Peptic ulcer disease
Peptic ulcer is a common condition. Ten per cent of the population suffer from it at some time or another. The incidence and severity of peptic ulcer disease are decreasing in theWestern world but they are increasing in developing countries. Because of the widespread use of non-steroidal anti-inflammatory drugs (NSAID), the incidence of ulcer disease in the elderly is increasing.
Peptic ulcers occur when the balance between acid pepsin digestion and the defence mechanism of the mucosa is disturbed. Classical sites for peptic ulcers are the first part of the duodenum, the angula incisura and the antrum of the stomach, the lower end of the oesophagus in patients with gastro-oesophageal reflux, the efferent limb of a gastroenterostomy, and inside a Meckel's diverticulum if there is ectopic gastric mucosa.
Acid hypersecretion was thought to be the most important factor in the causation of ulcers, in particular duodenal ulcers. The classical example of the effect of increased acid production is the Zollinger-Ellison syndrome. Gastrin produced by the pancreatic or duodenal adenoma causes maximal stimulation of the parietal cell mass, producing massive amounts of acid and resulting in a particularly aggressive form of peptic ulcer disease. Recent evidence, however, indicates that Helicobacter pylori, a Gram-negative organism that resides in the mucus layer of the antrum, is the real culprit in the majority of cases. The organism is found in more than 90% of patients with duodenal ulcers and about 70% of patients with gastric ulcers. The exact mechanism through which the bacteria cause peptic ulceration is still conjectural, but eradication of the bacteria heals the ulcer and prevents recurrence. Such a discovery has completely revolutionised the understanding of the pathogenesis and management of peptic ulcers.
Mucosal defence against acid-pepsin digestion consists of the mucous layer on the mucosa serving as a barrier between the lumen and the epithelial surface, the secretion of bicarbonate and the rapid turnover of mucosal cells. Helicobacter infection, NSAID intake, reflux of bile into the stomach and by mucosal ischaemia are factors that can weaken the mucosal defence and contribute to the development of ulcers.
‘Stress ulcers’ are common in severely ill patients, particularly those treated in intensive care units. Cushing's ulcers and Curling's ulcers are stress ulcers occurring after head injuries and severe burns, respectively. These ulcers are caused by increased acid production in stressed patients, and mucosal ischaemia as a result of splanchnic hypoperfusion.
Practically all duodenal ulcers occur in the duodenal bulb. This part of the duodenum is in the direct path of the acid contents of the stomach. Alkaline pancreatic juice and bile, which enter the duodenum in the second part, have not yet had an opportunity to neutralise the gastric acid. Duodenal ulcers are more common than gastric ulcers. They tend to occur in younger patients and are more common in men than in women. There is also a genetic predisposition; the disease is more common in family members of index cases, patients with blood group O, non-secretors of blood group antigens in the saliva, and those with high circulating pepsinogen.
The cardinal symptom of duodenal ulcer is pain. The pain is typically localised to the epigastrium, is dull or burning in character, starts several hours after a meal, wakes the patient at night and is relieved by food or antacids. Nausea and vomiting may be present during acute exacerbation but are not prominent features. In contrast to patients with non-ulcer dyspepsia, ulcer patients localise the pain to the epigastrium with one finger. Apart from mild tenderness in the epigastrium, patients with uncomplicated ulcer disease do not have physical signs.
The course of duodenal ulcer disease is one of relapses and remissions. The patient complains of episodes of severe pain lasting for weeks, interspersed by months of remission, the pattern repeating itself over several years. The disease may burn itself out after 10–15 years.
It is difficult to differentiate duodenal ulcer from other causes of dyspepsia (gastric ulcer, non-ulcer dyspepsia, reflux oesophagitis, gastric cancer, gallstone) with confidence on clinical grounds alone. Barium meal may show an ulcer crater. However, it may be difficult to differentiate active ulceration from scarring. Flexible endoscopy is the most accurate diagnostic method. The oesophagus, stomach and the first and second part of the duodenum can be clearly seen using this technique.
