Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®

Refractory or recurrent peptic ulcer disease

Section Editor
Mark Feldman, MD, MACP, AGAF, FACG
Deputy Editor
Shilpa Grover, MD, MPH


Most peptic ulcers respond to treatment with antimicrobial therapy for Helicobacter pylori, withdrawal of nonsteroidal anti-inflammatory drugs (NSAIDs), or treatment with potent antisecretory drugs. However, in some individuals, the ulcer is either refractory to conventional therapy or recurs following successful initial treatment. (See "Peptic ulcer disease: Management".)

The same overlapping set of factors underlies ulcers that fail to heal or that recur (table 1). The most important aspect of the assessment of such ulcers is to discriminate several elements that may influence natural history:

The presence of factors that perpetuate the ulcer itself, such as gastric hypersecretion due to gastrinoma, failed H. pylori detection or eradication, undiscovered or undisclosed occult continued use of NSAIDs, severe local scarring that retards healing, and comorbid disease.

Pathology that mimics ulcer disease, such as carcinoma.

Refractory symptoms in the absence of refractory ulceration, which are often part of a functional gastrointestinal or somatoform disorder.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Mar 2015. | This topic last updated: Jan 6, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2015 UpToDate, Inc.
  1. Yuan Y, Padol IT, Hunt RH. Peptic ulcer disease today. Nat Clin Pract Gastroenterol Hepatol 2006; 3:80.
  2. Bardhan KD, Nayyar AK, Royston C. History in our lifetime: the changing nature of refractory duodenal ulcer in the era of histamine H2 receptor antagonists. Dig Liver Dis 2003; 35:529.
  3. Goodman AJ, Kerrigan DD, Johnson AG. Effect of the pre-operative response to H2 receptor antagonists on the outcome of highly selective vagotomy for duodenal ulcer. Br J Surg 1987; 74:897.
  4. Soll AH, Graham DY. Peptic ulcer disease. In: Textbook of Gastroenterology, Yamada T (Ed), Wiley-Blackwell, Oxford 2009. p.936.
  5. Agréus L, Svärdsudd K, Nyrén O, Tibblin G. Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time. Gastroenterology 1995; 109:671.
  6. Cervero F, Gebhart GF. Visceral hypersensitivity. In: Functional Pain Syndromes: Presentation and Pathophysiology, Mayer EA, Bushnell MC (Eds), International Association for the Study of Pain, Seattle 2009. p.361.
  7. Bianchi Porro G, Parente F. Duodenal ulcers resistant H2 blockers: An emerging therapeutic problem. Scand J Gastroenterol 1988; 23:81.
  8. Boyd HK, Zaterka S, Eisig JN, et al. Helicobacter pylori and refractory duodenal ulcers: cross-over comparison of continued cimetidine with cimetidine plus antimicrobials. Am J Gastroenterol 1994; 89:1505.
  9. Mantzaris GJ, Hatzis A, Tamvakologos G, et al. Prospective, randomized, investigator-blind trial of Helicobacter pylori infection treatment in patients with refractory duodenal ulcers. Healing and long-term relapse rates. Dig Dis Sci 1993; 38:1132.
  10. Arkkila PE, Kokkola A, Seppälä K, Sipponen P. Size of the peptic ulcer in Helicobacter pylori-positive patients: association with the clinical and histological characteristics. Scand J Gastroenterol 2007; 42:695.
  11. Lanas A, Remacha B, Sáinz R, Hirschowitz BI. Study of outcome after targeted intervention for peptic ulcer resistant to acid suppression therapy. Am J Gastroenterol 2000; 95:513.
  12. Avsar E, Kalayci C, Tözün N, et al. Refractory duodenal ulcer healing and relapse: comparison of omeprazole with Helicobacter pylori eradication. Eur J Gastroenterol Hepatol 1996; 8:449.
