Saudi Journal of Gastroenterology
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Year : 1995  |  Volume : 1  |  Issue : 2  |  Page : 87-92
Refractory duodenal ulcer


Department of Medicine, Gastroenterology Division. College of Medicine, King Saud University, Riyadh, Saudi Arabia

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   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

How to cite this URL:
Al Freihi HM. Refractory duodenal ulcer. Saudi J Gastroenterol [serial online] 1995 [cited 2019 Nov 13];1:87-92. Available from: http://www.saudijgastro.com/text.asp?1995/1/2/87/34046



   Definition Top


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 [1],[2],[3] . Though such ulcers may heal if treatment with H,-receptor antagonists is con­tinued longer or dose is increased [1],[4],[5] or in response to other drugs such as omeprazole [6],[7],[8] , mucosal barrier agents [9] alone or in combination with other drugs like anticholinergics [10],[11] , bis­muth or antibiotics [12],[13] . The management of these patients represents a problem for the gas­troenterologist and the practicing physician.


   The scope of the problem Top


It has been estimated that 90-95% of duodenal ulcers (DU) will heal after eight weeks of full dose treatment with an antiulcer agent [2] . Therefore, only 5-10% of patients with DU will remain unhealed after eight weeks of treatment [13] . 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 Top


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 [14] . 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 Top


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 [12] . Factors like inadequate absorption or failure to suppress acid secretion could be excluded, since various investigators have demonstrated effective blood levels of H,-blockers [15],[16],[17],[18] and suppression of acid secretion to be similar in those with refractory and non-refractory ulcers [19] .

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 [20] . Hirschowitz reported that the majority of 35 patients with refractory duodenal and gastric ulcers and without gastrinoma were using aspirin surreptitiously [21] . 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 [22] . 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 [11] , Cargill et al [23] , and Hetzel et al [24] found that basal acid outputs tend to be higher in patients with nonhealed DU's. Collen and Coworkers [4] found the mean BAO of patients whose ulcer readily healed with ranitidine to be 6.6 mEq per hour. However. Strom et al [25] . Quatrini et al [5] , and Peterson et al [26] 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 [26],[27],[28]. However, others could not confirm the adverse effects of smoking on healing [5],[12],[24],[29],[31] . 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. [32]

Gender: Male sex has been frequently but not uniformly associated with nonhealing duodenal ulcers. Collen et al [4] 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 [33] . This fact may explain the preponderance of male gender among patients with refractory duodenal ulcers.

 Helicobacter pylori Scientific Name Search ori): It is well known that more than 90% of duodenal ulcers are associated with H. pylori [34] . 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 [12] . 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 [35] , large ulcer size [1],[36] , large parietal cell mass [37] , duration of symptoms, com­plications like hemorrhage, positive family history of ulcer and previous treatment with H 2 -blockers [1],[37] and heavy alcohol intake [1],[20] .


   Other causes with Different Etiologies Top


Ulcers occurring in the duodenal mucosa are not necessarily always peptic ulceration, albeit the majority are such [38] . The spectrum of nonpeptic duodenal ulceration extends from infection to malignancy or acid hypersecretory states like Zol­linger-Ellison Syndrome or systemic mastocytosis [3],[22] . 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 [2] . In the era where acquired immune deficiency syndrome is becoming increas­ingly prevalent, infections with cytomegalovirus, candida, herpes simples virus I or  Mycobacterium intracellulare Scientific Name Search 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 [39],[40] . 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 Top


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 [2] . 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 [4] and patients with peptic ulceration having H. pylori colonization [41] . Further studies of basal acid output have yielded inconsistent results and variation in basal acid output from day to day in the same patients [42] . 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 [12] . 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 [1],[12] . 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 [1] .

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 [1] 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 [4] 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 [43] , 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 [6] 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 [44] , 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 [45],[46] . 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 [47] . 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 Top


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 [48] . 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 [49] . 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 [50] . 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.