Helicobacter pylori can be demonstrated by serology, by the urea breath test, or in antral biopsies using microscopy or the rapid urease test. Culture of organisms is difficult and rarely performed in clinical practice. Serology detects past as well as current infection and is simple to conduct as only a drop of blood is necessary. The accuracy of the commercially available test kits have improved but their validity must be confirmed for each country as there are geographical differences in the genetic makeup of the bacteria. Serology cannot be reliably used to assess the success of eradication therapy, as antibody levels can remain raised for prolonged periods even after successful eradication In the urea breath test, urea labelled with a non-radioactive (C13) or radioactive (C14) carbon isotope is given by mouth. Helicobacter produces urease, which split the urea into ammonia and carbon dioxide. If C13 or C14 is detected in the exhaled breath the presence of Helicobacter is confirmed. The urea breath test is a reliable non-invasive way of confirming the success of eradication therapy. In patients who have undergone endoscopy, a convenient test is the rapid urease test. Antral biopsies are embedded into a gel containing urea and an indicator dye (neutral red). The ammonia produced as a result of urease is alkaline and changes the indicator dye to a red colour. This gives a rapid result—often within an hour—and is cheaper than histology. The use of proton pump inhibitors such as omeprazole lead to a suppression of organism numbers in the gastric mucosa. This can lead to false negative results in patients undergoing urea breath test, urease test and even histology. It is recommended that patients on proton pump inhibitors have these ceased at least 2 weeks prior to urea breath testing or, if testing is to be performed at endoscopy, that biopsies are taken for histology from both antrum and body of stomach to increase the yield.
The aim of treatment is to alleviate the ulcer pain, to heal the ulcer, to prevent recurrence and to forestall complications.With powerful anti-secretory drugs and effective regimens to eradicate Helicobacter, these aims can be achieved by medical therapy in the great majority of patients. Apart from giving up smoking and avoiding, if possible, ulcerogenic drugs, lifestyle modification such as a change in diet or avoidance of stress is not necessary. Such changes are difficult to make and there is little evidence that they accelerate ulcer healing. Nowadays, elective surgery for uncomplicated ulcer disease is rarely, if ever, indicated. Nearly all ulcer surgery is performed as an emergency procedure for complications.
Commonly used drugs
Antacids may be in tablet or liquid form. They are either magnesium based (liable to cause diarrhoea) or aluminium based (may cause constipation). Antacids give rapid relief of ulcer pain but do not heal ulcers unless taken in very high doses.
HISTAMINE-2 RECEPTOR ANTAGONISTS
Histamine-2 receptor antagonists (H2 blockers) are the first group of drugs that can effectively block gastric acid secretion. Examples are cimetidine, ranitidine and famotidine. Relief of pain occurs after a few days and up to 90% of ulcers heal after a 6-week course. Once the drug is stopped, however, acid production returns to normal and ulcer recurrence is highly likely.
PROTON PUMP INHIBITORS
Proton pump inhibitors such as omeprazole or lansoprazole leads to complete inhibition of gastric acid production. Symptomatic relief and ulcer healing is even more impressive than H2 blockers. However, once the drug is stopped ulcer recurrence is common. Proton pump inhibitors have been shown to both prevent and heal ulcers associated with NSAID use.
Sucralfate is a drug that is not absorbed but exerts its action by physically covering the ulcer base. Ulcer healing rates are similar to H2 blockers.
ERADICATION OF Helicobacter pylori
Eradication of H. pylori is now the cornerstone of ulcer treatment. It is also the main reason why elective surgery for peptic ulcer disease is now very rare. The bacteria dwells in, and is protected by, the mucous layer of the gastric pits and are difficult to eradicate. Multiple drugs need to be administered simultaneously. Effective combinations should result in eradication in more than 90% of patients, if patient compliance is satisfactory. Examples of such combinations are 1–2 weeks of triple therapy using bismuth, tetracycline and metronidazole. Side effects, especially gastrointestinal upsets, are common. Combinations of a proton pump inhibitor and two other antibiotics (e.g. amoxycillin and clarithromycin) taken for 1 week are equally effective and have fewer side effects. This combination has become first line therapy in most countries.
