Peptic Ulcer

Introduction to Peptic Ulcer Disease

Peptic ulcers are defects in the gastrointestinal mucosa that extend through the muscularis mucosa. Indigestion is the most common symptom in patients found to have peptic ulcer disease. The term gastritis is used to denote inflammation associated with mucosal injury. Gastropathy is defined as epithelial cell damage and regeneration without associated inflammation.

In recent years the discovery of the organism Helicobacter pylori has resulted in a dramatic change in our understanding of the aetiology and pathophysiology of peptic ulcer disease. What was once a chronic disease prone to relapse and recurrence has now become eminently treatable and curable.

Patients presenting to emergency departments may do so with ‘classic’ ulcer symptoms, undifferentiated abdominal or chest pain, or more dramatically with life threatening complications such as perforation or haemorrhage.

Pathophysiology

Peptic ulcer disease is associated with two major factors: Helicobacter pylori (H. pylori) infection and the consumption of non-steroidal anti-flammatory drugs (NSAIDs). Although the vast majority of patients harboring H. pylori are asymptomatic, it is now accepted that H. pylori is the major cause of peptic ulceration, or at least a major cofactor in the development of peptic ulcer disease.

H. pylori has been isolated from 20–50% of patients with dyspeptic symptoms. More importantly, 90-95% of patients with duodenal ulcers and 70% of those with gastric ulcers are infected with the organism. Eradication of H. pylori has been shown to markedly reduce the recurrence rate for ulceration. NSAIDs, including low-dose aspirin, are the second most common cause of peptic ulceration and account for most ulcers not due to H. pylori.

NSAIDs cause ulcers by inhibiting the production of prostaglandins in the stomach and duodenum (a vital part of the stomach’s mucosal defence mechanisms), and hence may also cause ulceration when given by non-oral routes. NSAIDs are more commonly associated with gastric ulceration. At least 50% of patients taking NSAIDs will have endoscopic evidence of erythema, erosions or ulcers, even if asymptomatic.

There are several risk factors that influence gastrointestinal toxicity due to NSAIDs, the most important being a prior history of clinical ulcer disease or ulcer complications. Other risk factors are the dose, duration of action and duration of therapy with NSAIDs, age of the patient (greater risk above 75 years) and comorbidity, especially with cardiovascular disease.

Combined therapy of NSAIDs with corticosteroids, anticoagulants, other NSAIDs or low dose aspirin dramatically increases the risk of ulcer complications. In a study of high risk patients with a prior history of GI bleeding, the antiplatelet agent clopidogrel was associated with a 12-month rebleeding rate of 8.6%, compared to 0.7% for aspirin combined with a proton pump inhibitor. Thu, clopidogrel is contraindicated in high-risk patients used either alone or in combination with NSAIDs.

Some NSAIDs are more likely to produce ulcers than others. In general, shorter-acting agents such as ibuprofen and diclofenac are less likely to lead to ulcers than longer-acting agents. Controlled trials with COX-2 selective inhibitors (coxibs) have demonstrated a reduction in the risk of peptic ulcers and their complications. Importantly, valdecoxib and refecoxib were removed from the market by the US Food and Drug Administration because of data indicating an increased risk of thrombotic cardiovascular disease.

Although there are concerns about the cardiovascular risks of celecoxib, especially at higher doses, it remains available at present. There is no evidence that coxibs have advantages over other NSAIDs for patients with unhealed ulcers. Coxibs appear to inhibit healing of peptic ulcers. Thus, they are not an attractive alternative for patients with active peptic ulcer disease.

Acid is an important ingredient in the pathogenesis of both NSAD- and H. pylori-induced ulceration. The interaction between NSAIDs and H. pylori is controversial and complex, but evidence from two controlled trials and a meta-analysis of observational studies identified synergism between H. pylori and NSAIDs in producing peptic ulcer and ulcer bleeding. Traditional risk factors such as smoking, alcohol and stress may increase the risk of ulceration and delay healing, but their relative importance as aetiological agents has fallen considerably with the discovery of H. pylori. Other causes of peptic ulceration, such as Zollinger-Ellison syndrome, are rare.

Gastritis is usually due to infectious agents (such as H. pylori) and autoimmune and hypersensitivity reactions. In contrast, gastropathy is usually caused by irritants such as drugs (e.g. NSAIDs and alcohol), bile reflux, hypovolaemia and chronic congestion.

Clinical Features

1. History

Peptic ulcers may present with a wide variety of symptoms, or may be completely asymptomatic until complications such as haemorrhage or perforation occur. As mentioned earlier, indigestion is the most common symptom in patients found to have peptic ulcer disease.

