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InnovAiT: The RCGP Journal for Associates in Training Peptic Ulcer Disease

P. J. Woodland and Ben Stubbs InnovAiT 2009 2: 486 DOI: 10.1093/innovait/inp087 The online version of this article can be found at:

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InnovAiT, Vol. 2, No. 8, pp. 486492, 2009


Peptic ulcer disease

eople in Western populations have a 1 in 10 lifetime risk of developing peptic ulcer disease. Although recent decades have seen major advances in our knowledge and treatment of peptic ulcers, symptoms and complications from peptic ulcers remain a signicant problem for primary and secondary care practitioners. Primary care practitioners have a central role in the prevention, recognition and treatment of peptic ulcers. This article summarizes the causes, presentations, investigation and current treatment of peptic ulcer disease.
The GP curriculum and peptic ulcer disease The RCGP Curriculum Statement 15.2 addresses digestive disorders. Specically relating to peptic ulcer disease, it states that a practitioner should Have knowledge of dyspeptic symptoms and peptic ulceration Have knowledge of Helicobacter pylori testing Have knowledge of secondary care investigations including endoscopy and abdominal imaging techniques Understand primary care management of peptic ulceration and be aware of secondary care management including surgery Have knowledge of the acute management of haematemesis and melaena

Peptic ulcers can develop anywhere in the gastrointestinal tract, but most commonly (and in this article) the term refers to mucosal defects in the stomach and duodenum. Histologically, they are necrotic mucosal defects that extend through the muscularis mucosae into the submucosa. They occur when the epithelial cells are damaged by the effects of acid and pepsin.

predisposition to peptic ulcers disease was often due to familial clustering of H. pylori infection. While there still may be genetic polymorphisms which predispose to peptic ulcer disease, it has thus far been very difcult to nd conclusive candidates.

Helicobacter pylori
Helicobacter pylori is a gram-negative, spiral, agellated bacterium which is uniquely adapted to survive in the stomach. One mechanism by which it is able to survive the acid environment is by production of urease, an enzyme that catalyses the breakdown of urea to carbon dioxide and alkaline ammonia. It is estimated that more than half of the worlds population is infected with H. pylori. Infection is probably spread via the faecaloral route, and rates of infection are inversely related to socio-economic status. Consequently, infection is very common in developing countries. In developed countries 20% of individuals under 40 years old and 50% of those older than 60 years old are currently infected. Infection is almost always contracted in childhood, and so these differences across age groups are likely to reect a cohort effect due to changing sanitation and antibiotic use over time. People infected with H. pylori have a relatively raised serum gastrin and tend to have high-normal or moderately raised gastric acid secretion compared to controls. They also have

Our understanding of the aetiology of peptic ulcer disease has progressed since the beginning of the last century, when stress and diet were thought to be the causes. Although the stomach and duodenum are very noxious environments for epithelial cells, these cells are usually protected by protective features and mechanisms such as a mucous layer, epithelial tight junctions and prostaglandin synthesis. Primary failure of these defensive features is rare. Now it is realized that the vast majority of peptic ulcers are caused by H. pylori infection or non-steroidal antiinammatory drugs (NSAIDs). Many studies suggesting a familial component to peptic ulcer disease were done in the era before the discovery of the importance of H. pylori, and observed familial


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impaired duodenal bicarbonate secretion. Gastritis is found in almost all people with H. pylori infection. Over time this can lead to gastric atrophy, intestinal metaplasia and neoplastic change. Helicobacter pylori has a very strong association with peptic ulceration. Around 80% of duodenal ulcers, and 60% of gastric ulcers, are associated with infection. The mechanism by which the organism causes ulceration is poorly understood.

Physiological stresses (stress ulcers have been seen to occur, usually in the Intensive Care setting, but rarely cause signicant haemorrhage in the absence of coagulopathy)

