REVIEW ARTICLE Management of Complicated

Stephen W. Behrman, MD

If anyone should consider removing half of my good to cure a small ulcer in my duodenum, I would run faster than he. C. E. Mayo, 1927

ur understanding of the pathophysiological features of peptic ulcer disease has rapidly evolved during the last century. Early understanding of gastric physiologic character- istics led to logical and time-tested surgical procedures aimed at acid reduction and a lowering of ulcer recurrence rates. A dramatic shift in treatment occurred with the rec- Oognition and growing knowledge of (HP). Where once dominated therapy for ulcer diathesis, medical therapy has now superseded. Just as gastric resection seemed radical to Dr Mayo, thus was medical treatment of peptic ulcer disease similarly approached with skepticism. What was the balance of medical and surgical management of peptic ulcer disease as we entered the 21st century? Complications of peptic ulcer disease requiring operative intervention have re- mained important. However, the absolute number of procedures performed has significantly dimin- ished in recent years.1 The reason for the decrease in surgical intervention, both emergent and elec- tive, is multifactorial. Improvements in therapeutic , the introduction of effective antacid therapy, and the recognition and treatment of HP infection have all greatly contributed to the suc- cessful nonoperative treatment of patients with peptic ulcer disease.2-5 With respect to complicated ulcer disease, treatment and eradication of HP infection have arguably led to a shift from treating pa- tients operatively to treating them nonoperatively. This changing management scheme has occurred despite a relative paucity of data regarding the incidence and contribution of HP infection to the eti- ology of complicated peptic ulcers. Indeed, reports in the literature regarding the incidence of HP in- fection in a surgical cohort have been sparse. From a surgeon’s perspective, data relative to HP infec- tion and the classic indications for surgery—perforation, bleeding, and gastric outlet obstruction (GOO)— have until recently been largely inferential based on treatment of those with uncomplicated peptic ulcers. Deviation from traditional surgical management might prove detrimental should other non- operative modalities be used. The purpose of this discussion is to review the known pathophysiologi- cal features of peptic ulcer disease with a focus on those complications encountered by the surgeon.

PATHOPHYSIOLOGICAL FEATURES Pavlov, PhD, described the cephalic phase of acid secretion in the dog model and re- Acid Secretion ceived the Nobel prize for his contribu- tions. In France, Mathieu Jaboulay, MD, Exceptional contributions by several physi- performed the first human . An- ologists and surgeons in the first half of dre Latarjet, MD, detailed the lesser curve the 20th century greatly added to our vagi, performed the first therapeutic va- 6 knowledge of gastric acid secretion. Ivan gotomy for treatment of an active peptic ulcer, and noted the deleterious effects of Author Affiliation: Department of Surgery, University of Tennessee Health Science vagotomy on gastric emptying. William Center–Memphis, Memphis. Bayliss, PhD, and Ernest Starling, PhD, elu-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 cidated secretin and its contribution to the gastric phase Several metabolic features allow the organism to re- of acid secretion. Lester Dragstedt, MD, PhD, reported main unharmed once colonization has ensued. Since it on the importance of pyloroplasty as an adjunct to va- is microaerophilic, survival is possible even with the low gotomy to prevent gastric stasis. Further, he noted that oxygen levels observed in the gastric lumen. It is a fac- the release of gastrin was due in part to an elevated gas- ultative acidophil and thus its enzyme systems function tric pH. He proposed that vagotomy combined with an- well at a low pH. Helicobacter pylori generates a high cata- trectomy was a superior operation for peptic ulcer dis- lase activity, which seems to be a protective mechanism ease owing to its eradication of the cephalic and gastric against oxidative injury induced by neutrophil attack and influences on acid secretion. In separate observations in hydrogen peroxide release. Finally, HP releases large quan- the 1950s, Farmer and Smithwick7 at Boston Univer- tities of , which hydrolyzes gastric intraluminal sity, Boston, Mass, and Edwards and Herrington8 at to and carbon oxide (the basis of the CLO [Cam- Vanderbilt University, Nashville, Tenn, reported the du- pylobacter-like organism] test). The ammonia effec- rability of vagotomy and antrectomy in the treatment of tively neutralizes local hydrochloric acid in the organ- complicated peptic ulcer disease with long-term recur- ism’s immediate environment—a process without which rence rates of less than 1%. Thus, the second half of the the bacteria cannot exist. Mutant HP that lack urease pro- 20th century was noteworthy for several operations based duction fail to survive in the stomach. on sound physiologic principles that resulted in effec- Physiologically, HP results in a relative hypergas- tive surgical treatment of complicated peptic ulcer dis- trinemia.16-19 This is thought to be on the basis of am- ease. Vagotomy