Patients describe a burning or gnawing pain in the epigastrium that may radiate into the chest or straight through to the back. Food may either exacerbate or relieve the pain. The pain is classically both fluctuating and periodic, with bouts of discomfort of variable severity interspersed with symptom-free periods.

The symptoms indigestion or dyspepsia, however, have relatively poor sensitivity and specificity for diagnosing the various peptic syndromes. Less than 25% of patients with dyspepsia have peptic ulcer disease proven by gastroscopy, and between 20% and 60% of patients presenting with complications of ulcer disease report no antecedent symptoms.

Some patients may present with the classic symptom complex. Others present with chest or abdominal pains that need to be differentiated from conditions such as myocardial ischaemia, biliary tract disease, pancreatitis and other abdominal emergencies.

Patients also present with the two most common complications of ulcer disease, namely acute gastrointestinal haemorrhage or acute perforation. The former gives symptoms of melaena with or without haematemesis, and the latter presents with sudden, severe abdominal pain.

2. Examination

In uncomplicated peptic ulcer disease abdominal findings may be limited to epigastric tenderness without peritoneal signs. If perforation has occurred, patients are in severe pain and look unwell. Abdominal findings include generalized tenderness, widespread peritonism and so-called ‘board-like’ rigidity. Those with gastrointestinal bleeding will usually have melaena on PR examination.

Investigations

The extent of investigations depends greatly on the patient’s presentation and the degree of severity of symptoms.

1. Haematology and Biochemistry

There are no established blood tests that can reliably predict the presence of peptic ulcer disease. Pathology investigations are aimed primarily at eliminating alternative diagnosis or identifying the complications of peptic ulceration.

2. Full Blood Examination

Anaemia is most likely to represent chronic rather than acute blood loss, unless bleeding is particularly heavy and hence clinically obvious. A microcytic, hypochromic anaemia suggests chronic blood loss with iron deficiency, and can be confirmed with iron studied. Unexplained anemia warrants a detailed evaluation and may raise concern for an underlying malignancy.

3. Blood Cross-Match

Patients with active bleeding may need replacement with blood products. Several units of blood may be required.

4. Clotting Studies

These are indicated in patients taking warfarin and those with massive bleeding and/or a history of liver disease or alcoholism.

5. Liver Function Tests/Amylase/Lipase

Biliary tract disease and pancreatitis are common differential diagnoses in patients presenting with non-specific epigastric or upper abdominal pain. Pancreatitis may also be the consequence of ulcer penetration through the posterior wall of the stomach.

6. Radiology

Radiological imaging has a very limited place in the diagnosis of uncomplicated peptic ulcer disease. However, an erect chest X-ray (CXR) is an important investigation when perforation is being considered. Gas is usually visible under the diaphragm, but its absence does not rule out perforation. Several studies have reported the sensitivity of erect CXR for detection of pneumoperitoneum as ranging from 70% to 80%. Lateral decubitus abdominal X-rays may be needed to demonstrate free gas in those unable to sit erect. CT scans of the abdomen may be more sensitive in detecting small pneumoneritoneums.

Contrast studies are no longer considered first-line investigations in the assessment of patients with dyspeptic symptoms. Abdominal X-ray and ultrasound studies are useful to exclude alternative diagnoses, as indicated.

7. Endoscopy

Endoscopy is the investigation of choice for patients with dyspeptic symptoms, allowing direct visualization of the mucosa of the oesophagus, stomach and proximal duodenum. It provides a definitive diagnosis, which forms the basis of drug therapy and allows biopsies to be taken to exclude malignant disease and to isolate H. pylori. Endoscopy may also be therapeutic in some cases of upper gastrointestinal haemorrhage. Patient selection for referral for endoscopy is described below.

8. H. Pylori Status

The discovery of H. pylori was quickly followed by the development of tests to identify its presence. Currently there are a number of tests available, both invasive and non-invasive, though their exact role in the emergency department (ED) setting has not been defined.

It should be remembered that the majority of patients infected with H. pylori do not in fact have peptic ulcer disease, and that the identification of H. pylori do not in fact have peptic ulcer disease, and that the identification of H. pylori infection often bears little relation to presenting symptoms. In particular, neither of the non-invasive tests can make a diagnosis of peptic ulcer disease, only of H. pylori infection. However, a negative test in a patient not taking NSAIDs makes the likelihood of peptic ulcer low.

The invasive tests for H. pylori include haematoxylin and eosin staining of mucosal biopsies and rapid urease tests (e.g. CLOtest). The non-invasive tests include urease breath tests and IgG serology. Urease breath tests are highly sensitive and specific for the presence of H. pylori They are most useful in assessing H. pylori eradication without the need for further gastroscopy.