Clinical features
Abdominal pain is the classical symptom of peptic ulcer disease. In two-thirds of patients, this pain is epigastric, but it may also be located in the right or left upper quadrants and may radiate to the back. Ulcer pain may be gnawing or burning in nature. Characteristically, the pain of duodenal occurs 23 hours after eating (or often in the middle of the night) and may be relieved by food. There may be several weeks of pain followed by several pain-free weeks. Gastric ulcer pain may be similar in nature, but tends to occur sooner after meals and less often at night and is less frequently relieved by eating (indeed eating may exacerbate pain). Unfortunately, such dyspeptic symptoms are neither sensitive nor specic. Only 1525% of patients with typical ulcer-type dyspepsia will have peptic ulcers at endoscopy. In addition, many patients (perhaps up to 70%) are completely asymptomatic. Not infrequently a serious complication such as bleeding or perforation is the rst presentation. The differential diagnosis of ulcer-type dyspepsia is relatively broad (Box 2). Box 2. The differential diagnosis of ulcer-type dyspepsia

Non-steroidal anti-inammatory drugs

Most ulcers not associated with H. pylori are associated with NSAID use. Asymptomatic ulcerations can be found endoscopically in 1545% of people taking chronic NSAID treatment, and 14% of patients receiving NSAIDs for 1 year will develop serious gastrointestinal complications. Compared to controls, patients taking NSAIDs are ve to six times more likely to develop peptic ulcers. NSAIDs may cause mucosal damage by local effects on epithelial cells, inhibition of cyclooxygenase (COX)-mediated gastric prostaglandin production and other effects including reduction of gastrointestinal blood ow. It is important to note that there are some additional factors that increase the risk of developing NSAID-associated peptic ulceration (Box 1).

Box 1. Additional risk factors for NSAID-associated peptic ulcers

Previous peptic ulcer disease Advanced age (more than 70 years old) Concomitant glucocorticoids (but note that glucocorticoids alone do not cause ulcers) Concomitant anti-coagulant therapy High doses of NSAIDs Combinations of NSAIDs Low dose aspirin Co-morbidity (cardiovascular disease, inammatory arthritis)

Other aetiological factors for ulcer development

Occasionally peptic ulcers are not due to NSAIDs or H. pylori. Other aetiological factors include Hepatic arterial infusion of 5-uorouracil chemotherapy Crack cocaine use (predisposes to gastric ulceration with a high risk of perforation) Bisphosphonates (predispose to oesophageal and gastric ulcers) Hypersecretory conditions (e.g. gastrinoma and systemic mastocytosis) Cigarette smoking (appears to increase the risk of peptic ulcer in H. pylori-infected subjects and also appears to inhibit ulcer healing) Psychological stresses (peptic ulcer complications appear to be more prevalent during times of natural disaster or extreme societal stress, e.g. war)

Peptic ulcer Non-ulcer dyspepsia Gastric or pancreatic neoplasm Pancreatitis Cholecystitis/biliary colic Gastro-oesophageal reux disease Crohns disease of the upper gastrointestinal (GI) tract Mesenteric ischaemia

The need to identify those patients with neoplastic pathology is of great importance. Hence, patients with alarm features (Box 3) require urgent gastroenterology referral for further investigation. Box 3. Alarm features

Onset of dyspepsia in person aged over 55 years Unintentional weight loss Persistent vomiting Overt upper gastrointestinal bleeding Dysphagia Iron deciency anaemia Epigastric mass Suspicious barium meal

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Not all patients with dyspepsia (broadly dened as abdominal pain of upper gastrointestinal origin) require further investigation. The National Institute for Health and Clinical Excellence (NICE) has produced guidelines for management of uninvestigated dyspepsia. In essence, these advocate a trial of proton pump inhibitor (PPI) or testing for H. pylori and treating those with positive results in those patients without alarm symptoms. It does not matter which approach is tried rst. Testing for H. pylori should occur after a 2-week washout period from PPIs (if necessary, the patient can be switched to H2-receptor antagonists for this period). Those patients with alarm features or those with inadequate response to initial therapy warrant referral to a gastroenterologist for further investigation. The gold standard test for diagnosis of peptic ulcer disease is upper gastrointestinal endoscopy (Fig. 1). As compared to barium swallow radiographic evaluation (Fig. 2), endoscopy offers better sensitivity for peptic ulcers (8090% vs. 60 80%) and offers the opportunity to obtain biopsy specimens. Since 80% of duodenal ulcers and 60% of gastric ulcers are associated with H. pylori, infection must be sought in all peptic ulcer disease. Helicobacter pylori infection can be sought via 13C-urea breath test, faecal antigen testing, serological testing or the rapid urease test. In primary care, the appropriate test to diagnose H. pylori infection is a 13C-urea breath test or faecal antigen test. Serological testing should only be done if the assay has been locally validated, and the rapid urease test is done at endoscopy. All gastric ulcers seen endoscopically are biopsied (at least six biopsies) as endoscopic appearances cannot always separate benign from malignant ulcers. Repeat endoscopy after 6

Figure 2. Barium follow through showing duodenal ulcer. Science Photo Library.

weeks of PPI therapy is the rule for gastric ulcers to ensure healing as malignancy must be sought in non-healing ulcers. The potential for malignancy in duodenal ulcers is small, so biopsy and repeat endoscopy is usually not required.

