Author: Craig Andrew Walker / Editor: Janet Skinner / Codes: CAP1 / Published: 17/08/2010 / Review Date: 17/08/2013
The Nobel Prize for Medicine and Physiology was awarded to Warren and Marshall in 2005 for discovering and establishing the role of Campylobacter pyloridis (later renamed Helicobacter pyloris) in Peptic Ulcer Disease (PUD) in 1982 (1). This altered the view of PUD from a primarily acid-driven entity to an infectious disease. Unfortunately, although there has been a decrease in its incidence in the latter 20th century, it remains a significant cause of morbidity and mortality. Even in HP-negative individuals, the widespread use of NSAIDs (including low-dose Aspirin) contributes to the persistence of PUD as a clinical problem. 10% of the population of Western countries are likely to develop a duodenal or gastric ulcer during their lifetime (3). In the United States, approximately 0.5 million people develop PUD each year, costing the US healthcare system an estimated $10 billion (2). Peptic Ulcer Disease is also the most common cause of upper GI bleeding worldwide.
1 in 10 people in the UK will develop PUD at some stage in their lives
Ulcers are defined as mucosal erosions greater than or equal to 0.5cm. Peptic ulcers occur in the gastrointestinal tract and are characterised by mucosal damage from pepsin and gastric acid secretion (4).
- Proximal duodenum
Less common sites:
- Lower oesophagus (e.g. within a sliding hiatus hernia; a Cameron ulcer )
- Distal duodenum
- Ileum (e.g. Meckles diverticulum, due to ectopic gastric mucosa)
Peptic ulcers are characterised by mucosal damage from pepsin and gastric commonly found in the stomach and proximal duodenum.
Basic Science & Pathophysiology
- Helicobacter pylori
- Others Cigarette smoking, Medications, Zollinger-Ellison Syndrome, Meckels diverticulum
1. Helicobacter Pyloris
Helicobacter pyloris is a gram-negative, motile, spiral-shaped bacterium. Estimates vary, but over half of the worlds population is thought to be infected. The prevalence is 50-90% in developing countries, with lower rates of 20-50% found in developed countries, such as the USA (5). It is thought that more than 50% of children are infected with HP by the age of 10 years (6). However, less than 20% of all infected individuals ever demonstrate clinical gastrointestinal disease.
H pylorus lives in the mucous layer above gastric surface epithelial cells. It multiplies optimally in a pH of 6.0 to 8.0. To allow it to do this in the acidic stomach, it produces high levels of urease enzyme. This converts the urea produced from gastric epithelial cells into ammonia and bicarbonate, thereby buffering the gastric acid and allowing its survival. In health, a low antral pH would normally stimulate release of somatostatin from D cells, acting in a negative inhibitory manner to decrease gastrin release from adjacent G cells, thereby increasing pH. However, the production of ammonia by HP prevents the D cells from sensing the true pH, allowing ongoing inappropriate gastrin release and excess acid production. HP also impairs neural pathways which would otherwise have lead to down-regulation of acid production. HP can only colonise gastric epithelial cells. However, excess acid secretion can provoke gastric metaplasia of duodenal cells, allowing colonisation. The infected cells then become more susceptible to erosion and ulceration (7). In addition to acid hypersecretion, the immune response provoked by H pylori impairs mucosal defences and can lead to ulceration through a complex interplay between epithelial-derived cytokines, neutrophils, macrophages, leukotrienes and B- and T-lymphocytes.
The urease enzyme produced by HP allows its survival and leads to inappropriate gastrin release and excess acid production.
2. Non-Steroidal Anti-Inflammatory Drugs
Up to 20% of peptic ulcer disease is attributable to the use of NSAIDs (8)(9). The annual risk of a life-threatening ulcer-related complication is 1 to 4 percent in patients who use NSAIDs long-term. (4). Ulcers and ulcer-related complications increase with older age, concurrent steroid or anticoagulant use, prior ulcer or bleeding and in those with major organ impairment (4)(9). NSAIDs cause mucosal injury through multiple mechanisms. The most well-known of these is through inhibition of prostaglandin synthesis by inhibiting cyclooxygenase (COX)-1. This can lead to reduced mucous and bicarbonate secretion, reduced mucosal blood flow and impaired platelet aggregration, all reducing host defences to injury (10). The much-publicised COX-2 inhibitors were developed in an attempt to increase GI tolerance. COX-2 inhibitors reduce but do not eliminate ulcers or their complications (11). Multiple studies have shown that COX-2 inhibitors increase cardiovascular mortality and many have been withdrawn from the market (12)(13)(14). Long-term use of non-selective NSAIDs also increases cardiovascular mortality. NSAIDs also exert a direct local toxic effect to gastric cells through a variety of mechanisms (10). The use of NSAIDs in patients with active H pylori infection increases the risk of PUD and of bleeding (17).
