Peptic Ulcer Disease

The term peptic ulcer refers to both gastric and duodenal ulcers. Helicobacter pylori infection is associated with about 95% of duodenal ulcers and 80% of gastric ulcers. Other important aetiological factors include non-steroidal anti-inflammatory drugs (NSAIDs), acid and pepsin, smoking, alcohol, bile acids, aspirin, steroids and stress. Defence mechanisms include mucus, bicarbonate, mucosal blood flow and prostaglandins.

Dyspepsia occurs in 40% of the population annually and leads to a primary care consultation in 5% and endoscopy in 1%.¹
Of those who undergo endoscopy:

• About 40% have functional or non-ulcer dyspepsia
• 40% have gastro-oesophageal reflux disease
• 13% have ulcer disease
• 2% have gastric cancer
• 1% have oesophageal cancer

In the past duodenal ulcer was 10 times as common in men as women and gastric ulcer had a male preponderance of 3:2. Now the frequency is much less, largely because of H pylori eradication and the sex incidence is more even.

The period prevalence of peptic ulceration in British primary care has decreased markedly, especially among younger people and those from more deprived areas:

• The annual age-standardised period prevalence of peptic ulceration decreased from 3.3/1000 in 1994 to 1.5/1000 in 1998 for men.
• Amongst women it decreased from 1.8/1000 to 0.9/1000.²
• Current trends are for a decreasing incidence in young men and an increasing number in older women.

Emergency admission rates for duodenal and gastric ulcer for complications or severe pain have shown remarkably little change over the last three decades.

In contrast, elective surgery has declined dramatically, as a result of advances in treatment but also from changes in the natural history.³

Symptoms

Symptoms of dyspepsia are very non-specific and diagnosis is unreliable on history alone:

• Epigastric pain usually 1 to 3 hours post-prandial - it may sometimes awake the patient in the night and be relieved by food
• Nausea
• Oral flatulence, bloating, distension and intolerance of fatty food - the last is also associated with gallstones
• Heartburn sometimes occurs although it is more typically associated with gastro-oesophageal reflux
• A posterior ulcer may cause pain radiating to the back
• Symptoms are relieved by antacids (very non-specific)

In Taiwan, silent peptic ulcer disease is not uncommon but in Western countries this is unusual.⁴

Signs

In uncomplicated cases there is very little to find on examination:

• There is often epigastric tenderness.
• If gastric emptying is slow, there may be a succussion splash.

• Gastro-oesophageal reflux
• Gastric carcinoma
• Gallstones
• Chronic pancreatitis
• Crohn's disease
• Irritable bowel syndrome
• Drug induced dyspepsia
• Hepatitis
• Acute ulcers (occur at times of severe physiological stress e.g. severe burns/head injury)
• If H. pylori is negative (or has been eradicated) but ulceration is refractory/recurrent, Zollinger-Ellison syndrome should be considered (rare)
• Coronary heart disease

• FBC may show evidence of iron deficiency anaemia if there has been significant bleeding but usually it is normal.
• Testing for H. pylori is worthwhile. Patients taking NSAIDs have 2 to 4 times the risk of ulceration if H. pylori is positive.⁵ Testing patients for H. pylori and eradication before starting NSAIDs reduces the incidence of ulcers.⁶
• Barium meal and follow through has been largely superseded by endoscopy.
• Unless the patient is presenting for the first time above the age of 55, or unless there are other warning signs, NICE guidelines state that endoscopy is not required.¹
  
  Warning signs ("red flags") include:
  • GI bleeding
  • Dysphagia
  • Unintentional weight loss
  • Abdominal swelling
  • Persistent vomiting
• Irrespective of age endoscopy is required if there is:
  • Iron deficiency anaemia
  • Chronic blood loss
  • Weight loss
  • Progressive dysphagia
  • Persistent vomiting
  • An epigastric mass
  • A suspicious barium meal
• In patients over 55 years, referral should be considered if there is:
  • Previous gastric ulcer
  • Previous gastric surgery
  • Pernicious anaemia
  • NSAID use
  • Family history of gastric carcinoma

Peptic ulcer is rare without the presence of H. pylori or the use of NSAIDs.⁷

Modification of behaviour

• If drugs are the cause then they should be stopped or replaced, but this may not be possible. Being more meticulous about the instructions for taking alendronate or taking NSAIDs including aspirin after food may be required.
• There has been no need for "ulcer diets" since the introduction of effective acid suppression but reduction of alcohol intake, coffee and spicy foods may require attention.
• Cessation of smoking should be advised if applicable. Smoking increases the risk of peptic ulcer and delays healing as well as opposing the action of H₂ antagonists. It has many effects on other parts of the gut including facilitating gastro-oesophageal reflux.
• The COX-2 inhibitors are less likely to cause ulcers than NSAIDs⁸ but it is dangerous to assume that they carry no risk of ulceration. This advantage is nullified if the patient also takes even low dose aspirin.