Over the 20th century, treatment of peptic ulcers progressed from bed rest, through antacids and H2 receptor antagonists, to PPIs and nally H. pylori eradication therapy. Antacids have been shown to be better than placebo in healing peptic ulcers, but the availability of more efcacious drugs has meant that their role is now mostly limited to symptomatic relief of dyspepsia. Aluminium-containing antacids can cause constipation, and magnesium-containing antacids can cause diarrhoea. Both types must be used with caution in renal failure. H2-receptor antagonists are generally a safe group of drugs with a favourable side effect prole. They act by reducing histamine-stimulated acid secretion, reducing basal acid output and meal-stimulated acid output. PPIs reduce acid secretion by inhibiting the H+,K+-ATPase of the gastric parietal cells and are more potent inhibitors of acid secretion than H2 receptor antagonists. They are prodrugs that must be activated by acid to have an effect, and so work better when taken when most proton pumps are active. This explains why it is suggested that they are taken just before a meal, usually breakfast. Generally, they are a well-tolerated group of drugs, with the main side effects being diarrhoea and headache. By suppressing the parietal cell acid secretion, PPIs produce a state of hypergastrinaemia. Although this produces a theoretical risk of gastric carcinoid tumour, there have been no reports of this in humans thus far.

Figure 1. Endoscopic image of a peptic ulcer. David M. Martin, MD/Science Photo Library.


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PPIs are more efcacious than H2-receptor antagonists at peptic ulcer healing. Prior to our understanding of the importance of H. pylori and NSAIDs in peptic ulcer, recurrence was usual after cessation of treatment. Todays greater understanding of these factors has enabled more effective treatment regimes to be developed. In general, treatment should be determined by the presence or absence of H. pylori or NSAIDs. Ulcers not associated with H. pylori or NSAIDs and ulcers refractory to treatment represent a more unusual group that require further careful consideration.

63% healing at 8 weeks), and 40 mg omeprazole is no better than 20 mg. Similarly, PPIs have been shown to be superior to misoprostol in this situation. NICE guidelines suggest a 2-month course of full-dose PPI or H2-receptor antagonist for treatment of NSAID-associated peptic ulcer. There is currently no good evidence to support substitution of NSAIDs with COX-2 inhibitors to facilitate healing of active peptic ulcers.

Treatment of ulcers associated with H. pylori

If H. pylori infection is present, then eradication therapy should be given, regardless of whether the patient is taking NSAIDs. The standard regime for H. pylori eradication is one week of Full-dose PPI (e.g. omeprazole 20 mg bd or lansoprazole 30 mg bd) and metronidazole 400 mg bd and clarithromycin 250 mg bd or amoxicillin 1 g bd and clarithromycin 500 mg bd This will eradicate the infection in around 85% of cases. Eradication of H. pylori alone has been shown to be better than the use of PPIs alone in several studies. A course of eradication therapy is usually sufcient to heal a peptic ulcer, and additional anti-acid therapy is not usually required (although is often thought wise if there had been a complication of the ulcer). Without H. pylori eradication, ulcers return in as many as 95% of cases, but with eradication, this percentage falls to less than 10%. Occasionally, it is necessary to repeat testing for H. pylori eradication (e.g. where symptoms persist or where the original ulcer was associated with complications and the stakes of ensuring eradication are higher). In this scenario, a 13C-urea breath test is perhaps most appropriate as it is non-invasive and has good accuracy. It should be noted that serological testing is not appropriate to test for eradication, as IgG antibody may remain present for many months after eradication. In the developed world, once H. pylori is eradicated, it is very rare for reinfection to occur.