and pyloroplasty, highly selective va- monia production, which locally raises pH exposed to gotomy, and vagotomy combined with antrectomy are G cells. In addition, somatostatin production—a negative- most commonly used. While complications such as dump- feedback inhibitor of gastrin—is reduced. The impact of ing, bile reflux, and gastric atony have been described, this hypergastrinemia on gastric acid secretion is less well long-term morbidity has remained very low. These op- characterized. In asymptomatic individuals with active erations have proven to be safe and effective with very infection, basal and peak acid outputs are normal. In low ulcer recurrence rates. symptomatic patients with an ulcer, basal and peak acid outputs may sometimes be elevated but may also be nor- HP Infection mal. Eradication of HP infection lowers acid output in those with elevated levels, though this may lag behind Our knowledge of the etiology of peptic ulcer disease and treatment by several months. surgery itself was soon to change by the description by War- Helicobacter pylori causes additional dysregulations in ren9 and Marshall10 in 1983 of a gram-negative bacteria gastric physiologic features.20 Mucosal inflammation re- noted in certain gastric specimens in association sults in gastric metaplasia within the duodenum. In con- with antral inflammation. Originally named Camphylo- junction with a high duodenal acid load, HP colonization bacter pylori, this organism was later renamed HP. De- is favored. This colonization results in further inflamma- spite the growing body of literature (the majority of it non- tion and additional gastric metaplasia with a resultant in- surgical), much is still unknown about this bacteria.11-14 crease in HP density in the duodenal bulb. This cycle may Approximately one half of the world’s population and one eventually allow the development of frank ulceration. The third of American adults are thought to be infected, yet inflammatory reaction caused by HP and the high duo- the majority are asymptomatic. The mode of transmis- denal acid production impairs bicarbonate secretion by the sion is not definitively known, but most likely transmis- duodenal mucosa and diminishes neutralization of duo- sion is from person to person either by the gastro-oral or denal acid. In addition, glycine-conjugated bile acids that fecal-oral routes.15 The decreasing incidence of HP infec- normally impair HP proliferation are precipitated in the tion in developed countries is thought to be related to im- presence of a high duodenal acid load and acidification of proved sanitation and hygiene. Prevalence rates are higher duodenal contents. Decreasing acid production and thereby in developing countries, and in these areas, infection is bile acid precipitation by various acid-reducing medica- much more common in the young. Reinfectivity rates have tions is helpful in reversing this process but cannot in and not been defined. In the United States, seropositivity dem- of itself lead to complete regression or eradication of HP. onstrates a linear relationship with age, ranging from less Other environmental factors are involved. Stress and smok- than 20% at age 20 years to 50% at age 60 years. ing increase gastric acid secretion and the duodenal acid The most dominant feature of HP is its ability to tol- load. Nonsteroidal anti-inflammatory drugs (NSAIDs) may erate the stomach environment with its acidic pH, con- injure duodenal mucosa and promote gastric metaplasia stant emptying, and rapidly exchanging epithelial layer. serving as a nidus for HP proliferation. Several adaptive features allow this organism to survive. Various strains of HP exist, and virulence likewise dif- Its motility allows it to burrow through the mucin layer fers. All strains of the bacteria cause mucosal inflamma- of the stomach to reach the gastric epithelial cells. Sub- tion but to a variable extent.21 Mechanisms whereby ac- sequently, adhesins on the bacterial wall are able to at- tive ulceration occurs in infected individuals or not tach to receptors on gastric mucosal cells. Receptors for remains to be elucidated. In fact, peptic ulcer preva- HP (mainly Lewis B antigens) are present only in the gas- lence differs within and between countries despite a com- tric epithelium and not elsewhere in the gastrointestinal parable prevalence of HP infection. One may hypoth- tract. The motility of the bacteria and its adherence mecha- esize that either the virulence and possibly the density nism allow it to colonize the stomach despite ongoing of the infecting organism is different and/or that other gastric motility. factors—environmental or genetic—are involved.