Healing ulcers

Clinical Knowledge Summaries recommend that if an ulcer is proven but H. pylori testing is negative, then acid suppression at full dose should be offered for 1 or 2 months.⁹ A lower maintenance dose may be continued after. The full course should be taken as there is little correlation between the relief of symptoms and the healing of ulcers and if medication is stopped too soon the ulcer will relapse.

• Acid suppression at full dose proton pump inhibitor (PPI) for 1 month or 2 will usually heal the ulcer.
• A policy of test for H. pylori and eradication if found without endoscopy is acceptable if there are no warning signs.¹ This is in addition to acid suppression.
• If NSAIDs are used, stop them if possible and give full dose PPI for 2 months.¹
• Adding eradication to acid suppression in ulcers associated with NSAIDs does not improve the rate of healing at 4 or 8 weeks but it does reduce the incidence of recurrence. NICE suggest acid suppression for 2 months before eradication. There is a suggestion that eradication may delay healing of NSAID associated ulcers but this is disputed.^5,10
• The management of peptic ulcer disease not related to H. pylori or NSAIDs has been described in a review and in the NICE guidelines.^1,5 If H. pylori was negative, give 1 or 2 months of PPI and look for other causes.¹¹

Helicobacter pylori eradication

If the infection is suspected or demonstrated, then eradication is the logical course of action. NICE suggests that eradication should be offered if a test is positive.¹

There are several regimes that are available. They usually consist of high dose acid suppression with a PPI and two antibiotics, also at quite high dose. The usual recommended duration of treatment is 7 days and it is said to give eradication in about 90% of cases. A 14 days course may produce a higher rate of eradication but the incidence of adverse effects may make compliance poor. Diarrhoea is common with two antibiotics at high dose.

The following is based on the recommendations of NICE:¹

• A PPI twice a day
• Bismuth 120 mg four times a day
• Metronidazole 400 mg three times a day
• Oxytetracycline 500 mg four times a day

All regimes are taken for 7 days.
Reinforce the importance of compliance as it is not easy to take so many tablets so many times a day, even for just a week.

Ulcers associated with NSAIDs

If a drug is thought to be the cause of peptic ulceration, it is sensible to stop the drug or change it to another with a lower risk. There may be times when it is desirable to continue that drug e.g. an elderly person may need treatment for arthritis to maintain mobility or aspirin may be required in cardiovascular disease. It is often possible to heal the ulcer without stopping the offending drug and a maintenance dose is continued to prevent relapse.¹³

• H₂ blockers are slow to heal the ulcers if the offending drug is not stopped and so, under these conditions, a PPI is preferred.
• H. pylori eradication is no more effective than omeprazole alone to heal ulcers, but if the infection is present, then eradication will reduce the rate of relapse.
• H. pylori is not associated with an increased risk of ulcer with NSAIDs in the elderly but there is an increased risk of bleeding.¹⁴

Misoprostol is a prostaglandin analogue that is both an antisecretory and a protective agent for the healing of both gastric and duodenal ulcers. Its use is limited as diarrhoea is a common adverse effect and acid suppression tends to be better tolerated.¹⁵ Only the higher doses of misoprostol match acid suppression for efficacy.¹⁶

Management of recurrence and its prevention

• For gastric ulcer with H. pylori infection, NICE recommends eradication therapy followed by proof of eradication and repeat endoscopy. This is a consensus statement. If eradication is successful but the ulcer unhealed then malignancy needs to be considered.
• Serology tests are applicable only for initial diagnosis as they remain positive for a long while.
• If patients are to be given long term NSAIDs a review from Hong Kong suggested that stratification of risk should be used to decide the plan for prevention and that all such patients should be checked for H. pylori infection.¹⁷
• H₂ antagonists are also less effective than PPIs.¹⁸
• For patients who have relapses, intermittent therapy and annual review is recommended.¹

Patients should be reviewed at the end of a course of treatment, especially H. pylori eradication, to confirm a satisfactory outcome.

The NICE guidelines give the following data on the effectiveness of interventions based on a number of sources:

• In duodenal ulcer, acid suppression for 4 to 8 weeks produces healing of the ulcer in 69%. This rises by an extra 5.4% with eradication therapy too. NNT=18.
• In duodenal ulcer relapse at 3 to 12 months after treatment is 39% after short term acid suppression alone but eradication increases this by 52% to 91%. NNT=2.
• In gastric ulcer, supplementation of acid suppression with eradication therapy does not improve healing rates but it does reduce relapse so that 3 to 12 months later 45% are free of ulcers after just acid suppression but eradication raises this by 32% to 77%. NNT=3.
• In patients taking NSAIDs, eradication did not improve ulcer healing rate but it did halve the number of endoscopically proven ulcers 6 months later from 18 to 9%.

