Medical treatment of peptic ulcer disease: Should the ...Key Words: l..aparoscopic surgery, Management, Peptic ulcer disease T raitement medical de l'ulcere gastro-duodenal. La chirurgie

REVIEW

Medical treatment of peptic ulcer disease: Should the

etnphasis be altered in view of laparoscopic surgery?

ABR THOMSON MD PhD FRCPC FACP FRS FACC

ABR THOMSON. Medical treatment of peptic ulcer disease: Should the em-phasis be altered in view of laparoscopic surgery? Can J Gastroenterol 1994;8(3):199-204. In the past Hz-receptor antagonist era, there w~ initially a lull as more and more 'me-too' drugs were developed. Then came the excite-ment of the proton pump inhibitors and the controversy of the pros and cons of moderate versus potent acid inhibition. The most recent explosion of knowledge has been in rhe discussion of pH versus Helicobacter pylori, but on the horizon is lurking the promise of the resurgence of the surgical option.

Key Words: l..aparoscopic surgery, Management, Peptic ulcer disease

T raitement medical de l'ulcere gastro-duodenal. La chirurgie laparoscopique indique-t-elle une nouvelle voie?

RESUME : Au cours de la recente epoque anti-Hz, on a d'abord connu une periode lente avant que n'apparaissent de nouveaux medicaments toujours plus nombreux. Puis, vinrent les inhibiteurs de la pompe a protons, qui ont souleve l'enthousiasme et la controverse au sujet des avantages et des inconvenients de !'inhibition moderee ou marquee de l'acide. Les decouvenes les plus recentes ponent sur le pH versus Helicobacter pylori, mais on note a l'horizon les promesses que pourraient receler !es interventions chirurgicales.

THE NUMBER OF SURGICAL PROCE-dures performed on patients with peptic ulcer disease has declined dra-matically in the past 20 years. This de-cline was associated with, but not en-

tirely explained by, the introduction in the mid-l 970s of, first, cimetidine and then other Hz-receptor antagonists such as ranitidine, famotidine and niza-tidine ( L,2). With the current possibil-

Presented at the Symposium on Minimal Access Surgery in Saskawon, Saskatchewan on Aiigust 7 and 8, 1992

NuLTirion and Metabolism Research GTOup, Division of Gastroenterowgy, Department of Medicine, University of Alberta., Edmonton, Alberw

Correspondence and reprints: Dr ABR Thomson, 519 Robert Newton Research Building, University of Alberta, Edmonton, A/berm T6G 2C2. Telephone (403) 492-6490, Fax (403) 492-7964

Received for publication September 29, 1993. Accepted November 15, 1993

CAN J GASIBOENTEROL VOL 8 No 3 MAY/JUNE l 994

icy of reducing incragascric hydrogen ion (H+) concentration by greater than 99% via proton pump inhibitors such as omeprazole, one might have hoped that peptic ulcer disease would be a condi-tion of the past. This has not occurred. O ne might also have wondered whether the medical management of peptic ulcer disease would completely replace surgical therapy of peptic ulcer disease, but that too has not occurred because of the problems of ulcer resis-tance, recurrence, drug complications and cost. With the benefits of minimal access surgery on the close horizon, these potential drawbacks of medical therapy need to be examined in closer detail, and need to be examined against the background of the possibility of cur-ing peptic ulcer disease with the eradi-cation of commonly associated Helico-bacter pylori infections.

RESISTANCE While the Hz-receptor antagonists

and proton pump inhibitors are effec-t ive in healing duodenal and benign gastric ulcers, there remains a small group of peptic ulcer disease patients who are apparently resistant to therapy. The mechanisms of this resistance have not been established, and while some patients respond when switched from one Hz-receptor antagonist to another, others only heal when switched from

199

TIIOMSON

an Hi-receptor antagonist to another therapeutic agent, such as a proton pump inhibitor. The recent report of Lauritsen et al (3) has shown that 100% of more than 1000 patients with duodenal ulcers healed after a course of omeprazole, so there may prove to be relatively few duodenal ulcer patients who do not heal on orneprazole.

Ulcer symptoms do not neces.sarily occur when the ulcer is present (4). The complications of hemorrhage and perforation may be independent of whether the ulcer has been clinically apparent or silent ( 5). In persons taking nonsteroidal anti-inflammatory drugs (NSAIDs), hemorrhage from the silent ulcer is frequent (4). Persons with a past history of peptic ulcer disease who are not on maintenance therapy may also present with complicated silent ulcers (6), and even patients on maintenance therapy may develop silent ulcers (7 ,8).

