| Abstract|| |
Refractory or intractable ulcer is defined as an ulcer that fails to heal completely after eight to twelve weeks, despite appropriate treatment with a modern antiulcer therapy in a compliant patient. Refractory ulcer should be suspected in individuals diagnosed to have peptic ulcer if their symptoms persist longer than usual: occurrence of complications or simply their ulcers fail to heal, since up to 25% of such patients remain asymptomatic. Conditions associated with refractory ulcer include noncompliance, continuous consumption of nonsteroidal anti-inflammatory drugs, acid hypersecretion, smoking. male gender and other factors with questionable role like advanced age, large ulcer size, prolonged duration of symptoms and the presence of complication like bleeding. Nonpeptic ulcers like tuberculosis, malignancy, Crohn's disease and primary intestinal lymphoma should always be considered in the differential diagnosis. Colonization with H. pylori which is well-known as a cause of frequent recurrences, has not been linked with refractoriness. Patients with refractory ulcers must undergo thorough reevaluation including repeated endoscopies, obtaining biopsies for microbiology and histology and determination of serum-gastrin level. Once diseases with identifiable etiologies have been ruled out, aggressive medical management with single or multiple antiulcer drugs should be instituted. Such treatments will virtually heal all refractory ulcers. Surgery should be reserved for patients whose ulcers fail to respond to optimal medical therapy or those who develop complications necessitating surgical intervention.
|How to cite this article:|
Al Freihi HM. Refractory duodenal ulcer. Saudi J Gastroenterol 1995;1:87-92
| Definition|| |
Refractory or intractable duodenal ulcer is an ulcer that fails to heal completely after eight to twelve weeks of full dose treatment with a modern antiulcer drug ,, . Though such ulcers may heal if treatment with H,-receptor antagonists is continued longer or dose is increased ,, or in response to other drugs such as omeprazole ,, , mucosal barrier agents  alone or in combination with other drugs like anticholinergics , , bismuth or antibiotics , . The management of these patients represents a problem for the gastroenterologist and the practicing physician.
| The scope of the problem|| |
It has been estimated that 90-95% of duodenal ulcers (DU) will heal after eight weeks of full dose treatment with an antiulcer agent  . Therefore, only 5-10% of patients with DU will remain unhealed after eight weeks of treatment  . This relative rarity of refractory DU's precluded indepth study of their nature or good clinical trials to indicate how they should be managed. The problem can be illustrated if one considers managing 1,000 ulcer patients and having, at the end of eight weeks treatment, 50-100 patients with unhealed ulcers. Even if all these patients will consent to enrollment in a clinical trial and comply with the requirement of the study including repeated endoscopies, the investigator will end up with a small sample and doubtful results.
| Persistent Symptoms Versus Refractory Ulcers|| |
It is crucial to thoroughly evaluate patients with persistent peptic symptoms who fail to respond to treatment as expected with endoscopies and biopsies if indicated. Refractory symptoms may not be always due to refractory ulcers and the latter may not be due to simple peptic ulcers that are difficult "stubborn" to heal. Symptoms may be related to another disease process including malignancy. tuberculosis or Crohn's disease or simply functional. Likewise, the absence of symptoms does not always mean healing of ulcer, since up to 25% of refractory ulcers remain asymptomatic  . Under normal circumstances - but not always - disappearance of symptoms indicates healing. It is important to note that at times even malignant ulcers may heal with potent antisecretory agents.
| Conditions Associated with Refractory Ulcers|| |
Noncompliance: One of the most obvious factors for treatment failure is noncompliance with an effective prescribed antiulcer regimen or the failure of the treating physician to prescribe the adequate dose  . Factors like inadequate absorption or failure to suppress acid secretion could be excluded, since various investigators have demonstrated effective blood levels of H,-blockers ,,, and suppression of acid secretion to be similar in those with refractory and non-refractory ulcers  .
Nonsteroidal Anti-inflammatory Drugs (NSAID): Consumption of such agents has been found to impair healing of ulcers with all but the most potent antisecretory agents  . Hirschowitz reported that the majority of 35 patients with refractory duodenal and gastric ulcers and without gastrinoma were using aspirin surreptitiously  . Even with known diagnosis of refractory ulcer. 60% of these patients did not admit aspirin consumption which was only detected by history from a family member, serum salicylate determination, or altered platelet function.