• Haematemesis or melaena are associated with erosion of a large blood vessel and significant haemorrhage. Urgent admission to hospital is required. In patients whose ulcers have bled, eradication of H pylori is more effective than even long term acid suppression without eradication.¹⁹
• Perforation of a peptic ulcer causes an acute abdomen with epigastric pain that may progress to generalised rigidity. In the presence of steroids the symptoms of perforation may be suppressed or absent.
• Scarring of the duodenum may lead to pyloric stenosis with vomiting and weight loss but this is rare these days with effective treatment. The classical feature is that the vomit shows food such as tomato skins that were eaten 12 to 24 hours ago.
• During H. pylori eradication, abdominal discomfort and diarrhoea are very common but the patient should be encouraged to persist to achieve eradication and to heal the ulcer permanently. Lactobacilli, usually ingested in the form of natural unpasteurised yoghurt, may be of value in replacing the natural flora of the gut and they may also have a suppressive effect on H. pylori.²⁰
• Adverse reactions to PPIs and H₂ blockers are usually rare and mild but severe problems can arise. Rare but not serious problems may include taste disturbance, peripheral oedema, photosensitivity, fever, arthralgia, myalgia and sweating. Serious problems include liver dysfunction, hypersensitivity reactions (including urticaria, angioedema, bronchospasm, anaphylaxis), depression, interstitial nephritis, blood disorders (including leucopenia, leucocytosis, pancytopenia, thrombocytopenia), and skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous eruption).
• Misoprostol often causes diarrhoea and abdominal pain, especially at higher doses.

Prognosis is excellent if the underlying cause such as H. pylori infection or drugs can be addressed. The eradication of H. pylori has led to a very substantial decrease in the rate of recurrence of ulcers. A study from Japan showed that annual recurrence rates of gastric, duodenal and gastroduodenal ulcer were 2.3%, 1.6%, and 1.6%, respectively.²¹ Excluding patients who took NSAIDs dropped the recurrence rates to 1.9%, 1.5% and 1.3%, respectively. The recurrence rate was significantly higher in gastric ulcer. Recurrence rates of patients who smoked, consumed alcohol, and used NSAIDs were significantly higher in those with gastric ulcer recurrence compared to duodenal ulcer. Relapsed ulcers tended to recur at the same or adjacent sites as the previous ulcers.

Even within the professional lifetime of many doctors still in practice, there has been an enormous change in the management of peptic ulcer disease. The state of the art in the 1970s was unrecognizable compared with today.

• Diagnosis was by barium meal and follow through. Now endoscopy has almost entirely replaced this.
• Advantages of endoscopy include:
  • Direct vision of the ulcer via the endoscope rather than looking at the shadows of radiology
  • Ability to see the inflammation of gastritis or oesophagitis
  • Ability to biopsy suspicious lesions
  • Ability to take samples for culture of H. pylori
  • No radiation
• Treatment was with antacids that gave some relief of short duration.
• If treatment with rather ineffectual antacids was unsuccessful, surgery was considered.
• This was major abdominal surgery. A number of procedures were used:
  • Polya or Billroth II gastrectomy involved removal of about half to two thirds of the stomach.
  • Vagotomy involved severing the trunk of the vagus nerves to the stomach. It had to be accompanied by pyloroplasty to facilitate gastric emptying or there would be stasis.
  • Highly selective vagotomy required great skill to divide only the relevant vagal fibres to the stomach and in doing so it was unnecessary to perform a pyloroplasty too. Failure to divide all the fibres would result in failure of the operation and dividing too many without pyloroplasty would cause stasis.
• The H₂ antagonists were revolutionary in providing effective acid suppression and the need for surgery was markedly reduced.
• They were followed by the PPIs that produced more profound suppression of longer duration.
• The discovery of the link to H. pylori enabled cure to be achieved as even the H2 antagonists and PPIs needed to be continued at low dose long term to prevent relapse.
• A better understanding of the place of H. pylori eradication, acid suppression and the possible role of the new COX-2 inhibitors has made the prescription of drugs for osteoarthritis in the elderly much safer.

Patients who have had such operations for peptic ulcer may still be seen today and the long term effects of these operations need to be known.

• A stomach of much reduced size can cause difficulty in obtaining adequate nutrition. Young people, especially young women were much at risk.
• Inadequate production of intrinsic factor can result in pernicious anaemia.
• There is an increased risk of tuberculosis.
• With vagotomy and pyloroplasty in particular there were problems of early and late dumping syndrome.
• Blind loop syndromes cause abnormal gut flora and malabsorption.
• Bile can reflux into the stomach. A reversal operation such as the Roux-en-Y may be required.
• Various forms of malabsorption and intestinal hurry may result.

If patients have had one of these operations 30 years or longer ago, they will have missed H pylori eradication and if it has not been done since, it is worth doing now.