 
   References Top

1.Bardhan KD. Refractory duodenal ulcer. Gut 1984:25:711-7.  Back to cited text no. 1    
2.Pounder RE. Intractable duodenal ulceration. Post­graduate Medicine 1988;83:115-20.  Back to cited text no. 2    
3.Ippoliti AF. Prognostic factors in ulcer disease: Are they real, are they relevant?. J Clin Gastroenterol 1985: 7:445­-6.  Back to cited text no. 3    
4.Collen MJ, Stanczak VJ, Ciarleglio CA. Refractory duodenal ulcers (Nonhealing duodenal ulcers with stan­dard doses of antisecretory). Dig Dis Sci 1989:34:233-7.  Back to cited text no. 4    
5.Quatrini M. Basilisco G, Bianchi PA. Treatment of "cimetidine-resistant" chronic duodenal ulcers with ranitidine or cimetidine: A randomized multicenter study. Gut 1984:25:1113-7.  Back to cited text no. 5    
6.Bardhan KD, Naesdal J, Bianchi PG. et al. Treatment of refractory peptic ulcer with omeprazole or continued H,­receptor antagonists: A controlled clinical trial. Gut 1991:32:435-8.  Back to cited text no. 6    
7.Tytgat GNJ. Lamers CB, Hameeteman W, Jansen JM. Wilson JA. Omeprazole in peptic ulcers resistant to His­tamine H,-receptor antagonists. Aliment Pharmacol Therapy 1987; 1;31-8.  Back to cited text no. 7    
8.Brunner GHG, Lamberts R. Creutzfeldt W. Efficacy and safety of omeprazole in the long-term treatment of peptic ulcer and reflux esophagitis resistant to ranitidine. Diges­tion 1990:47:64-8.  Back to cited text no. 8    
9.Guslandi M. More about refractory duodenal ulcers. Gut 1984; 25: 1433.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Williams JG. Deakin M, Ramage JK. Effect of cimetidine and pirenzepine on 24-hour intragastric acidity in subjects with previous duodenal ulceration. Gut 1986;27: 428-32.  Back to cited text no. 10    
11.Gledhill T. Buck M, Hunt RH. Effect of no treatment. cimetidine 1 g/day, cimetidine 2 g/day and cimetidine com­bined with atropine on noctural gastric secretion in cimetidine nonresponders. Gut 1984:25:1211-6.  Back to cited text no. 11    
12.Boyd HK. Zaterka JN, Eisig D. et al. Helicobacter pylori and refractory duodenal ulcers: cross-over comparison of continued cimetidine with cimetidine plus antimicrobials. Am J Gastroenterol 1994;89:1505-10.  Back to cited text no. 12    
13.Lam SK. Lee NW, Koo J. et al. Randomized cross-over trial of tripotassium dicitra to bismuthate versus high dose cimetidine for duodenal ulcers resistant to standard doses of cimetidine. Gut 1984;25:703-6.  Back to cited text no. 13    
14.Bianchi PG, Parente F. Duodenal ulcers resistant to H,­blockers: An emerging therapeutic problem. Scand J Gas­troenterol 1988,23:81­  Back to cited text no. 14    
15.Bodemar G. Norlander B, Walan A. Larson R. Short and long-term treatment with cimetidine in peptic ulcer disease and the pharmacokinetics of cimetidine. Scand J Gas­troenterol 1979:14:Suppl55:96-106.  Back to cited text no. 15    
16.Rune SJ. Hesselfeldt P, Larsen NE. Clinical and phar­macological effectiveness of cimetidine in duodenal ulcer patients. Scand J Gastroenterol 1979:14:489-92.  Back to cited text no. 16    
17.Barter DC. Peters MN. Eshelman FN. Richardson CT. Clinical comparison of cimetidine and ranitidine. Clin Pharmacol Ther 1982;32:484-9.  Back to cited text no. 17    
