia is able to buffer hydrogen ions within the stomach. This process raises the pH and allows the bacterium to survive.
• Adherence: The flagella of H. pylori propel the bacterium into the mucus layer of the gastric mucosa. This directs the bacterium towards the apical surface of epithelial cells. Here, H. pylori are able to bind tightly to the gastric epithelium. Once bound to gastric epithelial cells, it can secrete effector molecules via its type IV secretion system. Secretion systems are important for the delivery of effector molecules from the cytosol of bacteria.
• Virulence factors: CagA and VacA are important effector molecules secreted by H. pylori, which cause disruption of host cells. CagA has numerous cellular effects including tight junction disruption, altered morphology, differentiation, and apoptosis. VacA induces alterations in tight junctions leading to the formation of large vacuoles, which affects host cell permeability and induces apoptosis.

H. pylori associated malignancy

H. pylori has been associated with a number of GI malignancies. The exact pathogenesis are yet to be understood but as many individuals will have H. pylori without any malignancy developing, individual pre-disposing factors are key. The infection has been associated with:

• Gastric lymphoma
• Gastric adenocarcinoma

NSAIDS inhibition of COX-1 reduces the production of mucosal protective prostaglandins.

NSAIDs are a common cause of GI disturbance (e.g. PUD, gastritis) through their inhibition of cyclooxygenase-1 (COX-1). Most NSAIDs are non-selective inhibitors of cyclooxygenase (i.e. both COX-1 and COX-2) which are both important enzymes:

• COX-1: constitutively expressed, acts as an enzyme to catalyse production of mediators like prostaglandin and thromboxane from arachidonic acid. Important role in many physiological functions including protective effects on the gastric mucosa. It is the somewhat inadvertent inhibition of this system that leads to some NSAID related side effects like gastritis and PUD.
• COX-2: inducible expression in response to inflammation. Catalyses production of inflammatory prostaglandins (and other mediators) from arachidonic acid. These prostaglandins play a role in inflammation, pain and fever and it is inhibition of their effects that give the desired symptomatic relief from NSAIDs.

It is suspected that 50% of patients taking NSAIDs show mucosal damage, 30% of patients have ulcers seen on endoscopy and 5% of patients are symptomatic. 

Some newer NSAIDs (e.g. Celecoxib) have been developed that selectively target COX-2. These drugs may be taken in rheumatic disease to help reduce the number of GI side-effects. However use is limited owing to the increased risk of cardiovascular complications.

Zollinger-Ellison syndrome occurs secondary to a hyper-secreting gastrinoma within the pancreas. 

Hypergastrinaemia leads to the development of multiple peptic ulcers. Sporadic cases account for around 80% of cases of Zollinger-Ellison syndrome.

Approximately, 20% are part of multiple endocrine neoplasia type I (see notes on MEN syndromes).

The hallmark features of PUD are epigastric pain, dyspepsia and heartburn.

Symptoms

• Epigastric pain
• Dyspepsia (e.g. distension, bloating)
• Heartburn

Signs

• Mild epigastric tenderness

Acute presentations

Patients with PUD may present acutely with features of an acute upper GI bleed (UGIB) or perforation.

• Acute UGIB
  • Haematemesis +/- melaena
  • Features of shock may be present
• Perforation
  • Acute, severe abdominal pain & tenderness
  • Localised or generalised guarding
  • Features of shock may be present

Gastric outlet obstruction

Gastric outlet obstruction may occur in PUD secondary to stricturing and narrowing resulting from inflammation, ulcers and scarring. 

Patients present with nausea, vomiting and typically upper abdominal pain. Tenderness, distention and a succussion splash may be found on examination.

The definitive diagnosis of PUD is made on endoscopic examination. However, only a small number of patients presenting with dyspepsia/heartburn require upper GI endoscopy. 

Bedside

• Observations
• H. pylori testing (see below)
• ECG (cardiac pathology should be considered in patients presenting with epigastric pain/discomfort)

Bloods

• Full blood count (may show an iron-deficiency anaemia)
• Liver function tests (may be ordered if biliary pathology and gallstones a suspected differential)

Endoscopic

• Upper GI endoscopy

H. pylori testing may be non-invasive or invasive.

Non-invasive tests offer good sensitivity and specificity when used in the correct setting. Invasive testing may be completed during an upper GI endoscopy.

Non-invasive

¹³C Urea breath test: Is a useful screening test for the presence of H. pylori. The subject ingests ¹³C urea, which is converted to ¹³CO₂ in the presence of urease. It is a highly sensitive 97.6% and specific (96%) test. The breath test can be used for both diagnosis and testing for eradication. Importantly, patients must be off PPI’s prior to testing.