NSAIDs cause mucosal damage through both local and systemic effects.
3. Other Causes of Peptic Ulcer Disease
Cigarette smokers are twice as likely to develop PUD as non-smokers. It increases gastric acid secretion, duodenogastric reflux and decreases both gastroduodenal prostaglandin production and pancreaticoduodenal bicarbonate production, all of which may contribute to morbidity (9)(15)(16).
Alcohol, Steroids, potassium chloride, bisphosphonates, chemotherapy agents (e.g. 5-FU).
The most common congenital abnormality of the small intestine and caused by incomplete obliteration of the vitelline duct. This may result in ectopic gastric mucosa present in the distal ileum and can lead to ulceration and complications such as bleeding and perforation.
A gastrin-secreting tumour can cause increased gastric acid secretion in addition to parietal cell hyperplasia, resulting in peptic ulcer disease.
- Neoplastic lesions; primary or secondary
- Crohns disease
- Viral infections, esp. if immunocompromised (CMV,HSV)
- Post-partial gastrectomy
- Radiation damage
- Stress: physiological e.g. burns, major trauma and psychological
The most specific and classic features of peptic ulcer disease are:
- A history of episodic or epigastric pain
- Relief of pain after food intake
- Night-time awakening because of relief with food intake (4).
Epigastric pain is often described as gnawing or burning . Duodenal ulcers are typically worsened by hunger/fasting and relieved by eating. Conversely, gastric ulcers may cause pain on food intake. Fear of eating due to pain may even cause weight loss. Less commonly, there may be nausea, vomiting, abdominal bloating/fullness, early satiety, heartburn or intolerance of fatty foods.
Patients may present initially with complications such as bleeding and perforation. This absence of other symptoms is more likely with NSAID-induced ulcers (7). Patients should be specifically asked whether there has been a change in bowel habit e.g. melaena or rectal bleeding and whether there has been any coffee-ground or fresh haematemesis. Patients may not always volunteer such information due to fear or embarrassment.
Patients with NSAID-induced ulcers are the most likely to have minimal preceding symptoms and present initially with complications.
Physical examination is unreliable in predicting patients with peptic ulcer disease and therefore, if the history suggests PUD, then an assessment should be made for alarm features
- Evidence of GI Blood Loss
- Unexplained Weight Loss
- Upper Abdominal Mass
- Persistent Vomiting (18)(19)
Physical examination is of limited value in predicting patients with PUD (4).
- Baseline Observations: heart rate, blood pressure (including postural BP), Temperature, oxygen saturations, BM.
- Urinalysis and hCG in all females of child-bearing age to exclude an ectopic pregnancy
- FBC, Urea and Electrolytes: A low Hb (especially microchromic microcytic) and a raised urea may suggest bleeding.
- Liver function tests, Amylase: Patients with epigastric pain radiating to the back and/or RUQ may instead have biliary colic, acute cholecystitis or acute pancreatitis.
- Group & Save or Cross-Match: Required if evidence or suspicion of bleeding.
- 12-lead ECG: Atypical epigastric pain (and back pain) can be a feature of acute coronary syndromes.
- Chest X-ray: Persistent upper abdominal pain radiating to the back suggests perforation. May also be appropriate if anorexia, dysphagia or unexplained weight loss is present, suggesting cancer.
Emergency Department Management Goals
- Identify patients with life-threatening complications and/or haemodynamic instability and institute initial resuscitation.
- Identify patients with suspected PUD that require admission or urgent referral.
- Identify patients with suspected PUD that can be safely discharged from the ED.
- Arrange appropriate follow-up for those patients who are discharged.
Identify patients with haemodynamic instability and resuscitate appropriately.
- High concentration Oxygen through a variable flow mask with reservoir bag.
- 2 x large bore cannula
- IVFluids: 1-2 Litres crystalloid and reassess (colloid if known liver disease)
- Urgent referral to GI specialist and/or surgeon and Critical Care.
Management of the Complications of PUD
Approximately 25% of patients have a serious complication such as haemorrhage, perforation or obstruction. Patients taking NSAIDs are more likely to have silent ulcers and present with complications (4).
patients with an NSAID-induced ulcer are at a higher risk of complications.
Peptic ulcer disease is the commonest cause of upper GI bleeding (even in alcoholic patients) and is due to erosion of the ulcer into an artery.