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Nonsteroidal Anti-Inflammatory Drugs had documented eradication of active infection and ul- cer healing (141 with duodenal and 45 with gastric ul- Nonsteroidal anti-inflammatory drugs remain an impor- cers), and further antacid therapy was ceased. All 186 pa- tant cause of peptic ulcers. They are widely prescribed tients completed surveillance endoscopy for 1 year without and used particularly in high-risk aging populations. Other a single ulcer relapse. Ninety-six patients (64 with duo- risk factors for NSAID-induced ulceration are high- denal and 32 with gastric ulcers) had continued endo- dose or multiple-NSAID use, comorbid illness, history scopic follow-up for a median of 2.5 years (range, 0.5- of previous ulcer bleeding, cotherapy with corticoste- 9.8 years) without further ulceration and no evidence of roids or anticoagulation therapy, and probably concur- HP reinfection. While the fate of those without HP eradi- rent HP infection.22,23 The pathophysiological features of cation and the etiology of treatment failure are not re- toxic effects on the relate to a sup- ported, this study strongly suggests that elimination of pression of gastric prostaglandins.24 The reduction in HP infection prevents long-term ulcer recurrence with- prostaglandins leads to a decrease in epithelial mucus, out the need for prolonged antacid therapy. In a well- bicarbonate secretion, mucosal perfusion, epithelial pro- designed randomized controlled study, Graham et al33 re- liferation, and ultimately the mucosal resistance to in- ported on 109 patients with healed duodenal and gastric jury. The risk of life-threatening ulcer complications in ulcers who had HP infection. Patients were randomized long-term NSAID use ranges from 1% to 4%.25 to HP infection treatment vs histamine antagonists alone. Helicobacter pylori is present in approximately 50% of Treatment was discontinued after 16 weeks, and HP in- patients with NSAID-induced ulcer disease.26 It is the el- fection eradication was documented in those treated. Sur- derly population that is most at risk for HP infection as veillance endoscopy was performed for a 2-year period. well as NSAID-induced complications. Whether active Ninety-five percent of those with duodenal ulcers not re- HP infection increases the risk of ulcer formation in those ceiving HP infection treatment had ulcer recurrence vs taking NSAIDs remains speculative. Two long-term lon- 12% who received medical therapy. Corresponding rates gitudinal studies examining this issue have yielded con- for gastric ulcers were 74% and 13%, respectively. Other flicting results. Kim and Graham27 reported no signifi- studies with prolonged follow-up periods corroborate the cant increase in the incidence of gastroduodenal ulceration findings that eradication of HP infection markedly re- among long-term NSAID users with HP infection. How- duces recurrent gastroduodenal ulceration without the ever, patients with erosions detected at index endos- need for long-term antacid therapy.34,35 Can we expect copy were excluded. In contrast, Taha et al28 found that results of HP infection eradication in those with uncom- patients with HP-positive ulcer erosions were more likely plicated ulcer disease to extrapolate to those with com- to progress to frank ulceration during NSAID treatment plicated ulcers encountered by the surgeon? compared with HP-negative patients. Finally, Chan et al29 randomized patients with active HP infection to HP eradi- SURGICAL COMPLICATIONS OF PEPTIC cation vs no therapy prior to an 8-week course of NSAID ULCER DISEASE: PATHOPHYSIOLOGICAL treatment. Ulcers developed in 12 of 47 patients ran- FEATURES AND MANAGEMENT domized to NSAID alone vs 1 of 45 receiving successful antimicrobial therapy. Taken together, these reports sug- Perforation gest that treatment of HP infection in those with pre- sumed NSAID-induced ulceration seems reasonable. Acute perforations of the duodenum are estimated to oc- Whether routine HP infection assessment and treat- cur in 2% to 10% of patients with ulcers. In the latter half ment prior to embarking on an NSAID regimen is rec- of the 20th century, appropriate surgical management of ommended remains unanswered at this time. perforated ulcers remained controversial. Many recom- Several recommendations for treatment among those mended simple patch closure in what is frequently an ill with NSAID-associated peptic ulceration can be made. patient population, though others argued for a more for- All anti-inflammatory and antiplatelet drug treatments mal antiulcer procedure.36-43 Recurrent ulcer disease was should be withdrawn. Any long-term anticoagulation a concern unless prolonged antacid therapy was insti- should be temporarily reversed. Assessment and treat- tuted or a definitive antiulcer procedure was per- ment of HP infection, if present, seems reasonable. If fur- formed. Long-term medical therapy had significant eco- ther anti-inflammatory drugs are to be used, consider- nomic and compliance issues. Prolongation of surgery ation for cyclooxygenase inhibitor–specific therapy should for a definitive procedure in the face of peritonitis was be entertained.30 Data relative to any impact of NSAID often felt to be ill advised and remained controversial. use in the treatment algorithm for complicated ulcer dis- In the absence of long-term antacid therapy or a defini- ease will be discussed further. tive antiulcer procedure, remedial surgical therapy for re- current peptic ulcer was not uncommon. HP INFECTION AND UNCOMPLICATED Following simple patch closure, the clinical course of PEPTIC ULCER DISEASE these patients remained difficult to predict. Many re- mained asymptomatic, but others required continued The impact of HP infection treatment on the reduction of medical therapy to control ulcer symptoms or even sur- uncomplicated ulcer recurrence has been well docu- gical remediation. The natural history of perforated duo- mented.31 In a report with prolonged follow-up evalua- denal ulcer treated with suture application alone was well tion, Van der Hulst et al32 studied 247 patients with histo- documented by Griffin and Organ.38 They followed the logically confirmed HP infection. One hundred eighty-six clinical course of 122 patients during a 25-year period.