  13. Tseng GY, Lin HJ, Fang CT, et al. Recurrence of peptic ulcer in uraemic and non-uraemic patients after Helicobacter pylori eradication: a 2-year study. Aliment Pharmacol Ther 2007; 26:925.
  14. Hirschowitz BI, Lanas A. Intractable upper gastrointestinal ulceration due to aspirin in patients who have undergone surgery for peptic ulcer. Gastroenterology 1998; 114:883.
  15. Hirschowitz BI, Lanas A. Atypical and aggressive upper gastrointestinal ulceration associated with aspirin abuse. J Clin Gastroenterol 2002; 34:523.
  16. STEIGMANN F, SHULMAN B. The time of healing of gastric ulcers: implications as to therapy. Gastroenterology 1952; 20:20.
  17. Reynolds JC, Schoen RE, Maislin G, Zangari GG. Risk factors for delayed healing of duodenal ulcers treated with famotidine and ranitidine. Am J Gastroenterol 1994; 89:571.
  18. Shih SC, Tseng KW, Lin SC, et al. Expression patterns of transforming growth factor-beta and its receptors in gastric mucosa of patients with refractory gastric ulcer. World J Gastroenterol 2005; 11:136.
  19. Annibale B, De Magistris L, Corleto V, et al. Zollinger-Ellison syndrome and antral G-cell hyperfunction in patients with resistant duodenal ulcer disease. Aliment Pharmacol Ther 1994; 8:87.
  20. Walt RP, Daneshmend TK. Resistant duodenal ulcer: when, why and what to do? Postgrad Med J 1988; 64:369.
  21. Bianchi Porro G, Lazzaroni M, Barbara L, et al. Tripotassium dicitrate bismuthate and ranitidine in duodenal ulcer. Healing and influence on recurrence. Scand J Gastroenterol 1988; 23:1232.
  22. Collen MJ, Stanczak VJ, Ciarleglio CA. Refractory duodenal ulcers (nonhealing duodenal ulcers with standard doses of antisecretory medication). Dig Dis Sci 1989; 34:233.
  23. Burget DW, Chiverton SG, Hunt RH. Is there an optimal degree of acid suppression for healing of duodenal ulcers? A model of the relationship between ulcer healing and acid suppression. Gastroenterology 1990; 99:345.
  24. Howden CW, Hunt RH. The relationship between suppression of acidity and gastric ulcer healing rates. Aliment Pharmacol Ther 1990; 4:25.
  25. Park TY, Choi CH, Yang SY, et al. A case of hypereosinophilic syndrome presenting with intractable gastric ulcers. World J Gastroenterol 2009; 15:6129.
  26. Tee HP, Swartz D, Tydd T, Leong RW. Gastrointestinal: Eosinophilic enteritis manifesting as brown-pigmented duodenal ulcers. J Gastroenterol Hepatol 2009; 24:1892.
  27. Siaw EK, Sayed K, Jackson RJ. Eosinophilic gastroenteritis presenting as acute gastric perforation. J Pediatr Gastroenterol Nutr 2006; 43:691.
  28. Fujita T, Ando T, Sakakibara M, et al. Refractory gastric ulcer with abundant IgG4-positive plasma cell infiltration: a case report. World J Gastroenterol 2010; 16:2183.
  29. Delchier JC, Isal JP, Eriksson S, Soule JC. Double blind multicentre comparison of omeprazole 20 mg once daily versus ranitidine 150 mg twice daily in the treatment of cimetidine or ranitidine resistant duodenal ulcers. Gut 1989; 30:1173.
  30. Bardhan KD. Is there any acid peptic disease that is refractory to proton pump inhibitors? Aliment Pharmacol Ther 1993; 7 Suppl 1:13.
  31. van Rensburg CJ, Louw JA, Girdwood AH, et al. A trial of lansoprazole in refractory gastric ulcer. Aliment Pharmacol Ther 1996; 10:381.
  32. Samloff IM. Peptic ulcer: the many proteinases of aggression. Gastroenterology 1989; 96:586.
  33. Primrose JN, Axon AT, Johnston D. Highly selective vagotomy and duodenal ulcers that fail to respond to H2 receptor antagonists. Br Med J (Clin Res Ed) 1988; 296:1031.