In part due to ageing populations, mortality for such bleeding has remained at around 10% over the past 2 decades (20)(21). It is the most common cause of death and the most common indication for surgery. High dose PPIs post-endoscopy (e.g. Pantoprazole 40mg IV) have been shown to reduce rebleeding rates, the need for surgery and further endoscopic treatment (23). They are often given pre-endoscopy although the current SIGN guideline advises them to be withheld until post-endoscopy (22). A pragmatic approach is to consider them pre-endoscopy in high risk patients, particularly when a delay to endoscopy is envisaged. NSAIDs should be stopped in patients who present with bleeding and only restarted if there is a clear indication and once HP eradication and ulcer healing has been confirmed. Bleeding may be subtle and should be actively sought-out in history, examination (including digital rectal exam if there is any doubt) and appropriate tests (including lying and standing BPs and lab tests).
A full discussion of the assessment and management of upper GI haemorrhage is covered within the appropriate CEMpaedia section.
In terms of upper GI bleeding caused by PUD, the Rockall score is used for risk stratification. The higher the score, the higher the mortality rate. The full score requires endoscopy findings but a modified pre-endoscopy score is used as a marker for severity in the UK.
A pre-endoscopy score of 0 equates with a mortality of 0.2%, a score of 3 with a mortality of 11% and a score of 7 with a 50% mortality.
Patients with upper GI bleeding may require active resuscitation and haemodynamic instability require urgent upper GI endoscopy.
Acute perforation occurs in 2 to 10% of patients with peptic ulcer disease (24). It normally involves the anterior wall of the duodenum (60%) but may also affect the gastric antrum (20%) and lesser curvature (20%). This surgical emergency and the resultant bacterial peritonitis carries with it a mortality of 30 to 50% in older patients (4).
- Often sudden, severe abdominal pain which rapidly worsens.
- Pain may radiate to the back or either shoulder.
- Generalised abdominal tenderness with guarding, rebound tenderness and/or rigidity with hypoactive bowel sounds may be present.
- Patients may be tachycardic, hypotensive with fever and/or oliguria
An erect chest x-ray may show free subdiaphragmatic air. However, it may be normal and further investigation, depending on the patients clinical state and likelihood of perforaton, may be required (e.g. CT or surgery).
Initial Management as per resuscitation flow chart plus:
- Broad-spectrum IV antibiotics (normally 3rd generation cephalosporin and metronidazole or Tazocin)
Surgical intervention normally consists of laparotomy, placement of an omental patch and washout of peritoneal contents. Perforated gastric ulcers are treated with an omental patch, wedge resection of the ulcer, or a partial gastrectomy and reanastomosis (4).
Gastric Outlet Obstruction
PUD accounts for 5-8% of cases, with pyloric stenosis common in paediatric populations and neoplastic lesions (especially pancreatic cancer) more common in older populations.
- Recurrent large-volume vomiting containing undigested food.
- Abdominal distension; often tympanic and may be associated with a palpable epigastric mass +/- visible peristalsis.
- Weight loss, lethargy, malaise.
- There may be a hypochloraemic, hypokalaemic metabolic alkalosis.
Initial management consists of resuscitation, CXR + AXR, NG tube insertion for aspiration of gastric contents and senior surgical review. Upper GI Endoscopy is performed to assess the site, severity and nature of the disease. Surgical removal of the obstructive lesion may be possible. Malignancy should be actively investigated.
Obstruction caused by inflammation and oedema due to PUD usually responds to HP eradication and PPIs.
Management of Patients with no Haemodynamic Instability or Complications
Patients with symptoms or signs suggesting a neoplastic lesion but without complications and who are managing at home should be discussed with a Gastroenterologist who may opt for urgent outpatient investigation (UGIE, CT) rather than admission. In patients with uncomplicated dyspepsia (with no alarm features), an initial approach of lifestyle advice (decrease or stop smoking, alcohol and illicit drug use; weight reduction; healthy eating advice) is recommended.
If this fails to resolve symptoms, there is insufficient evidence as to whether a trial of either a Proton Pump Inhibitor (PPI) or H2-receptor antagonist (HRA) for 1 month or a Test and Treat strategy should be offered first. Either therapy may be appropriate. This advice was included in the last SIGN and NICE guidelines (18)(19).
Patients need to be at least 2 weeks free of PPI and 4 weeks free of antibiotic therapy prior to HP testing or this may cause a false-negative result.If symptoms persist, a Test and Treat strategy for H Pylori should be adopted. This involves performing a non-invasive H. pylori test, eradication of infection in all those who test positive and providing symptomatic relief for those who test negative.
- A non-invasive test and treat strategy is as effective as endoscopy in the initial management of patients with uncomplicated dyspepsia who are less than 55 years old (18).
- This initial strategy may also be as appropriate as early endoscopy for patients greater than 55 years old presenting with uncomplicated dyspepsia (18).