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Forty-six patients either died of unrelated causes or were dence of recurrent ulceration vs 38% of those treated with lost to follow-up. Of the 76 followed up long-term, 5 died antacids alone—a highly significant difference. It is im- of recurrent ulcer–related complications, 5 had recur- portant to emphasize that neither group received long- rent perforation, and 34 underwent a definitive antiul- term acid-suppression therapy. Notably, the low ulcer re- cer procedure because of recurrent symptoms. An addi- currence rate in those treated for HP infection in this series tional 15 patients received prolonged medical therapy for is comparable with historical studies using immediate, persistent ulcer symptoms. In total, 48% of the original definitive antiulcer procedures, suggesting that ulcer re- study population required further ulcer treatment. In the currence in the past may have been on the basis of per- past, recurrent ulceration was thought to be on the ba- sistent HP infection.56 sis of acid hypersecretion. Most recently, cocaine use and The etiology of perforated duodenal ulcers appears to HP infection have been reported as important factors con- be multifactorial but most often is associated with HP in- tributing to perforated duodenal ulcer. fection. Reports to date suggest that in most patients, The pathophysiological features of perforated duode- simple patch closure alone with postoperative assess- nal ulcer in those abusing cocaine remains specula- ment for HP infection should suffice. Treatment and eradi- tive.44-48 Most plausible is that perforation occurs be- cation of HP infection results in a very low risk for re- cause of a localized focal vasoconstriction or vascular current ulceration and allows withdrawal of long-term thrombosis. Feliciano et al48 reported on the cases of 50 antacid therapy. Since a small percentage of patients will patients with cocaine-related perforations, which in their have other etiologies of ulcer disease (Zollinger-Ellison series represented almost 40% of all patients with jux- syndrome, Crohn’s disease), it is important to docu- tapyloric perforations in this inner city hospital. Omen- ment HP infection and not treat empirically. tal patch closure alone was most often used. The au- thors suggest that this operation should suffice in the Bleeding majority of patients but that a concurrent definitive an- tiulcer procedure should be considered in those with a The incidence of gastroduodenal bleeding secondary to history of gastroduodenal ulceration due to compliance acid-peptic disease and hospital admissions for this com- issues. In the latter years of this study, the authors as- plication have not significantly changed in the last 2 de- sessed their study population for HP infection by direct cades.57-59 Further, despite improvements in nonsurgi- antral biopsy at the time of patch closure and found in- cal modalities such as proton pump inhibitors and fection in 4 of 5 tested. It may be, as the authors hypoth- therapeutic endoscopy, operation for peptic ulcer bleed- esize, that active HP infection predisposes crack co- ing has remained constant; such operations are per- caine addicts to gastroduodenal perforation. formed on 10% to 20% of all patients hospitalized for up- Recent literature strongly implicates active HP infec- per gastrointestinal tract hemorrhage.60,61 Evidence tion as the cause of perforated duodenal ulcer. Rein- suggests that bleeding is more common as age in- bach et al49 noted an incidence of HP infection in 47% of creases. As such, mortality rates following ulcer bleed- 80 patients undergoing operation for perforated duode- ing have remained at approximately 10%.61-63 The need nal ulcer. Chu et al50 also reported an infectivity rate of for surgical intervention in this cohort remains impor- 47% confirmed by postoperative endoscopy with bi- tant. In a large, prospective national survey by the Ameri- opsy at a mean of 6 years following surgery. Endoscopic can Society for Gastrointestinal Endoscopy (Oakbrook, evidence of an ongoing ulcer diathesis was found in 84.4% Ill), 347 (15.6%) of 2225 patients with bleeding ulcers of those with active HP infection vs only 3.5% of those required surgical intervention.64 A further study at the without, suggesting that if HP infection is not present, University of California at Irvine noted that 19% of pa- then recurrent ulcer disease following simple patch clo- tients undergoing therapeutic endoscopy for ulcer bleed- sure should be a rare event. Others have uniformly re- ing required surgery.5 Importantly, surgery was neces- ported infectivity rates ranging from 70% to 92%.51-54 sary on an emergent or urgent basis in 70% and 100% of Evidence suggests that medical treatment aimed at patients requiring operation in these respective series. eradication of HP results in permanent resolution of a Thus, surgery is most often necessary in the acute set- future ulcer