A number of IgG serology tests are available with varying specificities and sensitivities. They are inexpensive, non-invasive and well suited to primary care, and potentially emergency medicine, practice. Large studies have found uniformly high sensitivity (90–100%), but variable specificity (76–96%); the accuracy has ranged from 83% to 98%.

Management

Traditional management of patients with dyspeptic symptoms requires the exclusion of other diseases, the removal of known precipitants such as NSAIDs, alcohol and cigarettes, the institution of simple treatment measures aimed at symptomatic relief, and referral for further investigation and management. This remains a reasonable option.

Alternatively, cost-effectiveness analysis and consensus statements support the treatment of H. pylori-positive dyspeptic patients with antimicrobial and anti-secretory therapy, followed by endoscopic study only in those with persistent symptoms, so it would also be reasonable to begin symptomatic therapy, order serological testing for H. pylori, and refer for early follow-up with a primary care provider for initiation of antibacterial therapy if the test results are positive.

The choice of approach is open to debate. Early treatment prior to endoscopy may cure some patients without the need for expensive invasive procedures. However, this plan of action may hinder subsequent H. pylori isolation and delay definitive diagnosis, including the diagnosis of malignant disease.

It should be noted that the prevalence of H. pylori is lower in patients with complicated duodenal ulcers (those complicated by bleeding or perforation) than in those with uncomplicated disease. Patients with H. pylori-negative ulcers appear to have a significantly worse outcome, especially if treated empirically for infection. Thus, documenting infection is an appropriate caution prior to initiating antimicrobial therapy.

For patients with mild symptoms of recent onset, empirical treatment with antacids and/or histamine receptor antagonists aimed at symptomatic relief is reasonable.

Given the poor correlation between dyspeptic symptoms and gastro-oesophageal disease, gastroscopy should be considered, particularly if symptoms are not controlled or promptly recur.

A recent review of the literature concluded that for patients with non-ulcer dyspepsia, H₂-receptor blockers were significantly more effective than placebo at reducing symptoms, whereas proton pump inhibitors and bismuth salts were only marginally so. Antacids and sucralfate were not statistically superior to placebo.

1. Antacids

Antacids, containing combinations of calcium, magnesium, local anaesthetics and alginates, are useful in providing symptomatic relief for patients with relatively mild symptoms. In many instances patients have already tried these agents prior to presentation.

2. Histamine-Receptor Antagonists

The H₂-receptor antagonists such as cimetidine, ranitidine, famotidine and nizatidine all have similar efficacies with regard to ulcer healing. All are well absorbed orally, but their absorption may be reduced when used with antacids but not by food.

Eighty to 90% of duodenal ulcers will be healed in 4–8-weeks, and 70% of gastric ulcers within 8 weeks. Relapse rates of 80% over the course of 1 year are to be expected if H. pylori eradication is not also undertaken. H₂ antagonists are also useful in the treatment of gastro-oesophageal reflux disease and management of dyspepsia. Due to renal excretion, dosage adjustments must be made in patients with renal failure.

3. Proton Pump Inhibitors (PPIs)

The PPIs omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole effectively block acid secretion by irreversibly binding to and inhibiting the H⁺/K⁺ATPase pump of the gastric parietal cells, thereby inhibiting the cell’s proton pump.

Acidic compartments within the stimulated parietal cell are essential for activation of a PPI. Thus PPIs work poorly in fasting patients or those with simultaneous dosing with other antisecretory agents (H₂-receptor antagonists, anticholinergic agents or somatostatin). PPIs are most effective when taken with or shortly before meals. Compared to H₂-receptor antagonists, these agents result in more rapid ulcer healing and pain relief over 2–4 weeks, although differences at 8 weeks are not significant. Again, relapse rates are high, particularly if H. pylori is present and eradication therapy is not used.

4. Cytoprotectants

Cytoprotective agents include colloidal bismuth subcitrate (De-Nol) and sucralfate. Both act by binding to or chelating with proteins in the base of the ulcer.

Bismuth compounds also suppress H. pylori. A 6–8 week are still high. Bismuth compounds lead to the formation of black stools that may be confused with melaena. The primary concern with bismuth is bismuth intoxication. Sucralfate should not be taken with antacids as it requires an acid environment to achieve its optimal effects. Sucralfate has minimal adverse effects other than possible aluminium toxicity.

5. Prostalglandin Analogues

Misoprostol, a synthetic analogue of PGE₁, interferes with histamine-dependent gastric acid secretion as well as being cytoprotective. It is particularly useful in the prevention of NSAID-induced ulcers, although it is probably no better than the other agents in actually treating such ulcers.

6. H. pylori Eradication

All patients with duodenal ulcers associated with H. pylori infection should undergo therapy to eradicate the organism. This recommendation is based on overwhelming data showing that cure of H. pylori infection reduces ulcer recurrence and complications such as bleeding.