  34. Pan SA, Liao CH, Lien GS, Chen SH. Histological maturity of healed duodenal ulcers and ulcer recurrence after treatment with colloidal bismuth subcitrate or cimetidine. Gastroenterology 1991; 101:1187.
  35. Moshal MG, Gregory MA, Pillay C, Spitaels JM. Does the duodenal cell ever return to normal? A comparison between treatment with cimetidine and denol. Scand J Gastroenterol Suppl 1979; 54:48.
  36. Van Deventer GM, Elashoff JD, Reedy TJ, et al. A randomized study of maintenance therapy with ranitidine to prevent the recurrence of duodenal ulcer. N Engl J Med 1989; 320:1113.
  37. Piai G, Sabbatini F, Minieri M, et al. The influence of severe bulb deformity on duodenal ulcer relapse. Hepatogastroenterology 1990; 37:131.
  38. Chang CC, Pan S, Lien GS, et al. Deformity of duodenal bulb, gastric metaplasia of duodenal regenerating mucosa and recurrence of duodenal ulcer: a correlated study. World J Gastroenterol 2005; 11:1802.
  39. Paoluzi P, Pallone F, Zaccardelli E, et al. Outcome of ulcer-associated duodenitis after short-term medical treatment. Dig Dis Sci 1985; 30:624.
  40. Takemoto T, Namiki M, Ishikawa M, et al. Ranitidine and sucralfate as maintenance therapy for gastric ulcer disease: endoscopic control and assessment of scarring. Gut 1989; 30:1692.
  41. Harris AW, Gummett PA, Phull PS, et al. Recurrence of duodenal ulcer after Helicobacter pylori eradication is related to high acid output. Aliment Pharmacol Ther 1997; 11:331.
  42. Laine L, Hopkins RJ, Girardi LS. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the United States been overstated? A meta-analysis of rigorously designed trials. Am J Gastroenterol 1998; 93:1409.
  43. Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988; 2:1437.
  44. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996; 110:1244.
  45. Frederiksen HJ, Matzen P, Madsen P, et al. Spontaneous healing of duodenal ulcers. Scand J Gastroenterol 1984; 19:417.
  46. Penston JG, Wormsley KG. Review article: maintenance treatment with H2-receptor antagonists for peptic ulcer disease. Aliment Pharmacol Ther 1992; 6:3.
  47. Jensen DM, Cheng S, Kovacs TO, et al. A controlled study of ranitidine for the prevention of recurrent hemorrhage from duodenal ulcer. N Engl J Med 1994; 330:382.
  48. Ström M, Bodemar G, Gotthard R, Walan A. Duodenal, prepyloric, and combined duodenal/prepyloric ulcer disease: three distinct entities of juxtapyloric ulcer disease? Scand J Gastroenterol 1986; 21:1105.
  49. Bardhan KD, Hinchliffe RF, Bose K. Low dose maintenance treatment with cimetidine in duodenal ulcer: intermediate-term results. Postgrad Med J 1986; 62:347.
  50. Martin DF, Montgomery E, Dobek AS, et al. Campylobacter pylori, NSAIDS, and smoking: risk factors for peptic ulcer disease. Am J Gastroenterol 1989; 84:1268.
  51. Anda RF, Williamson DF, Escobedo LG, Remington PL. Smoking and the risk of peptic ulcer disease among women in the United States. Arch Intern Med 1990; 150:1437.
  52. Chan FK, Sung JJ, Lee YT, et al. Does smoking predispose to peptic ulcer relapse after eradication of Helicobacter pylori? Am J Gastroenterol 1997; 92:442.
  53. Bardhan KD, Graham DY, Hunt RH, O'Morain CA. Effects of smoking on cure of Helicobacter pylori infection and duodenal ulcer recurrence in patients treated with clarithromycin and omeprazole. Helicobacter 1997; 2:27.
  54. Boyd EJ, Wilson JA, Wormsley KG. The fate of asymptomatic recurrences of duodenal ulcer. Scand J Gastroenterol 1984; 19:808.
  55. Wolosin JD, Gertler SL, Peterson WL, et al. Gastric ulcer recurrence: follow-up of a double-blind, placebo-controlled trial. J Clin Gastroenterol 1989; 11:12.