The classical operations for duodenal ulcer disease are designed to reduce gastric acid production (Table 22, “Operations for duodenal ulcers”). Nowadays their use is almost entirely confined to the management of ulcer complications. Essentially one can remove the acid-producing part of the stomach or sever the vagus nerve, which controls acid secretion.
|Side Effects||Recurrence rate (%)|
|Vagotomy and drainage||1||+||5–10|
|Highly selective vagotomy||<0.5||±||15|
|Vagotomy and antrectomy||2–5||++||1|
Acid is secreted by parietal cells in the body and the fundus of the stomach. In order to ensure adequate reduction of acid output, at least two-thirds of the stomach needs to be resected. Patients who have had this operation are unable to tolerate large meals. Weight loss, malnutrition and anaemia are common. The rapid entry of food into the intestine leads to ‘dumping syndromes’; the patient feels faint or unwell after a meal. This may be due to transudation of fluid in response to an osmotic load in the gut (early dumping, occurring 10 minutes after a meal) or rapid absorption of glucose, leading to insulin release and rebound hypoglycaemia (late dumping, occurring 2–3 hours after a meal).
TRUNCAL VAGOTOMY AND DRAINAGE
Gastric acid production may also be decreased by dividing the vagus nerve, thus removing the nervous stimulation of the parietal cell mass. If the whole vagal trunk is cut, delay in gastric emptying occurs in a significant number of patients because the motor supply to the antrum is also severed. A drainage operation, either a pyloroplasty or gastro-enterostomy, is necessary. These operations are relatively easy to perform and are useful in emergency situations. Between 5 and 10% of patients complain of diarrhoea, due to rapid transit of food through the gut.
HIGHLY SELECTIVE VAGOTOMY
This operation aims to divide the vagal fibres supplying the parietal cell mass but leave the innervation of the antrum (the nerve of Laterget) intact. The operation is technically demanding and time-consuming. Side effects are almost non-existent but the recurrence rate is higher than other procedures.
VAGOTOMY AND ANTRECTOMY
In this operation the vagal trunks are divided to remove the vagal stimulation of acid production and the antrum is resected to remove the source of gastrin, another potent stimulator of gastric acid secretion. Continuity of the gastrointestinal tract is restored by gastroduodenal anastomosis. The main attraction of this operation is the very low ulcer recurrence rate.
Gastric ulcers are less common than duodenal ulcers. They affect the older age group. Gastric ulcers are more common in patients from lower socioeconomic groups. Non-steroidal anti-inflammatory drugs are a common cause of gastric ulcers.
As in duodenal ulceration the usual presentation is epigastric pain. The pain is typically exacerbated by food; nausea, unremitting pain and weight loss are common. Differentiation from duodenal ulcer (and gastric cancer) is unreliable.
In double-contrast barium meal examination the stomach wall is coated with a thin layer of barium and effervescent drink is given to distend the stomach with gas. Benign gastric ulcers appear as craters, penetrating beyond the expected stomach contour, with mucosal folds radiating from the ulcer like spokes of a wheel. Irregular ulcer edges, a crater protruding into the lumen of the stomach, irregular mucosal folds with no peristalsis, and ulcers located at sites other than the lesser curvature and the antrum, suggest malignancy. All demonstrated gastric ulcers must be investigated by endoscopy and biopsy.
Through the endoscope a benign gastric ulcer has smooth, regular margins. The most common site is the angular incisura, followed by the lesser curvature and the antrum. An ulcer seen outside these locations should be presumed malignant. Malignant ulcers are irregular with raised, rolled-up edges.With potent acid suppression, even malignant ulcers may completely heal over temporarily, leaving an area of mucosal irregularity. All gastric ulcers must have multiple biopsies taken from all four quadrants of the ulcer. After a course of therapy, repeat endoscopy to assess healing and repeat biopsy are mandatory.