The problem of 'resistance' to the usual therapeutic doses of ulcer-healing drugs has been reviewed (9, 10). Duode-nal ulcers are defined as 'resistant' or 'refractory' if they are unhealed after treatment with the usual healing doses of Hi-receptor antagonists after eight weeks; less than 10% of duodenal ulcers are resistant when using this definition ( 11 ). When ulcers fail to heal, a num-ber of diagnostic considerations must be undertaken (12). 1n the patient who has been on Hi-receptor antagonists for eight weeks, persistence of symp-toms is not necessarily associated with persistence of ulceration. If persistent ulceration is confirmed on endoscopy, it is important to assess the patient's compliance, use of NSAIDs or smoking, the possible previous presence of a larger ulcer ( which rakes longer to heal than a small ulcer), gastric hypersecre-tory state or a persistent H /)ylori infec-tion (13,14).

Failure of conventional doses ofHi-receptor antagonists to inhibit gastric acid secretion has been reported in some duodenal ulcer patients (15). The inhibitory effect of Hi-receptor antago-nists on 24 h intragastric pH profiles may be less in nonresponders than in responders (16). This cannot be the entire explanation for resistance to Hz-receptor antagonist treatment because

200

some patients may develop nocturnal achlorhydria on Hi-receptor antago-nists and yet still not heal ( 17,18).

Therapeutic manipulations chat have been used to treat resistant ulcers include: higher than 'normal' doses of Hz-receptor antagonists; use of 'no r-mal' doses of Hi-receptor antagonists for longer periods (15,19,20); or switching from an Hi-receptor antago-nist to a proton pump inhibitor (21 ), to colloidal bismuth subcitrate (22) or to a prosraglandin analogue (23). Lf there is H pylori infection associated with a duodenal ulcer, one therapeutic ap-proach is co use triple antibiotic ther-apy or omeprazole plus amoxicillin. In the patient who has not healed with Hi-receptor antagonists and who has a highly selective vagotomy, the inci-dence of recurrence of duodenal ulcers is IO times greater than if the ulcer were not resistant (24 ).

RECURRENCE Once acute d1erapy has been dis-

continued, peptic ulcer disease recurs at a rate of approximately 80% per year, and 90% of ulcers relapse within two years of healing irrespective of the in-itial ulcer healing therapy (25). This rate of recurrence can be reduced with the continuous administration of l Ii-receptor antagonists, but despite main-tenance therapy, some patients will have a symptomatic recurrence and some will have an asymptomatic recur-rence. The rates of duodenal ulcer re-currence may prove to be even lower with maintenance therapy using a pro-ton pump inhibitor. Mose of these re-current ulcers will heal when the dose of maintenance medication is in-creased to approximately twice the high levels of Hi-receptor antagonists needed for acute therapy.

Wormsley (26) has outlined the dif-ferent methods of treating ulcers: the variants of therapy with arui-ulcer drugs range from demand ( caking a few tablets of an anti-ulcer drug for a few days while sympr.oms persist) to periodic ( lak-ing a few tablets at specific intervals, suc_h as weekends or seasonally). through inter-mittent, reheaUng ea.ch symptomac.ic re-lapse with standard courses of anti-ulcer drugs gitleTI for one to two months to long

1ern1, continuous (maintenance) treat-ment.

Weekend therapy with ranitidine 300 mg may be comparable with con-tinuous use of ranitidinc 150 mg at night-ttme (27). Seasonal treatment with ranitidinc in March and April and again in September and October result:. in relapse rates almost twice as high over 24 months of therapy, compared with continuously treated patients (28). Giving therapy for symptomatic relapse (intermittent treatment) has been discussed (29); its potential con-traindications extend co include most patients with relapsing ulcer disease.

Are agents other than Hi-receptor antagonists useful for maintenance therapy? Sucralface may be effective for maintenance therapy in duodenal ul-cers (30,3 1) but not for gastric ulcers (32). Pirenzepme is of limited use for maintenance therapy (33). The results of a large multicentre maintenance trial of omcprazole in patients with duodenal ulcers will soon be available.

American views of maintenance therapy have been analyzed (34). lt re-mains controversial whether duodenal ulcers 'bum out' over time {34,35). ln any case, maintenance therapy should be continued for at least one year (36). When point prevalence rates of recur-rence of duodenal ulcers during main-tenance therapy arc assessed, the cumulative rate of recurrence is 48% after 12 monms, and 71 % of rnese re-currences are painless (8).

