GI Consult: Peptic Ulcer Disease

Who are the patients at greatest risk for hemorrhage from peptic ulcer disease? What are the steps that should be taken initially when you suspect this type of bleeding? When should endoscopy be performed? The authors address these and other questions.

By Luis F. Lara, MD, and Girish Mishra, MD

What exactly is a "bleeding ulcer" and what causes it?

Peptic ulcer disease (PUD) is the most common cause of upper gastrointestinal hemorrhage in the United States, accounting for more than 50% of cases, followed by gastric erosions and esophageal variceal hemorrhage. Ulcers occur when the normal defense mechanisms of the intestinal mucosa, which include a mucous barrier, bicarbonate secretion, and epithelial cell integrity, are disrupted. The most common causes of PUD are Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Other factors like alcohol ingestion and excessive production of or epithelial exposure to acid and pepsin can contribute to the formation of ulcers. Additional causes of PUD include G-cell hyperplasia, infection by herpes simplex virus and cytomegalovirus, vascular insufficiency, radiation and chemotherapy, and hypersecretory syndromes such as gastrinomas.

Peptic ulcer disease is more common in patients over 60 years of age. Overall mortality from PUD-related bleeding is approximately 10%.

What is the evidence implicating H. pylori as a cause of PUD?

Patients with H. pylori develop PUD at a rate of about 1% per year, which is three times the rate of the H. pylori-negative population. Infection by H. pylori was reported to be as high as 90% in patients with duodenal ulcers, but recent reports show a declining prevalence. Nevertheless, H. pylori is still associated with PUD in more than 60% of cases, and eradication of the infection reduces PUD recurrences to less than 5%. Spontaneous ulcer healing occurs in only 20% of patients when H. pylori is not eradicated.

How does H. pylori cause PUD?

Infection by H. pylori increases gastrin levels and gastric acid output and causes an inflammatory response that leads to tissue damage. The resultant mucosal defects allow back diffusion of hydrogen ions and diffusion of acid and pepsin into the cell with direct cytotoxic effects. Helicobacter pylori also decreases bicarbonate secretion and may affect mucous production. Certain strains of H. pylori, capable of producing cytotoxins like Cag A, are more ulcerogenic than others.

What is the role of NSAIDs in causing PUD?

Nonsteroidal anti-inflammatory drugs contribute to PUD by inhibiting prostaglandins, which impairs formation of the protective mucous barrier. Overall lifetime risk for PUD in persons taking NSAIDs is around 20%, similar to that for patients with H. pylori infection. Identified risk factors for PUD in patients taking NSAIDs include age over 75, the presence of cardiac disease, and concomitant corticosteroid use. It is important to point out that steroid use, in itself, does not increase the risk of PUD or gastrointestinal hemorrhage. For those patients who must take NSAIDs and who either have had PUD or are at risk for it, long-term use of proton pump inhibitors (PPIs) may prove beneficial. Misoprostol has also been shown to decrease the risk of PUD in patients taking NSAIDs, but its side effects (diarrhea, cramping, and abdominal pain) have limited its use.

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Are there any other causative factors associated with PUD?

Patients with blood type O or a family history of PUD, as well as those who abuse cocaine or tobacco, are at increased risk for ulcer bleeding or rebleeding, probably due to direct cytotoxic effects or altered mucosal blood flow.

What are the presenting signs and symptoms of PUD and upper gastrointestinal bleeding?

Signs and symptoms of PUD lack sensitivity or specificity. More than half of patients may experience heartburn, but 20% of patients with PUD are asymptomatic. Patients with a bleeding peptic ulcer will usually present with more definitive symptoms, such as melena or hematemesis. Hematochezia may be present if upper gastrointestinal bleeding is brisk, indicating significant blood loss. The classic sign of duodenal ulcers is epigastric pain two to three hours after a meal, when the buffering effect of food has dissipated. Pain in patients with penetrating ulcers is more intense and more localized; it may also radiate to the back. Hemodynamic decompensation with severe abdominal pain may indicate perforation, and vomiting may occur with gastric outlet obstruction due to inflammation surrounding the ulcer.

Is there an accepted algorithm for diagnosing and managing PUD when an upper gastrointestinal bleed is suspected?

Vital signs should be assessed immediately so that the patient can be transferred to acute care if necessary. Blood counts and chemistries, liver enzymes, and coagulation studies should be done and two large-bore intravenous lines established. At least two units of packed red blood cells should be typed and crossmatched, and a transfusion should be considered in patients with active bleeding, tachycardia, hypotension, postural changes, or a history of vascular or cardiac disease. A nasogastric tube may be inserted to confirm that the source of the bleeding is the upper gastrointestinal tract, but up to 15% of patients will have a false negative aspirate, usually because of pyloric spasticity or occlusion preventing duodenal bleeding from refluxing into the stomach. Obtaining bile in the aspirate decreases the false negative rate. A rising blood urea nitrogen level can also indicate gastrointestinal hemorrhage in this population. The patient must be hemodynamically stabilized before endoscopy is performed.

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At what point is an esophagogastroduodenoscopy (EGD) indicated? How useful is this procedure for diagnosing and managing a PUD-related gastrointestinal hemorrhage?