Although acid output is normal or low in patients with gastric ulcers, ulcer pain is controlled and the ulcer heals with acid suppression. H2 blockers or omeprazole may be used. Because gastric ulcers are larger than duodenal ulcers they generally take longer to heal. Some 70% of gastric ulcers are associated with H. pylori. Eradication of the bacteria is indicated in such patients to reduce the recurrence rate. Other gastric ulcers are caused by NSAID. If it is not possible for the patient to stop taking NSAID, a proton pump inhibitor taken concurrently confers a degree of protection.
Gastric cancer may masquerade as a gastric ulcer. If complete healing of the ulcer is not achieved with two or three courses of medical therapy, surgical resection of the ulcer is indicated.
The aim of surgical treatment is to resect the ulcer-bearing part of the stomach. The operation of choice for gastric ulcers is Billroth I gastrectomy, in which the distal half of the stomach is removed and gastroduodenal continuity restored. In elderly, frail patients, and in those with an ulcer high on the lesser curvature where resection would entail removal of most of the stomach, excision of the ulcer with vagotomy and pyloroplasty may be an alternative.
Complications of ulcer disease
Complications of duodenal ulcers include bleeding, perforation and gastric outlet obstruction.
Peptic ulcer bleeds occur when the ulcer erodes an artery in the ulcer base. Classical textbook cases of posterior duodenal ulcers eroding the gastroduodenal artery and gastric ulcers eroding the left gastric artery are rarely seen. Most cases of ulcer bleeding result from erosion of medium-sized arteries in the submucosa.
Peptic ulcer bleeding is the most common cause of upper gastrointestinal haemorrhage and is a frequent cause of emergency hospital admission. The mortality is about 10% and has remained constant despite advances in diagnosis and treatment. This is due to an increase in the number of elderly people presenting with this condition.
About 85% of bleeding ulcers stop bleeding spontaneously and do not require specific measures to stop the haemorrhage. The mortality in those who continue to bleed or develop rebleeding while in hospital is 10-fold higher. The likelihood of rebleeding may be predicted on clinical grounds and the appearance of the ulcer on endoscopy. Haematemesis and shock on admission suggest a large initial bleed and are associated with a higher risk of recurrent haemorrhage. Ulcers with stigmata of recent haemorrhage, such as a visible vessel or an adherent blood clot seen on endoscopy, are also more likely to rebleed. On the other hand, if a cleanbased ulcer is seen on endoscopy the risk of rebleeding is very low. The risk of rebleeding decreases with time after the initial bleed. If rebleeding does not occur within the first 72 hours it is unlikely to occur.
The patient may vomit fresh blood and clots (indicating torrential bleeding) or coffee-ground material (acid-haematin resulting from the action of gastric acid on haemoglobin). More commonly the patient passes melaena (semi-liquid, tarry stool with a characteristic sickly smell). The consistency and colour of the melaena may give some clue to the rapidity of the bleeding; the redder and less well formed the stool, the brisker the haemorrhage. There may be a background of long-standing peptic ulcer disease, and history of another episode of bleeding in the past. In 30% of patients there is a history of recent intake of NSAID or aspirin. The patient may complain of dizziness or faint on getting up from a supine position or after going to the toilet.
Apart from melaena on rectal examination, patients with a mild to moderate amount of blood loss show little abnormality on examination. A postural drop of blood pressure is the first clinically detectable sign of hypovolaemia. Tachycardia, sweaty palms, hypotension, anxiety and agitation are signs of shock and call for urgent blood volume replacement.
All patients who have had a significant gastrointestinal bleed within the past 48 hours should be admitted to hospital. A large-bore intravenous cannula should be inserted and blood drawn for baseline tests and crossmatching. In the acute stage, the haemoglobin level is a poor guide to the need for transfusion as haemodilution may not have occurred. The decision to replace the blood volume by plasma expanders or blood should be based on signs of hypovolaemia and the rapidity of the bleeding. In elderly patients with poor cardiac reserve, or in patients with massive bleeding, monitoring the central venous pressure by a central venous line gives a more accurate indication of the amount of fluids needed.