With cimetidine maintenance treatment, symptomatic relapse occurs in 17 .2% of duodenal ulcer patients during the first year, 9.6% in the second year and 8.8% in the third year (37). In another study of patients with duodenal or gastnc ulcers main1.ained on cimetid-ine for as long as six years, life-table analysis showed that the cumulative symptomatic relapse rates for duodenal ulcers were 13, 19, 24, 26 and 28% during the first five years (38). TI1us, mainte-nance therapy may reduce the risk of ulcer recurrence, but even better main-tenance therapy would be desirable.

While mamrenance therapy may re-duce d1e risk of ulcer recurrence, docs it reduce the risk of complications? Yes-over a three-year penod of mainte-

CAN J GASTROENTEROL VOL 8 No 3 MAYnUNE 1994

nance therapy, the cumulative rate of ulcer hemorrhage during periods with-out active treaonent was approxi-mately 15% compared with an incidence of ulcer bleeding during six years of continuous maintenance ther-apy of approximately 1.3% (39).

Sonnenberg ( 40) developed a Markov chain to study the long term outcome of maintenance with Hi-recep-tor antagonists, intermittent treaonent with Hz-receptor antagonists and proximal gastric vagotomy. With main-tenance treatment, the rate of compli-cations and the number of deaths related to ulcers were slightly higher than after proximal gastric vagotomy, but because the few deaths from this procedure occur at treatment start, the loss of life-years during maintenance treaanent exceeded that of proximal gastric vagotomy only after 20 years. Thus, 'surgical maintenance therapy' with proximal gastric vagotomy may be a useful option for the patient requiring prolonged suppression of gascric acid-ity.

HELICOBACTER PYLORI Many duodenal or gastric ulcer pa·

nents are faced with the prospect of remaining on medication for the rest of their Lives. ln some persons the ten-dency for ulcer recurrence may be the result of persistence of an infection with H pylori. Strong evidence suggest-ing causation of duodenal ulcers by H pylori has been reviewed (41). H pylori is found in more than 90% of persons with duodenal ulcers (42-46), but in about one patient in 10, duodenal ul-cers will occur in the absence of H pylori (demonstrated with the methods cur-rently available). The eradication of H trylori is associated with the healing of gastritis ( 44 ), and a marked reduction m the race of recurrence of duodenal ulcers (43,47-5 1).

Ulcers may recur in patients who Jo not have H pylori infection, and pa· tients with H pylori do not necessarily have ulcers or ulcer recurrences (43,49). Eradication of H pylori using tetracycline 2 g, metronidazole 750 mg and bismuth subsalicylace five or eight tablets ( l 51 mg bismuth/tablet) plus ra-n1tidine 300 mg in patients with duode-

Peptic ulcer disease

Duodenal Ulcer Gastric Ulcer Q) 100 100 u C Q) .....

80 80 ..... :::, u Q)

a: 60 60 ..... Q) u

:::> ..c 40 40 ..... • Ranitidine Alone· ~ • Triple Therapy ..... 20 20 C Q) ""------- ----- - -u ..... ,, ... Q) a.. 0

8 16 24 32 40 48 0 8 16 24 32 40 48

Weeks Weeks

Figure 1) Life-UJble recurrence of duodenal and gasr:ric ulcers for one -year af r.e:r successful healing wirh raniculine alone or r:ripk rherapy plus raniculine (adapted. wirh permission from Graham et al Ann Intern Med /992; I 16:70)

nal or gastric ulcers is associated with much lower rates of ulcer recurrence at 48 weeks (Figure 1 ). Life-table analysis demonstrates that patients whose ul-cers have healed but who continue to have H pylori infection have a 95% chance of developing a recurrent ulcer by the end of one year. For patients whose H pylori infection is eradicated, the risk of ulcer recurrence is less than 10%.

Interestingly, if H pylori infection is cleared in patients with duodenal ul-cers, smoking does not appear to pose a risk for ulcer recurrence (51 ). Unfonu-nately, compliance with the available complicated three- or four-agent treat-ment therapies remains a problem (52). Also, the long term safety of bismuth needs to be clarified; bismuth levels in urine remain elevated for weeks after therapy with bismuth~containing com-pounds (53). Unfortunately, in vitro sensitivity of H pylori to antibiotics does not predict drug efficacy in vivo (54,44 ). Recurrent H pylori infection may occur rapidly after initial clearance ( 44), and the strain that emerges is usu-ally identical to the original infecting strain (56). If H pylori is absent six weeks after completion of therapy (eradica-tion), cultures will usually remain nega-tive after one year (49). Thus, it is pos-

sible that ulcer disease - and not just ulcers - may be cured by treating the H pylori infection effectively. If this hy-pothesis is confirmed in future studies, then medical or surgical maintenance therapy may become a thing of the past. And the need to consider today's to-morrow - minimal access surgery - for surgical maintenance therapy may also become a thing of the past.

