ABSTRACT: Undiagnosed or persistent Helicobacter pylori infection and surreptitious or unrecognized NSAID use are the most common causes of refractory peptic ulcers. The use of antibiotics, bismuth, or proton pump inhibitors (PPIs) suppresses the H pylori bacterial load and may obscure the diagnosis. H pylori infections have also become more difficult to cure because of increased antibiotic resistance. For refractory infection, select an antibiotic based on in vitro susceptibility testing. When this is not available, combination therapy with a PPI, tetracycline, metronidazole, and bismuth is often effective. To detect surreptitious or inadvertent NSAID use, review the drug history in detail. When there is any doubt about such use, check platelet cyclooxygenase function.
The development of effective antimicrobial therapy to eradicate Helicobacter pylori infection and the widespread use of potent proton pump inhibitors (PPIs) have revolutionized the management of peptic ulcer disease. Most peptic ulcers heal within 1 to 2 months of conventional anti- secretory treatment; however, 5% to 10% fail to heal within this period or persist despite prolonged antisecretory drug therapy.1 The small number of ulcers that persist despite conventional treatment are considered refractory.2,3
Here we review the causes of refractory ulcer and describe specific management strategies.
PEPTIC ULCER DISEASE: A BRIEF OVERVIEW
Peptic ulcerations are excavated mucosal defects that result from destruction of epithelial cells by the caustic effects of acid and pepsin in the GI lumen. Ulcers have been defined histologically as necrotic mucosal defects that extend through the muscularis mucosae and into the submucosa or deeper layers (Figure). Necrotic defects that are more superficial are considered erosions.4,5 Ulcers can also be characterized as acute or chronic depending on the absence or presence of fibrosis. This article focuses on chronic peptic ulcers.
Figure – Endoscopy revealed a large, deep, slow-healing, NSAID-associated ulcer on the anterior wall of the antrum (A). The paient's test results for Helicobacter pylori were negative. Six months later, after continuous twice-a-day omeprazole therapy, the ulcer had almost completely healed (B). Within a week of restarting low-dose NSAID therapy (the proton pump inhibitor was discontinued), the ulcer recurred (C). Histological findings after resection were typical of gastric ulcer.
The most common causes of peptic ulcer disease are H pylori infection and NSAID use (Table).6 Clinically, the natural history of peptic ulcer disease is one of exacerbation and remission. Unless the causative factor is eliminated, the recurrence rate ranges between 60% and 100% per year. Elimination of the causative factor is expected to cure the disease and prevent recurrence.
DEFINITION OF REFRACTORY ULCER
Lanas and colleagues7 defined refractory ulcers based on the type and duration of treatment. Refractory duodenal ulcers were those that did not heal after 8 weeks of full-dose H2-receptor antagonist therapy or after 6 weeks of PPI therapy. Refractory gastric ulcers were defined as those that did not heal after 12 weeks of full-dose H2-receptor antagonist therapy or 8 weeks of PPI therapy. In this article, we define refractory ulcers as those that do not heal after 12 weeks of therapy with PPIs or those that recur rapidly after antisecretory drug therapy is discontinued.
Factors that facilitate healing. Ulcer healing is initiated by the secretion of growth factors in the ulcer margin and ulcer bed; the mucosal defect is filled with cells that migrate from the ulcer margin and with connective tissue.8,9 The epidermal growth factor, transforming growth factor-α, hepatocyte growth factor, and trefoil factors have been implicated in this process. These growth factors regulate cell proliferation, migration, differentiation, and secretion and degradation of the extracellular matrix—all of which are essential for tissue healing.9
Gastric mucosal blood flow is also important for ulcer healing. In one study, the refractory ulcers persistently had significantly lower mucosal blood flow than that of normal stomachs and healing ulcers.10
Factors that impede healing. Clinical markers associated with slow ulcer healing include11,12:
• Large ulcer size.
• Persistent ulcer symptoms.
• Alcohol use.
• Cigarette smoking.
• NSAID use.
In one study, 90% of aspirin-associated gastric ulcers of less than 0.5 cm in diameter healed within 8 weeks of treatment with cimetidine and antacids despite the continued use of aspirin, whereas only 25% of gastric ulcers of greater than 0.5 cm in diameter healed in this same setting.13
NSAID use is the most common factor associated with slow healing and rapid recurrence of peptic ulcers. NSAIDs are thought to delay healing by interfering with the action of growth factors, decreasing epithelial cell proliferation in the ulcer margin, decreasing angiogenesis in the ulcer bed, and slowing maturation of the granulation tissue.8
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• Bardhan KD, Naesdal J, Bianchi Porro G, et al. Treatment of refractory peptic ulcer with omeprazole or continued H2 receptor antagonists: a controlled clinical trial. Gut. 1991;32:435-438.
• Guzzo JL, Duncan M, Bass BL, et al. Severe and refractory peptic ulcer disease: the diagnostic dilemma: case report and comprehensive review. Dig Dis Sci. 2005;50:1999-2008.
• Lanas A. NSAID use and abuse in gastroenterology: refractory peptic ulcers. Acta Gastroenterol Belg. 1999;62:418-420.