A number of eradication therapies have been postulated, all with very high eradication (>80%) and low relapse rates (<5%). The development of resistance to metronidazole has resulted in amoxicillin and clarithromycin being recommended as the antibiotics of choice. These are usually combined with a proton pump inhibitor or colloidal bismuth subcitrate for 1 week. Several single-prescription packages are now available. It is generally accepted that acid suppression therapy be continued for 4–8 weeks after cessation of antibiotic therapy.

H. pylori eradication therapy in patients with non-ulcer dyspepsia may have a small yet statistically significant effect on symptoms

Misoprostol significantly reduces the risk of endoscopic ulcers. Standard doses of H₂-blockers were effective at reducing the risk of duodenal but not gastric ulcers. Double-dose H₂-blockers and proton pump inhibitors were effective at reducing the risk of both duodenal and gastric ulcers, and were better tolerated than misoprostol.

7. Treatment of NSAID-Induced Ulcers

NSAIDs, including aspirin, should be ceased if at all possible. Treatment should consist of a 4–8-week course of an H₂-receptor antagonist or proton pump inhibitor.

8. Surgical Management

With the success of medical treatment for peptic ulcer disease, surgical intervention has been restricted to the management of complications rather than of the primary disease.

Complications

There are four major complications of peptic ulcer:

1. Haemorrhage
2. Perforation
3. Penetration
4. Obstruction

1. Haemorrhage

Peptic ulceration is a common cause of GI bleeding Opens in new window, occurring in 10–20% of ulcer patients and accounting for approximately 50% of all upper GI bleeds. Urgent endoscopy is usually indicated, and surgical intervention may be required in a small proportion of patients. A recent meta-analysis concluded that the use of acid-reducing agents was associated with a statistically significant decrease in rebleeding, but not mortality.

2. Perforation

Perforation occurs in approximately 5% of ulcers, with duodenal, antral and gastric body ulcers accounting for respectively 60% , 20% and 20% of perforations. One-third to one-half of perforated ulcers are associated with NSAID use; these usually occur in elderly patients. Chemical peritonitis develops suddenly, with acute severe generalized abdominal pain. Examination reveals a sick patient with a rigid, quiet abdomen and rebound tenderness. Delay in presentation and treatment, which may occur in the elderly and debilitated, sees the rapid development of bacterial peritonitis and subsequent sepsis and shock. The overall mortality rate is about 5%.

Rapid diagnosis is essential as the prognosis is excellent if treated within the first 6 hours, but deteriorates to probable death after more than a 12-hour delay. Diagnosis should be confirmed with an erect chest X-ray, bearing in mind a sensitivity of 70–80%. If free air is found, no other diagnostic studies are necessary. If there is diagnostic uncertainty, CT or ultrasound can be useful to detect small amounts of free air or fluid.

Vigorous fluid resuscitation should be instituted and renal function (via urine output) should be closely monitored. Ampicillin, gentamicin and metronidazole should be given, along with adequate analgesia. Cardiac and respiratory support may be needed in some cases.

The majority of patients with perforation should undergo surgery for decontamination and repair. Non-operative management, including intravenous fluids, nasogastric suction, antibiotics and anti-secretory drugs, may be successful in some patients in whom the leak seals quickly in response to medical management. There is some evidence that an initial period of non-operative treatment with careful observation is safe in younger patients (under 70 years), but this is not yet regarded as standard practice.

3. Penetration

Posterior ulcers may perforate the gastric or duodenal wall and continue to erode into adjacent structures, most commonly the pancreas, without free perforation and leakage of luminal contents into the peritoneal cavity.

Surgical series suggest that penetration occurs in 20% of ulcers, but only a small proportion of penetrating ulcers become clinically evident. Patients may describe their pain as becoming more severe and constant, radiating to the back, and no longer eased by antacids and food. There is also loss of cyclicity of pain with meals. The serum amylase level may be mildly raised. Endoscopy may reveal ulceration, but ‘penetration’ is difficult to confirm.

4. Gastric Outlet Obstruction

This is the least frequent ulcer complication and may occur in up to 2% of patients with ulcer disease. It may arise acutely secondary to inflammation and oedema of the pylorus or duodenal bulb, or more commonly as a consequence of scarring due to chronic disease.

A single episode of abdominal pain/discomfort (without any alarm features) does not need to be referred for further work-up, as this complaint is very common and is usually self-limiting and non-specific.

Discharge Advice

Patients should be asked to return to the ED immediately should they develop fever, lower abdominal pain, persistent diarrhoea or vomiting. This is because upper abdominal pain may be an early symptom of other pathologies, e.g. acute appendicitis.