IDENTIFY THE BLEEDING POINT
If facilities allow, all patients admitted with upper gastrointestinal haemorrhage should undergo endoscopy within 24 hours of admission. Patients who vomit fresh blood or are in shock may have ongoing massive blood loss and should undergo endoscopy once they are resuscitated. An accurate diagnosis forms the basis of logical treatment, and the precise location of bleeding is of paramount importance should surgery be needed to control bleeding.
Ulcer bleeding stops spontaneously in about 80% of patients. Only a small percentage require specific measures to stop bleeding. In recent years endoscopic procedures have become the first-line method of controlling ulcer bleeding. The most popular methods are injection therapy using adrenaline solution and/or sclerosants, such as polidocanol, absolute alcohol or ethanolamine, contact thermal methods, such as the heater probe or multipolar electrocoagulation, or a combination of the above. Endoscopic haemostasis should be applied for ulcers with active bleeding or stigmata of recent haemorrhage predictive of high risks of rebleeding. Surgery remains the most definitive method of controlling ulcer haemorrhage, and is indicated when endoscopic haemostasis fails to control the bleeding, or when rebleeding occurs. The morbidity and mortality of emergency surgery for ulcer bleeding is high. In principle, the operation performed should be the minimum compatible with permanent haemostasis. The choice of operations is determined by the site and size of the ulcer as well as the experience and preference of the surgeon. Most bleeding duodenal ulcers may be managed by underrunning the bleeding vessel together with vagotomy and pyloroplasty. Large, deep ulcers destroying the first part of the duodenum may require a Pólya's gastrectomy. Bleeding gastric ulcers are best treated by gastrectomy. In frail, elderly patients an alternative is ulcer excision, with or without vagotomy and drainage.
Perforation occurs when the ulcer erodes through the full thickness of the gut wall. Gastric and duodenal contents spill into the peritoneal cavity causing generalised peritonitis. The most frequent site of perforation is the anterior wall of the first part of the duodenum. Males outnumber females in a ratio of 9 to 1. The incidence of ulcer perforation in the elderly is increasing because of the increased use of NSAID.
The patient presents with sudden onset of severe abdominal pain. The onset of pain is so sudden that the patient can often accurately pin-point the exact moment when the perforation occurred. Approximately 10% of patients have no preceding history of dyspepsia. The physical signs in the abdomen are dramatic. There is generalised tenderness, guarding and rebound tenderness. The abdominal muscles are held rigid, giving the classical ‘board-like rigidity’. Abdominal respiratory movements and bowel sounds are absent. The percussion note over the liver may be resonant because of free intraperitoneal air. In patients in whom the perforations are sealed off by adjacent organs the signs may be localised to the epigastrium. In other cases the spillage from the perforation may track down the right paracolic gutter, resulting in maximal tenderness in the right iliac fossa. This is the so-called ‘right paracolic gutter syndrome’ and may be mistaken for acute appendicitis.
A plain chest radiograph with the patient in the erect position shows free gas under the diaphragm in 80% of cases.
Once a definitive diagnosis is made, the patient should be given parenteral opiates for pain relief, intravenous fluids should be administered and a nasogastric tube passed as soon as possible to decompress the stomach to avoid ongoing contamination. Unless there is clear evidence that the ulcer has been sealed off, an operation should be performed without delay. The operation of choice is a simple patch repair. A piece of omentum is sutured over the perforation to plug it (Patch repair of perforated duodenal ulcer with a pedicle of omental plug.). This is followed by a thorough lavage of the peritoneal cavity with copious amounts of warm saline to remove all the exudate and food particles.
If facilities and a surgeon experienced in laparoscopic surgery are available the patch repair can be performed laparoscopically, avoiding a painful wound.