Prophylaxis of NSAID-associated ulcers

We often need to consider giving primary ulcer prophylaxis to those patients taking NSAIDs. The important considerations are which agent to use and when to use it. The best evidence for ulcer prophylaxis when taking NSAIDs exists for misoprostol and PPIs. Misoprostol at a dose of 800 mcg per day in association with NSAIDs has been shown to signicantly reduce the incidence of peptic ulcer and ulcer complications. However, this dose of misoprostol is often associated with signicant gastrointestinal upset. PPIs have been shown to be better than placebo and ranitidine at reducing the incidence of peptic ulcers with chronic NSAID use. In practice, PPIs may be a better option than misoprostol as they are usually very well tolerated. COX-2 inhibitors have a controversial role in this area. Studies have shown conicting data regarding their gastrointestinal benets, although they may be comparable to NSAID plus PPI. A further consideration in using COX-2 inhibitors is concern about cardiovascular risk. Three randomized controlled trials have indicated that there may be a class risk of myocardial infarction with long-term COX-2 inhibitor use. In general, patients at low risk for peptic ulcer disease (i.e. no additional risk factors from Box 1) have a very low probability (1% per annum) of developing ulcers when using NSAIDs and do not need concomitant prophylaxis against ulcers. Patients with any additional risk factors should usually take prophylaxis (i.e. PPI or high-dose misoprostol) against peptic ulcers when taking NSAIDs. Patients who have had previous peptic ulcer complications, take concomitant aspirin or glucocorticoids or have multiple risk factors should ideally avoid NSAIDs altogether. The risk versus benet of any use should be carefully weighed. Antiulcer therapy with PPI or misoprostol should certainly be used, and whether or not this should be in combination with a COX-2 instead of NSAID is still to be evaluated.

Peptic ulcers associated with NSAIDs

If a peptic ulcer is associated with NSAID usage, if possible, NSAIDs should be stopped. A study that considered healing with H2 receptor antagonists where NSAIDs had been stopped found that all ulcers had healed by 12 weeks. Where NSAIDs must be continued, omeprazole has been shown to be superior to ranitidine in clinical trials (80% vs.

Refractory ulcers
A minority of ulcers do not resolve after appropriate therapy. In such cases, a number of questions should be considered.

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Is the patient concordant with anti-ulcer treatment? Is the patient denitely not taking NSAIDs? Is the patient smoking? Is there a persistent H. pylori infection? Is there another diagnosis? (Box 4)

A multidisciplinary approach by gastroenterologists, surgeons and sometimes intensivists is required to manage peptic ulcer bleeding. Bleeding from a peptic ulcer will spontaneously stop in approximately 80% of cases. The key is to identify the remaining 20% with signicant mortality that require urgent endoscopy. A validated tool used in risk stratication is the Rockall score (Table 1). The score can be seen to be composed of pre- and post-endoscopy components, such that the maximum preendoscopy score is seven and the maximum post-endoscopy score is eleven. In general, a score of less than three carries an excellent prognosis, and a score of greater than eight carries a high mortality risk. Ulcers with an adherent clot or a visible vessel require endoscopic treatment. In general, the therapeutic options are injection (commonly with adrenaline which causes a local vasoconstriction and tamponade effect), thermal techniques (commonly a heater probe) and mechanical methods (endoscopic haemoclip application). A combination of injection plus thermal or mechanical treatment has been shown to reduce the rate of rebleeding, emergency surgery and mortality compared to a single modality. Studies have shown that in patients with a visible vessel or active bleeding at endoscopy, a bolus infusion of omeprazole reduced rebleeding rates compared to placebo. The use of PPI prior to endoscopy is controversial. While it is unlikely to cause harm, the benets of intravenous PPI prior to endoscopy is yet to be condently proven. In patients in whom the bleed cannot be controlled endoscopically, and in those who rebleed, surgery is indicated. The usual operation for gastric ulcer bleeds is a partial gastrectomy. Duodenal ulcer bleeds are usually surgically treated by ligation of the bleeding vessel.

Box 4. Alternative diagnoses for refractory ulcer

Hypersecretory condition (gastrinoma, systemic mastocytosis, basophilic myeloproliferative disorders) Infection (e.g. cytomegalovirus, tuberculosis) Inltration (e.g. sarcoidosis, Wegeners granulomatosis) Cocaine use Crohns disease Neoplasm

The major complications of peptic ulcers are bleeding, perforation, penetration and obstruction and all require emergency referral to secondary care.