Acid Hypersecretion: It is believed that patients with refractory DU's have elevated basal acid output (BAO) with either Zollinger - Ellison Syndrome or the more rare gastric hypersecretion associated with systemic mastocytosis  . In cases of nongastrinoma refractory DU's, evidence has been present for and against a role for basal or nocturnal acid hypersecretion or an increased maximal acid output. Gledhill et al  , Cargill et al  , and Hetzel et al  found that basal acid outputs tend to be higher in patients with nonhealed DU's. Collen and Coworkers  found the mean BAO of patients whose ulcer readily healed with ranitidine to be 6.6 mEq per hour. However. Strom et al  . Quatrini et al  , and Peterson et al  found that there were no differences in BAOs between patients who healed their duodenal ulcers and those who did not during treatment with antiulcer medications. It seems likely that at least some but certainly not all patients with refractory duodenal ulcers have basal acid hypersecretion.
Smoking: Smoking has been implicated in the etiology of duodenal ulcers and in delaying of healing by many investigators ,,. However, others could not confirm the adverse effects of smoking on healing ,,,, . Specifically, smoking has been implicated in the pathogenesis of increased parietal cell mass and therefore enhancement of basal and vagally and maximally-stimulated gastric acid and pepsin secretions. 
Gender: Male sex has been frequently but not uniformly associated with nonhealing duodenal ulcers. Collen et al  found a significant difference in male-female ratio between those with refractory duodenal ulcers and those whose duodenal ulcers healed during treatment with standard doses of antisecretory agents. In the same study 31 of 35 patients with BAO's of greater than 10.0 mEq per hour were males. Kirkpatric and Hirschowitz found similar results in that, all of their patients with elevated BAO's were males  . This fact may explain the preponderance of male gender among patients with refractory duodenal ulcers.
Helicobacter pylori ori): It is well known that more than 90% of duodenal ulcers are associated with H. pylori  . However, there is no conclusive evidence that H. pylori is an important determinant of refractoriness of duodenal ulcers as it was found that the distribution of H. pylori in patients with refractory DU's is similar to those with nonrefractory duodenal ulcer patients  . Nevertheless, the same investigators found that the combination of cimetidine with antimicrobial agents increased the proportion of refractory DU's that healed.
Miscellaneous factors: In addition to the factors addressed so far, there are others which probably play a role in the refractoriness of DU's. These include: old age  , large ulcer size , , large parietal cell mass  , duration of symptoms, complications like hemorrhage, positive family history of ulcer and previous treatment with H 2 -blockers , and heavy alcohol intake , .
| Other causes with Different Etiologies|| |
Ulcers occurring in the duodenal mucosa are not necessarily always peptic ulceration, albeit the majority are such  . The spectrum of nonpeptic duodenal ulceration extends from infection to malignancy or acid hypersecretory states like Zollinger-Ellison Syndrome or systemic mastocytosis , . In non-industrial countries, tuberculosis must be considered when ulcers fail to respond to adequate therapy as expected, or constitutional symptoms like anorexia, weight loss, and fatigabilitv are present  . In the era where acquired immune deficiency syndrome is becoming increasingly prevalent, infections with cytomegalovirus, candida, herpes simples virus I or Mycobacterium intracellulare should be considered. Crohn's disease should be thought of as it may affect any part of the gastrointestinal tract. Primary lymphoma of the gastrointestinal tract has been reported with relatively high frequency from Middle Eastern countries including the Kingdom of Saudi Arabia , . Lastly, carcinoma of the duodenum or of the pancreas eroding into the duodenum are rare causes of refractory DU's that should be emphasized.