COMPLICATIONS There is a small potential for com-

plications arising from continuous use of Hi-receptor antagonists or proton pump inhibitors. For example, there may be interference with the metabo-lism of some medications, and there often is mild hypergastrinemia (the biological significance of which is un-known}. lntergascric acidity is de-creased more by omeprazole (-94%) than after proximal gastric vagotomy (-78%), but plasma gastrin concentra-tions are increased more after proximal gastric vagotomy ( +284%) than during treaanent with omeprazole ( + 186%) (57). There is no evidence that H2-receptor antagonists or proton pump inhibitors cause gastric cancer; post· cimecidine surveillance for up to 10 years does not indicate an increased incidence of carcinoma of the stomach

CANJ 0ASTR0ENTEROL VOL8 No 3 MAvnUNE 1994 201

THOMSON

or esophagus (58). Case-control studies have also suggested that long term use of Hz-receptor antagonists does not predispose to gastric cancer (59). Gas-tric surgery may be associated with the later development of srump cancer, but the relative risk of postgastric surgery carcinoma is highly disputed.

Cimetidine may reduce serum corti-sol concentrations (which may be re-versed by taking ascorbic acid (60]), an effect not seen with ranitidine. Cimetidine inhibits the plasma aldos-terone response to angiotensin II, whereas this does not occur with rani-tidine (61). Hz-receptor antagonists may rarely cause a disturbance of car-diac rate and rhythm (62). Famotidine, but not cimetidine or ranitidine, may have a small negative inotropic influ-ence on cardiac performance (63). The hepatic cytochrome P450 enzyme sys-tems are inhibited in varying degrees by the different Hz-receptor antagonists and by omeprazole (64,65), but the clinical importance of this interaction, while noteworthy, may be small.

While initial reports suggested that genotoxicity might be associated with the use of omeprazole (66,67), meth-odological considerations have been raised and differences between studies may be based, in part, on the species of rat used (68-72). A technique using hy-droxyurea has suggested a weak positive genotoxicity effect of omeprazole at a dose of 100 rng/!

Lrcacmenr of

THOMSON

duodenal ulcer ;:issociatcd with 63. Kirch W, Halabi A, Linde M, Santos The ccontribution of the stomach to eradication of Helicobacter /Jylori. S R, O hnhaus EE. Negative effects of ethanol oxidation in the rat. Life Sci Lancet 1990;i:1233-5. famotidine on cardiac performance l 987;4 l: l 021-7.

51. George LL, Borody TJ, Andrews P, assessed by noninvasive hemodynamic 78. Fraser AG, Prewett EJ, HuJson M, et al. Cure of duodenal ulcer after measurements. Gastroenterology Sawyer AM, Rosalki SB, Pounder RE. eradication of Helicobacter pylori. Med J l 989;96: 1388-92. The effect of ranitic.linc, cimetic.linc or Ausr 1990;153:145-9. 64. Leiber BL, Antell LA. Cimetidinc and famotid inc on low-dose post-prandial

52. G raham DY, Lew G M, Malaty HM, the cytochrome P=450 system. Am J alcohol absorption. Aliment et a l. Factors influencing the Gastroentcrol 1988:83: I 006. Pharmacol T her 1991 ;6:263-72. eradication of Helicobac1er /Jylori with 65. Chcnery RJ , Ayrton A, O ldham HG, 79. Fu llarton GM, McDonald AMI, triple therapy. Gastrocnterology Norman SJ, Standring P. The McColl KEL. Rebound hypersccretion 1992;102:493-6. interaction of omeprazole with rat liver after Hz-antagonist withdrawal: A

53. Hamilton I, Worsley BW, O'Connor cytochrome P450 mediated comparative study with nizatidinc, HJ , Axon AT. Effects of rripocassium monooxygenase reactions in vivo and ranitidine and famotidinc. A liment dicirrato bismuthatc (TDB) tablets or in vitro. Biochem Pharmacol Pharmacol Thcr l 991 ;4:391-8. c imctidinc in the treatment of 1988;37: 1407- 14. 80. Jordan PH. Surgery for peptic ulcer duodenal ulcer. Gut 1983;24: 1148-5 l. 66. Burlinson B, Morriss S H, Gatehouse disease. Curr Prob[ Surg [991;28:265-330.