18.Gugler R. Fuchs G, Dieckmann M. Somogyi A. Cimetidine plasma concentration-response relationships. Clin Pharmacol Ther 1981;29:744.  Back to cited text no. 18    
19.Foschi D. Nosenzo MA, Rovati V. The effects of intraven­ous cimetidine on pentagastrin stimulated secretion in patients with duodenal ulcer refractory to cimetidine therapy. Hepato Gastroenterol (Abstract) 1980: 27: F16.  Back to cited text no. 19    
20.Domschke W, Lam SK. Pounder RE. Anderson D. H,­blocker resistant duodenal ulceration. Gastroenterol Int 1989:2: 85-91.  Back to cited text no. 20    
21.Hirschowitz BI. Lanas A. Intractable and recurrent post­surgical peptic ulceration is due to aspirin (ASA) abuse. much of it surreptitious. Gastroenterology 1992: 102:A84.  Back to cited text no. 21    
22.Richardson CT. Peters MN. Feldman M. et al. Treatment of Zollinger-Ellison syndrome with exploratory laparotomy. proximal gastric vagotomy. and H,-receptor antagonists: A prospective study. Gastroenterology 1985:89:357-67.  Back to cited text no. 22    
23.Cargill JM, Peden N. Saunders JHB. Wormsley KG. Very long-term treatment of peptic ulcer with cimetidine, Lan­cet 1978;2;1113-5.  Back to cited text no. 23    
24.Hetzel DJ. Hanskv J. Shearman DJC. et al. Cimetidine treatment of duodenal ulceration: Short-term clinical trial and maintenance study. Gastroenterology 1978:74: 389­-92.  Back to cited text no. 24    
25.Strom M. Berstad A. Bodemar G, Walan A. Results of short and long-term cimetidine treatment in patients with juxtapylori ulcers. with special reference to gastric acid and pepsin secretion. Scand J Gastroenterol 1986:21:521-­30.  Back to cited text no. 25    
26.Peterson WI, Sturdevant RAL, Frankl HD. et al. Healing of duodenal ulcer with an antacid regimen. N Engl J Med 1977:297:341-5.  Back to cited text no. 26    
27.Lam SK. Hui WM. Lau WY, et al. Sucralfate overcomes adverse effect of cigarette smoking on duodenal ulcer heal­ing and prolongs subsequent remission. Gastroenterology 1987;92:1193-201.  Back to cited text no. 27    
28.Korman MG. Hansky J. Eaves ER. Schmidt GT. Influ­ence of cigarette smoking on healing and remission. Gas­troenterology 1983;85:871-4.  Back to cited text no. 28    
29.Lam SK. Lai CL. Lee LNW, Fok KH. Ng MMt. Siu KF. Factors influencing healing of duodenal ulcer: Control of nocturnal secretion by H, blockade and characteristics of patients who failed to heal. Dig Dis Sci 1985:30: 45-51.  Back to cited text no. 29    
30.Lee Fl, Reed PR. Crowe JP. Mclsaac RL. Wood JR. Acute treatment of duodenal ulcer: A multicenter study to compare ranitidine 150 mg twice daily with ranitidine 300 mg once at night. Gut 1986;27:1091-5.  Back to cited text no. 30    
31.Guslandi M. More about refractory duodenal ulcers. Gut 1984:25:1433-4.  Back to cited text no. 31    
32.Lanas A. Hirschowitz BI. Influence of smoking on basal and on vagally and maximally-stimulated gastric acid sec­retion and pepsin secretion. Scan J Gastroenterol 1992:27:208-13.  Back to cited text no. 32    
33.Kirkpatrick PM. Hirschowitz BI. Duodenal ulcer with unexplained marked basal gastric acid hypersecretion. Gastroenterology 1980:79:4-10.  Back to cited text no. 33    
34.Marshall BJ. Helicohacter Pylori. Am J Gastroenterol 1994;89:S116-28.  Back to cited text no. 34  [PUBMED]  