The discovery that peptic ulcer disease can be cured by eradication of H. pylori has diminished the enthusiasm for definitive surgery at the same time as the patch repair. For patients who are Helicobacternegative, an ulcer-curing operation (e.g. vagotomy and pyloroplasty, or highly selective vagotomy) may be considered if there has been a long history of troublesome ulcer disease with complications, provided that the condition of the patient is good and the degree of contamination of the abdomen not too severe.
Long-standing duodenal or prepyloric ulcers may cause gastric outlet obstruction. It may be due either to fibrosis resulting from chronic ulceration and healing or to oedema associated with acute ulceration.
The cardinal symptom is repeated vomiting of undigested food that is non-bile-stained. There may be weight loss and dehydration. Abdominal examination shows a dilated, distended stomach. Succussion splash (splashing noise on rocking the patient's abdomen) is present several hours after a meal.
The inability to take fluids by mouth and vomiting of gastric juice lead to severe fluid and electrolyte problems. The patient rapidly becomes dehydrated and salt depleted. Loss of acid and chloride ions in the gastric juice result in hypochloraemic alkalosis. There may be a large deficit of total body potassium. Because of the severe sodium depletion, the distal renal tubules secrete potassium and hydrogen ions in exchange for sodium ions in the glomerular filtrate. The urine is therefore acidic in severe cases of gastric outlet obstruction, although the patient is alkalotic. This is the so-called paradoxical aciduria.
A gastric cancer in the antrum or the pyloric canal causing obstruction may present in an identical manner.
Fluid and electrolyte losses should be replaced by infusion of normal saline. Large amounts of potassium are likely to be required. Administration of potassium supplements should be guided by estimation of the serum level and acid-base balance. It should only commence when renal failure is excluded. Correction of alkalosis is not necessary. Once the fluid and electrolyte deficiencies are corrected the body's homeostatic mechanisms will restore the acid-base balance.
The stomach should be decompressed with a nasogastric tube. Food particles may block the tube. Irrigation and lavage through a wide-bore stomach tube is usually necessary. Intravenous omeprazole is given. Once the stomach is cleansed endoscopy should be carried out to confirm the diagnosis and to exclude malignancy. If the obstruction is due to oedema around an active ulcer, such measures may restore patency. In the majority of cases, operative management is required. The obstruction is either enlarged (vagotomy and pyloroplasty, pyloric dilatation with highly selective vagotomy), bypassed (vagotomy and gastroenterostomy) or resected (Pólya's gastrectomy, vagotomy and antrectomy). In elderly patients unfit for surgery, dilatation of the stenotic area using a balloon catheter under endoscopic guidance may be considered.
This is a rare disease caused by overproduction of gastrin by G cell tumours of the pancreas or the duodenum. Maximal stimulation of the parietal cells leads to intractable peptic ulcerations. Ninety per cent of gastrinomas occur within the ‘gastrinoma triangle’ bounded by the cystic duct and bile duct, the junction of the head and neck of the pancreas, and the second and third parts of the duodenum. Two-thirds of all gastrinomas occur outside the pancreas. More than 60% of gastrinomas are malignant. Twenty per cent of patients with Zollinger-Ellison syndrome have micro-adenomatosis of the pancreas rather than discrete tumours.
The diagnosis should be suspected when peptic ulcers occur at unusual sites, such as the second part of the duodenum or the jejunum, or ulcers recur after adequate surgery. One-third of patients have watery diarrhoea due to high gastric output. Dehydration, and acid-base or electrolyte imbalance may occur.
Measurement of gastric acid output
Because of the high circulating gastrin, the basal acid output (BAO) is high and stimulation with pentagastrin does not elicit significant increase. A BAO of more than 15 mmol/h and a BAO to maximal acid output ratio (BAO : MAO) of more than 0.6 is highly suggestive.
Gastrin can be measured by radioimmunoassay. The diagnosis is confirmed by demonstrating a high fasting gastrin level.
The aim of treatment of Zollinger-Ellison syndrome is two-fold:
- to control the high gastric acid output and sever the ulcer diathesis
- to treat the gastrinoma