54. Graham DY, Klein PD, Opekun AR, DG, Tweats DJ. Genoroxicity srudies 81. Johnston GW, Spencer EF, W ilkinson et al. In vivo susceptibility of of gastric acid inhibiting drugs. Lancet AJ, Kennedy TL. Proximal gastric Cam/Jylobacter /Jylori . Am J l 990;335:419-20. vagotomy: Follow-up at 10-20 years. Gastroentcrol 1989;84:233-8. 67. Burlinson B, Morris S, Gatehouse DG, Br J Surg 199 I ;78:20-3.

55. McNulty CAM, Gearty JC, Crump B, Tweats DJ, Jackson MR. Uptake of 82. Kelly KA. Operations for peptic ulcer. et al. Cam/)ylobacter pyloridis and tritiated thymidine by cells of the rat Surgery 199 1;109:802-3. (Edit) associated gastri tis: Investigator blind, gastric mucosa after exposure to 83. Schache DJ, Masters A, Tovey Fl, placebo controlled trial of bismuth loxtidine or omeprazole. Mutagencsis Heald RJ, Recs M. Long term salicylate and crythromycin l99 J ;6:ll-8. recurrence patterns following proximal ethylsuccinatc. Br Med J 68. Wright NA. DNA synthesis and gastric vagotomy. Aust NZ J Surg l 986;293:645-9. gcnotoxicity. Digestion 1990;47(Suppl 1989;59:387-90.

56. Langenberg W, Rauws EA, 1):24-30. 84. Soper NJ, Kelly KA, van l-leerden JA, Widjojokusumo A, Tytgat GN, Zancn 69. Larsson H, Fryklund J, Helander HF, llstrup OM. Long-term clin ical results HC. Identification of Cam/)ylobacter Wallmark B. Partial pronase digestion after proximal gastric vagoromy. Surg pyloridis isolates by restriction of rat gastric mucosa isolates cells Gynecol Obstet 1989;169:488-94. endonuclease DNA analysis. J C lin undergoing replicative DNA synthesis. 85. Muller C, Martineli S, eds. Die M icrobiol 1986;24:4 l 4-7. Mutagencsis 199 1;6:3-9. Proximal-Selektive Vagoromie in dcr

57. Lind T, Cederberg C, O lausson 0, 70. Holt S. Anrisccrecory therapy and Bchandlung dcr Gastroduodcnalen Olbe L. 24-hour intragastric acid ity genocoxicity. Dig Dis Sci Ulcuskrankhcit. Berlin: and plasma gastrin concentration after 1991 ;36:545-7. Springer-Verlag, 1985. omcprazole treatment and after 71. Scott D, Reuben MA, Zampighi G, 86. Em"s S, Fernstrom M. Prospective, proximal gastric vagocomy in duodenal Sachs G. Cell isolation and randomized trial of selective vagoromy ulcer patients. Gastroenterology genocoxicity assessment in gastric with pyloroplasty and select ive l 990;99: l 593-8. mucosa. Dig Dis Sci 1990;35:1217-25. proximal vagotomy with and without

58. Colin-Jones DG, Langman MJS, 72. Fraser AG, Debnam ES, Dhillon AP, pyloroplasty in the treatment of Lawson DH, Logan RFA, Paterson KR, Pounder RE. The effect of variation in duodenal, pyloric and prcpyloric Vessey MP. Post-cimetidinc strain of rat on gastric mucosa! ulcers. Am J Surg l 985;1 49:236-43. surveillance fo r up to ten years: proliferation after treatment with 87. Jordan PH Jr. Duodenal ulcers and Incidence of carcinoma of the stomach antisecretory drugs. Gasrroencerology their surgical treatment: Where did and oesophagus. Q J Med 1991;78:13-9. 199 1; 100:A66. they come from? Am J Surg

59. La Vecchia C, Negri E, D'Avanzo B, 73. Furihaca C, Hirose K, Matsushima T. 1985; 149:2- 14. Franceschi S. Hiscaminc-2-rcccpcor Gcnocoxicity and cell proliferative 88. Langman MJS. Peptic ulcer treatment antagonists and gastric cancer risk. activity of omeprazolc in rat stomach now and tomorrow. J Clin Lancet 1990;336:355-7. mucosa. Murat Res 1991;262:73-6. Gasrroenterol l987;9(Suppl 2):2-6.

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204 CAN J GASTROENTEROL VOL 8 No 3 MAY/JUNE 1994

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Medical treatment of peptic ulcer disease: Should the ...Key Words: l..aparoscopic surgery, Management, Peptic ulcer disease T raitement medical de l'ulcere gastro-duodenal. La chirurgie