35.Sonneberg A. Muller-Lissner SA, Vogel E. et al. Predic­tors of duodenal ulcer healing and relapse. Gastroenterol­ogy 1981:81:1061-7.  Back to cited text no. 35    
36.Lam SK, Koo J. Accurate prediction of duodenal ulcer healing rate by discriminant analysis. Gastroenterology 1983: 85: 403-12.  Back to cited text no. 36    
37.Lam SK. Lai CL, Lee LNW. et al. Factors influencing healing of duodenal ulcer. Dig Dis Sci 1985: 30: 45-51.  Back to cited text no. 37    
38.Cockel R. Diseases of the duodenum. In: Misiewicz JJ. Pounder RE. Venables C, eds. Diseases of the gut and pancreas. St Louis: CV mosby (Blackwell Scientific) 1987: 404-18.  Back to cited text no. 38    
39.Al Mofleh IA. Endoscopic features of primary upper gas­trointestinal lymphoma. Clin J Gastroenterol 1994;19:69­-74.  Back to cited text no. 39    
40.Omar YT, Al Nakib B, Jacob GS, et al. Primary gastroin­testinal lymphoma in Kuwait. An 11-year retrospective analysis of 108 cases. Eur J Cancer Clin Oncol 1985.21:573-7.  Back to cited text no. 40    
41.El-Omar E, Penman I, Dorrian CA. Ardill JES, McColl KEL. Eradicating Helicobacter pylori infection lowers gastrin- mediated acid secretion by two thirds in patients with duodenal ulcer. Gut 1993;34:1060-5.  Back to cited text no. 41    
42.Feldman M, Richardson CT. Gastric acid secretion in humans: In: Physiology of the gastrointestinal tract, Vol 1. LIZ Johnson (ed). New York, Raven Press. 1981;693-707.  Back to cited text no. 42    
43.Tytgat GNJ. Lamers CB, Hameeteman W, et al. Omep­razole in peptic ulcers resistant to histamine H,-receptor antagonists. Aliment Pharmacol Therapeut 1987; 1: 31-8.  Back to cited text no. 43    
44.Tytgat GNJ. Lee A, Graham DY. et al. Eradication of H. pylori leads to virtual elimination of ulcers relapse. Gas­troenterol Int 1993: 6:76-89.  Back to cited text no. 44    
45.Parente F, Lazzaroni M, Sangaletti O, Bargiggia S, Bian­chi PG. Short and long-term outcome of HP positive resis­tant duodenal ulcers treated with colloidal bismuth subcit­rate (CBS) plus antibiotics or sucralfate (Abstract). Gas­troenterology 1992:102:A142.  Back to cited text no. 45    
46.Newman RD. Gitlin N, Lacayo EJ, et al. Misoprostol in the treatment of duodenal ulcer retractorv to H,-blocker therapy. A placebo-controlled, multicenter, double-blind, randomized trial. Am J Med 1987;83:27-31.  Back to cited text no. 46    
47.Van Deventer GM. Schneidman D. Walsh JH. Sucralfate and cimetidine as single agents and in combination for treatment of active duodenal ulcers. A double-blind, placebo-controlled trial. Am J Med. 1985:79:39-44.  Back to cited text no. 47    
48.Gledhill T. Buck M. Paul A. Hunt Rh. Cimetidine or vag­otomy ?. Br J Surg 1983:70:704-6.  Back to cited text no. 48    
49.Primore IN, Axon ATR, Johnston D. Highly selective vagotomy and duodenal ulcers that fail to respond to H 2 -, receptor antagonists. Br Med J 1988: 296:1031-5.  Back to cited text no. 49    
50.Hansen JH, Knigge U. Failure of proximal gastric vag­otomy for duodenal ulcer resistant to cimetidine. Lancet 1984,2:84-6.  Back to cited text no. 50  [PUBMED]  

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Correspondence Address:
Hussein M Al Freihi
Gastroenterology Division (59) College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


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