ED patients presenting with uncomplicated dyspepsia should be given lifestyle advice and advised to attend their GP for further investigation (e.g. HP testing). If symptoms are severe, a PPI or HRA may be prescribed in the interim, although this could delay HP testing.
Non-invasive validated tests for HP infection include the 13C-Urea Breath Test (CUBT) and faecal antigen tests.
These tests confirm active infection and are therefore also useful in retesting post-HP eradication. *The CUBT should not be performed within 2 weeks of PPI therapy or within 4 weeks of antibiotic therapy as false negative results may occur* (18) . Serum ELISA tests can confirm HP infection but these are the least accurate test, cannot distinguish between previous and current infection and are therefore not suitable for post-eradication confirmation (4). In patients who undergo initial upper GI endoscopy (e.g. for investigation of suspected neoplastic lesions), biopsy specimens can be tested for HP: CLO (Campylobacter-like organism) tests give a result within 30mins of sampling.
13C-urea breath test and faecal antigen tests are the non-invasive tests of choice for active HP infection.
If test results are positive, the infection should be eradicated with antibiotics in association with acid-inhibiting therapy. Local guidelines vary but normally consist of a PPI and two antibiotics. If HP eradication is successful and the patient remains asymptomatic with no alarm features, endoscopy is not required. If the patient has persistent or recurrent symptoms despite eradication (which may be confirmed on CUBT or faecal antigen testing), specialist referral for endoscopy is indicated.
Consideration should be given as to whether the patient has an NSAID-associated ulcer. If the patient is taking regular NSAIDs, these should be discontinued if possible. If this is not possible or if symptoms persist, prescription of a PPI or HRA for 1 month is appropriate. If symptoms are severe or persistent, specialist referral for UGIE should be considered (4)(7). Treatment options for NSAID-associated HP-negative ulcers include co-prescription of a PPI and Misoprostol or (if low cardiovascular risk), changing to a COX-2 inhibitor + PPI or Misoprostol (7).
Other Medical Therapies
|Histamine-2 Receptor Antagonists (HRA)||Selectively blocks Histamine binding on H2 receptors in parietal cells||Ranitidine, Cimetidine.||Largely replaced by the more potent acid suppression of PPI.|
|Proton Pump Inhibitors (PPI)||Selectively block the H+K+ ATPase of parietal cells||Omeprazole, Pantoprazole, Esomeprazole.||Treatment for all HP-negative ulcers, included in eradication regimes, prevention of NSAID ulcers.|
|Prostaglandin analogues||PGE1 analogue; decreases cAMP generation of parietal cells which is triggered by histamine and enchance mucosal defences||Misoprostol||Used in HP-negative gastric ulcers and prevention of NSAID-ulcers.|
(PPI + 2 antibiotics)
|Eradication of Helicobacter pylori||Omeprazole + Amoxicillin & Clarithromycin||Standard therapy in HP-positive dyspepsia or ulcers.|
|Bismuth salts||Weak antibacterial effect; increase muscosal PG synthesis||Tripotassium dicitratobismuthate||In quadruple therapy for HP-eradication when standard eradication has failed.|
Table produced from the information contained within (7)
Endoscopy in PUD
- Haemorrhage control in patients with upper GI bleeding
- Confirmation of PUD in patients with persistent dyspepsia
- Biopsy for confirmation of HP infection and/or neoplasia
- Reassessment in patients with ongoing symptoms despite HP-eradication or withdrawal of NSAIDs.
Endoscopic Treatment Options for UGI Haemorrhage
Direct injection of Adrenaline 1:10,000.
If high-risk stigmata (i.e. blood in lumen or visible vessel), consider dual- or triple-therapy which consists of:
- Mechanically clipping the vessel +/-
- heat application (either by heater probe, Argon plasma coagulator or multipolar probe).
If ongoing bleeding despite the above, patient requires emergency surgery.
- Oesophageal Banding.
- Gastric Direct injection of thrombin or cyanoacrylate glue.
If still unable to control bleeding, insertion of a Sengstaken-Blakemore tube is indicated.
In this scenario, consideration should be made about performing TIPSS (Transjugular Intrahepatic Porto-Systemic Shunt) to improve the underlying portal hypertension.
Safety pearls and Pitfalls
Failure to actively assess for alarm features in all patients presenting with dyspepsia may result in delays in diagnosis of cancers and may miss those with complications such as potentially fatal upper GI bleeding.
It may be entirely appropriate for some patients to be discharged to attend follow-up with their GP but a full assessment for alarm features and complications must be carried-out prior to discharge.
Bleeding may be subtle and should be actively sought-out during all consultations in patients presenting with dyspepsia.
Always keep the alarm symptoms of PUD in mind when assessing patients with dyspepsia.
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