Though it can identify an ulcer crater and might differentiate benign from malignant ulcers, gastrointestinal radiology is not recommended in the patient with an acute upper gastrointestinal bleed. The preferred procedure is EGD because it is more accurate, with a sensitivity of more than 90%, and because of other diagnostic and potentially therapeutic advantages. For example, direct visualization of the bleeding site has prognostic value and can help guide therapy. The risk of rebleeding has been found to be 80% to 100% if arterial spurting is evident on endoscopy, 40% if a vessel is visible but not spurting, 20% to 30% if there is an adherent clot, 10% if there is a flat, dark spot at the ulcer base, and less than 5% if the ulcer base is clean. We recommend endoscopy in all patients with an upper gastrointestinal bleed, despite suggestions in the literature that endoscopy might be withheld or delayed in certain populations, such as young adults with improving symptoms and without further bleeding.

The timing of endoscopy is important because stigmata of recent hemorrhage are more frequently found the sooner the procedure is performed after the onset of the initial bleed. Our institution has also reported decreased use of blood products and decreased intensive care stay and overall hospital stay when endoscopy was performed as soon as possible after gastrointestinal bleeding started.

Can an EGD provide any clues to the etiology of PUD?

Aspirin or NSAID use should be suspected in patients with ulcer recurrence, refractory ulcers, postsurgical ulcers, or multiple ulcers. Distal duodenal ulcers or jejunal ulcers should raise the suspicion of Zollinger-Ellison syndrome, and malignancy should be considered whenever gastric ulcers are found. Even when gastric ulcers appear benign, usually smooth and flat on endoscopy, a repeat EGD is recommended to ensure that the ulcer has healed and to avoid missing a neoplastic lesion. Biopsy specimens may be deferred until this second EGD so as not to provoke bleeding.

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When performed appropriately and urgently, how useful is EGD in controlling gastrointestinal bleeding?

Because endoscopic treatment has been shown to reduce mortality, it is important to recognize ulcers that are at high risk of rebleeding, such as those with active bleeding or a visible vessel. Endoscopic therapy is usually not recommended in patients with a clean-based ulcer. Ulcers with a flat, dark spot or adherent clot may hide a vessel. Removal of the clot with a snare or biopsy forceps is indicated in patients with prior massive bleeding or with a large ulcer (more than 10 mm in diameter).

Endoscopic therapy for PUD includes thermal methods (laser therapy, electrocoagulation, and heater probes), injection therapy, and hemoclips. Thermal methods have been successful, with no one technique being more effective than another. However, laser therapy has been abandoned because it is relatively cumbersome and expensive. Monopolar electrocoagulation carries a high risk of tissue damage and is not generally used. On the other hand, multipolar electrocoagulation has been shown to be safe; it reduces rebleeding and decreases hospital stays and blood transfusion requirements. It may also decrease the need for emergency surgery, which carries a high mortality. Heater probes have been reported to be as successful as electrocoagulation. Injection therapy has also been shown to be successful in controlling hemorrhage. Epinephrine, ethanol, saline, or sclerosants like 50% dextrose or polidocanol are used. In addition, improved results have been reported with a combination of injection therapy followed by multipolar coagulation compared with either method used alone. Recently, hemoclips have been reported to be as effective as electrocoagulation, but further trials are needed to confirm their therapeutic role.

The actual method used in any particular situation varies with the experience and comfort level of the endoscopist, the size of the ulcer, and the patient's bleeding status. At our institution, we usually try to remove adherent clots to expose vessels and inject epinephrine (1:10,000) around and into the ulcer. We follow this with multipolar electrocoagulation.

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How successful is medical management with PUD?

Treatment of H. pylori infection is indicated in patients with PUD. When H. pylori is eradicated, the risk of rebleeding decreases by at least 80%. Several antibiotic regimens, combined with a PPI, have proven effective in eliminating H. pylori. Proton-pump inhibitors are usually started in the emergency department. Oral PPI administration has not been shown to affect acute bleeding, but subsequent clot formation and stabilization does require a pH higher than 4, which all PPIs achieve for at least 14 hours after each dose. Recently, a continuous infusion regimen of omeprazole 8 mg/hour for 72 hours (after an 80-mg intravenous bolus dose) was shown to reduce the risk of ulcer rebleeding when compared to oral PPI therapy, presumably because peak antisecretory effectiveness is achieved sooner. The only intravenous PPI currently available in the United States is pantoprazole.

Proton pump inhibitors have an excellent safety profile. Initial concerns about the potential risk of gastric hyperplasia have been disproven after more than 15 years of follow-up. H2-receptor antagonists also produce a pH above 4, especially when given in a continuous intravenous infusion; however, their use is limited by the risk of tachyphylaxis and fairly rapid loss of antisecretory effectiveness. Prostaglandins inhibit acid secretion and help maintain mucosal integrity; significant gastrointestinal side effects, however, such as abdominal pain and diarrhea, curtail their usefulness.

What is the long-term prognosis for patients with PUD? Is there still a role for surgery in the management of PUD?

Up to 20% of patients will rebleed after endoscopic therapy. We usually repeat an EGD in these patients because about half of them will respond to repeat therapy. However, repeat therapy carries a higher risk of complications, especially perforation, so we tend to avoid a repeat endoscopy in patients with a persistent massive gastrointestinal bleed, a large ulcer, or an ulcer in a hard-to-reach location, like the curve between the duodenal bulb and the second portion of the duodenum. Most of these patients will require radiologic or surgical intervention.

Other factors associated with worse outcomes in patients with bleeding from PUD include age over 60, presence of underlying disease, bleeding during hospitalization (which in some reports carries a 25% mortality risk), and the need for emergency surgery (which increases the mortality risk at least threefold). Despite aggressive therapy, about 10% of patients with PUD-related hemorrhage will require surgical intervention, with a mortality rate of 20%.

Nevertheless, most patients with PUD-related hemorrhage do well with some combination of the above treatment strategies. Long-term acid suppression therapy and risk factor modification are recommended after hospital discharge.

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