Serological test: A blood test is taken which checks IgG antibodies against H. pylori. This is a useful test for diagnosis and epidemiological studies. In general, it is a good test (sensitivity 90% and specificity of 83%). However, it cannot be used to check for eradication owing to the persistence of antibodies within the serum.

Stool antigen test: The stool test assesses the faeces for the presence of H. pylori antigen. It is a reliable test (sensitivity 97.6% and specificity 96%), and can be used for both diagnosis and testing for the eradication of H. pylori. Like the breath test, patients must be off PPI's prior to testing. 

Invasive

Urease test: The urease test is also known as the CLO test (campylobacter-like organism test). Biopsies are taken from the mucosa during endoscopy and added to a medium containing phenol red and urea. The presence of urease leads to the splitting of urea, and the release of ammonium that leads to a pH colour change. The test may be falsely negative in the presence of PPI therapy. 

Histology: A section of a biopsy taken during endoscopy can be examined under a microscope with a Giemsa stain looking for the organism.

Culture: A biopsy specimen taken at the time of endoscopy can be used for culture of the organism. This test is useful for assessment of antibiotic sensitivities.

Luminal surface with scattered H.pylori on and above the surface

Image courtesy of Ed Uthman

Management of PUD involves lifestyle modifications, PPIs and antibiotics.

Patients who test positive for H. pylori should be offered eradication therapy. The length of treatment (and need for specialist intervention) is dependent on H. pylori status, NSAID involvement and symptomatic control.

General points

Lifestyle modifications are key to the management of PUD. Patients should maintain a healthy diet avoiding foods and drinks that exacerbate their symptoms.

• Avoid triggers: Patient may encounter certain foods that trigger discomfort and pain, common examples include coffee, tomato and spicy foods.
• Obesity: In patients who are overweight help and advice for healthy weight-loss should be given.
• Smoking & alcohol: Where appropriate smoking cessation advice and help should be given. Alcohol should be reduced where necessary and within the national advised limits.
• Mental health: Assess the patients for any psychological conditions such as anxiety or depression that may impact on symptoms.

PUD associated with H.pylori

• No association with NSAIDs: Patients are given the first-line eradication therapy.
• Association with NSAIDs: Patients are given two months of full-dose PPI, after this is complete they are given first-line eradication therapy.

For details of H.pylori eradication therapies see the chapter below.

PUD not associated with H.pylori

Patients who test negative for H.pylori are given 4-8 weeks of full-dose PPI.

Follow-up

Due to the possibility of underlying malignancy, gastric ulcers should be biopsied and reassessed after treatment. This means a follow-up endoscopy to ensure healing in 6-8 weeks. Duodenal ulcers do not routinely require follow-up endoscopy.

H. pylori eradication therapy needs to take into account previous antibiotic therapy and patient allergies.

1^st line eradication

Patients are given a 7-day course of triple-therapy, which includes a PPI and dual antibiotic therapy.

• Non-penicillin allergy
  • Proton pump inhibitor
  • Amoxicillin
  • Clarithromycin/metronidazole
• Penicillin allergy
  • Proton pump inhibitor
  • Clarithromycin
  • Metronidazole

2^nd line eradication

If 1st line therapy fails patients are given a different antibiotics and an extended course. The choice of pharmacotherapy is dependent on allergy status and previous antibiotic exposure. 

• Non-penicillin allergy
  • Proton pump inhibitor
  • Amoxicillin
  • Clarithromycin/metronidazole
  • Quinolone/tetracycline
• Penicillin allergy
  • PPI
  • Metronidazole
  • Levofloxacin/tetracycline
  • Bismuth

Referral

Specialist referral is warranted in patients with disease that has not responded to second-line therapy or with unexplained symptoms.

Peptic ulcer disease may be complicated by perforation, haemorrhage and gastric outlet obstruction.

• Perforation: Due to earlier recognition and treatment the incidence of PUD related perforations has decreased though it remains a life-threatening condition with a mortality of up to 20%. Patients typically present with severe abdominal pain with signs of infection. Management tends to take the form of supportive care, antibiotics and laparoscopic repair / omental patch.
• Haemorrhage: Can cause a massive upper GI bleed, a life-threatening condition with mortality estimated to be 5-10%. The classical description of bleeding in PUD is of a posterior duodenal ulcer eroding through into the gastroduodenal artery. However many occur secondary to erosions through smaller-sized blood vessels within the submucosa. Bleeding may be mild and chronic resulting in iron deficiency anaemia. See our Upper GI bleeding notes for more information.
• Gastric outlet obstruction: May occur secondary to inflammation, ulceration and scarring leading to narrowing and stricturing of the gastric outlet. Patients tend to present with nausea and vomiting, abdominal pain and distention.

Last updated: March 2021