Approximately 50% of acute upper GI haemorrhage is due to peptic ulcer disease, with a mortality of 510%. Bleeding from peptic ulcers is strongly associated with NSAID and aspirin use. The presentation may be with haematemesis, melaena or both and varying degrees of circulatory compromise. In the initial stages, the serum haemoglobin concentration may not fall. Often the serum urea may be increased due to gastric breakdown of haemoglobin and subsequent amino acid absorption.

Table 1. Rockall score Criterion Score 0 Age Shock <60 years None 1 6079 years Pulse 100 and systolic blood pressure 100 mmHg 2 80 years Systolic BP < 100 mmHg 3




Renal, liver, and malignancy

Mortality for pre-endoscopy score 0 = 0.2%, 7 = 50% Endoscopic diagnosis Stigmata of recent haemorrhage No lesion or MalloryWeiss tear None All other diagnoses Malignancy Clot, visible vessel, and blood in stomach

Mortality for overall score 0 = 0%, 3 = 2.9%, 5 = 10.8%, 8 = 41.1%


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Perforation of an ulcer into the peritoneal cavity is a potentially life-threatening event. There is no prior history of peptic ulcer disease in 1015%. In 10% of cases, perforation may be associated with haemorrhage. The usual sites of perforated peptic ulcers are the anterior duodenal bulb and the lesser curve of the stomach. Classically, there are three clinical stages to perforation. Initially, there is sudden onset of severe abdominal pain, often associated with hypotension and which may last minutes to hours. Next, the patient may look and feel better (possibly as the acidic uid is buffered and diluted by uid released from injured tissue). This should not mistakenly be dismissed as no longer needing attention. Physical examination will usually still elicit signs of peritonitis. The nal stage (usually more than 12 hours after the perforation) is of frank peritonitis which progresses to death without appropriate treatment. Occasionally, a conservative approach can be taken where a sealed perforation is conrmed by clinical and radiological assessment. However, in the majority of cases, surgical intervention is indicated to remove peritoneal contamination and to treat the ulcer. Surgical therapy of duodenal ulcers is usually by oversew of the ulcer with an omental patch. Subsequent H. pylori eradication dramatically reduces relapse rate (to 5% at 1 year). Overall results from surgery to duodenal ulcers are very favourable in around 90% of cases. Perforation of gastric ulcers is becoming increasingly frequent, especially in elderly populations on NSAID therapy. Gastric perforation carries a higher mortality than duodenal perforation, with rates ranging from 10% to 40%. Unless the patient has an unacceptably high operative risk, surgery usually involves a partial gastrectomy due to the possibility of malignancy.

Around a half of patients will improve sufficiently with this regime as the resolution of oedema relieves the obstruction. Endoscopic therapy is possible in the majority of patients with obstruction. This usually takes the form of balloon dilatation resulting in 80100% of immediate relief of obstruction. Relapse rates have reduced dramatically with the advent of the discovery and treatment of H. pylori. In approximately 30% of patients, surgical relief of obstruction is required. The type of surgery is usually decided at the time of operation, but usually involves either a drainage procedure (by gastrojejunostomy or pyloroplasty) or antrectomy.

Key points

Peptic ulcers are common and are a potential source of signicant morbidity and mortality Most peptic ulcers are caused by H. pylori or NSAID use Appropriate investigation of dyspepsia and judicious use of NSAIDs and anti-ulcer therapy are key to prevention of complications Endoscopy and surgery are the mainstays of treatment for complications


Penetration occurs when an ulcer burrows through the gastric or duodenal wall, but instead of free perforation, it penetrates into an adjacent organ (usually the pancreas or liver). Often, this will not be symptomatically apparent, but sometimes, it can cause a change in ulcer pain characteristics.

Gastric antral, pyloric or duodenal ulcers can cause gastric outlet obstruction as a result of either oedema or scarring. Typically, this presents with epigastric pain, bloating, early satiety, vomiting shortly after meals and sometimes severe weight loss. On physical examination, a succussion splash may be evident. Initial treatment is with fluid resuscitation, electrolyte replacement and nasogastric tube insertion. Nutrition can be given via an endoscopically placed nasojejunal tube or parentally. Acid suppression therapy is given.

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Dr P. J. Woodland SpR, Gastroenterology, North East Thames E-mail: Mr Ben Stubbs SpR, General Surgery, North East Thames


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