| Management of Refractory Duodenal Ulcers|| |
When ulcer symptoms persist beyond eight weeks of appropriate treatment in a compliant patient, further investigation including upper gastrointestinal endoscopy must be undertaken without delay. Roughly. half of patients will have their ulcers healed and diagnosis of irritable bowel syndrome or other conditions must be entertained while the other half will have their ulcers persistent  . The latter group should have biopsy obtained and appropriate imaging studies requested. Diseases affecting the duodenum like tuberculosis, Crohn's disease, lymphoma, carcinoma etc.. which might be the cause of refractory duodenal ulcers, will have characteristic histology recognizable on simple light microscopy. Fasting serum gastrin concentration should be measured to rule out Zollinger-Ellison Syndrome realizing that patients receiving antisecretory agents may have borderline high levels. If in doubt, these agents must be discontinued for 48 hours and repeat sample he withdrawn. Acid output determination may not be helpful since it will he elevated in the majority of patients with refractory DU's  and patients with peptic ulceration having H. pylori colonization  . Further studies of basal acid output have yielded inconsistent results and variation in basal acid output from day to day in the same patients  . Search for H. pylori will not aid in determining refractoriness, since its presence in the gastric antral or duodenal mucosa was found to be equal among patients with refractory and non-refractory duodenal ulcers  . However, the combination of antibiotics with antisecretory agents will increase the proportion of healing in refractory duodenal ulcers.
Once diseases with identifiable etiologies have been ruled out, aggressive management of refractory duodenal ulcers should he instituted. The correct method of management of such patients remains uncertain. There are three principal approaches: 1) measures to increase acid inhibition ideally combined with eradication of H. pylori, 2) measures to increase mucosal defenses, 3) surgery as last resource if medical management has failed , . Healing of refractory DU's could he achieved simply by extending the course of H,antagonists. Bardhan was able to attain healing in 37 patients out of 66 by continuing treatment with cimetidine for an average of 7.4 months  .
Increased acid inhibition can be achieved by increasing the dose of H, - blockers beyond their standard dose, combination of these agents with anticholinergics like pirenzipine or through the use of omeprazole. Bardhan  reported progressive healing rate of patients with refractory duodenal ulcers by stepwise increasing the dose of cimetidine from I gm to 3 gm. Collen et al  was able to achieve complete healing of 20 patients with refractory DU's by increasing the dose of ranitidine to a mean of 675 mg/day (range 600-1200 mg/day). In a multicenter European trial  , omeprazole was administered to 18 patients with duodenal, gastric, or jejunal ulcers who failed initially to respond to at least 12 weeks therapy with an H, - receptor antagonist. These patients received 40 mg of omeprazole once daily for up to eight weeks anco all ulcers healed. In a recent trial Bardhan et al  reported that omeprazole has a better effect on refractory peptic ulcer than other drugs. Combination of antisecretory agents with antibiotics was found to increase the proportion of refractory duodenal ulcers that heals. This effect, in addition to the well-documented value of eradicating H. pylori and its impact on virtual elimination of ulcer relapse  , makes such combination a very attractive treatment modality for such ulcers. Therapeutic agents aiming at increasing mucosal defenses like carbenoxolone. sucralfate or prostanoids have failed to attain comparable results to antisecretory drugs in controlled trials of refractory duodenal ulcers treatment , . Even the combination of H,-receptor blockers with sucralfate produced only a very modest enhancement of healing of unselected duodenal ulcers at two but not four weeks  . Therefore, one can conclude from these data that such agents will not add any significant therapeutic effect to the management of refractory duodenal ulcers and that their use is not justifiable.
| Surgery for Refractory Duodenal Ulcers|| |
The results of highly selective vagotomy (HSV) for strictly defined refractory duodenal ulcers are discouraging. HSV generally inhibits acid secretion to a slightly greater extent than H,-blockers  . Primorse et al noted a 5-year post HSV recurrence rate of 34% in 57 patients whose preoperative ulcers were refractory to 3 or more months of standard dosage H,-blocker therapy compared with a 3 recurrence rate only in patients whose ulcers had healed on H,-blockers therapy  . They concluded that duodenal ulcers that fail to respond to H,-blockers represent a more severe ulcer diathesis, for which HSV is less effective. Another series of 45 H,-blockers refractory ulcer patients also did poorly, with 17 patients developing ulcer recurrence between 20 and 67 months post HSV  . It is therefore strongly recommended to initially utilize maximal medical therapy, which will heal virtually all refractory duodenal ulcers as stated before. Surgery should then be reserved for patients whose ulcers fail to respond to optimal medical therapy or those who develop certain complications like perforation, stenosis, or hemorrhage which can not be controlled by conservative means.
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Hussein M Al Freihi
Gastroenterology Division (59) College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461
Source of Support: None, Conflict of Interest: None