diathesis without the need for long-term ant- ting, typically within 48 hours of initial bleeding. acid therapy or surgical intervention. Ng et al55 per- To what degree can therapeutic endoscopy obviate the formed a randomized controlled study examining this is- need for surgical intervention and should it be consid- sue. Of 129 patients with duodenal ulcer perforation, 104 ered more than once? Lau et al3 attempted to answer this (81%) were infected by HP. The diagnosis was made via question in a randomized prospective study. During a upper endoscopy and biopsy performed at the time of lapa- 4-year period, approximately one third of 3500 patients rotomy. Postoperatively, patients were randomized to re- admitted to the hospital with bleeding peptic ulcers re- ceive anti-HP therapy or a 4-week course of omeprazole ceived therapeutic endoscopy. Seventeen patients (1.5%) alone after which treatment with all medications was dis- went directly to surgery following failure of primary en- continued. Patients completing the study protocol were doscopic control. Bleeding recurred in 100 patients or followed up for 1 year with repeat endoscopy for ulcer 8.7% of the entire population. Median blood transfu- surveillance and HP infection assessment by repeat bi- sion in this final group was 5 U, suggesting significant opsy. At 8 weeks following treatment, HP infection eradi- hemorrhage. Of the 48 patients randomized to repeat en- cation rates were significantly higher in those treated for doscopy, 27% percent underwent a failed endoscopy and HP infection (84% vs 17%). At the 1-year endoscopic required emergency surgical intervention with a post- evaluation, 5% of the HP infection–treated group had evi- operative complication rate of 46%. In those with a suc-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 cessful second endoscopy, complications occurred in 14%. centage of patients with bleeding ulcers had HP infec- In contrast, 93% of patients going directly to surgery with- tion. Hemoglobin levels (9-10 g/dL) and transfusion out repeat endoscopy achieved permanent hemostasis with requirements (2 U) at hospital admission were modest, a postoperative complication rate of 36%. On analysis, suggesting this population would typically not be evalu- the authors noted that hypotension prior to the second ated for surgical intervention. Only 5 of 51 patients in endoscopy and an ulcer larger than 2 cm significantly cor- the study by Jaspersen et al required blood transfusion, related with endoscopic failure. Mortality in those un- and those with actively bleeding ulcers were excluded dergoing repeat endoscopy was 10%, which was not sig- from analysis. It is unclear if any patient in the study by nificantly different from those undergoing surgical Rokkas et al underwent therapeutic endoscopy, and the intervention for recurrent bleeding. Importantly, 4 of the number requiring transfusion was not reported. While 5 deaths in the repeat endoscopy arm occurred in those HP infection elimination was effective in preventing re- undergoing salvage surgical therapy for persistent bleed- current ulceration in these studies, it is difficult to ex- ing. While a second therapeutic endoscopy may negate trapolate these results to a population with massive bleed- the need for surgery, fully one quarter of these patients ing, which is most commonly encountered by the surgeon. will fail necessitating emergency surgery with a signifi- It is becoming clear from several reports that the in- cant complication rate. Curiously, although the authors cidence of HP infection in a surgical cohort with signifi- assessed for HP infection at the index endoscopy (via the cant bleeding is much lower, ranging from 39.1% to 55%, CLO test), no results were reported. than in those with uncomplicated ulcers or minor de- With the recognition that HP infection significantly grees of bleeding.54,65,68,69 Data from the University of Ten- contributes to the etiology and persistence of uncompli- nessee, Memphis, suggest that in contrast to other popu- cated ulcer disease, its role in the treatment algorithm lations, HP infection is even less common as age increases for patients with significant gastrointestinal tract bleed- in those with massive bleeding.69 Further, this de- ing was questioned. Specifically, can therapy directed at creased infection in older populations could not be ex- HP infection eradication complement therapeutic en- plained on the basis of excessive NSAID medication be- doscopy and reduce the number of patients requiring op- cause use was equal in those with and without HP eration for hemorrhage? The question remains: Can early infection. In this series, only 2 of 39 patients ultimately treatment for HP infection, if present, avert surgery in undergoing operation for a bleeding ulcer had those with massive bleeding? Clearly, a rapid diagnosis performed to assess for the presence of HP infection, most of HP infection would be necessary. Techniques to di- likely because of significant bleeding and the emer- agnose HP infection, such as serologic testing and his- gency nature of the procedure. In addition, one half of tologic analysis, require several days for confirmation. these patients required emergency operation before di- Only 2 tests are available to rapidly assess for HP infec- agnosis of HP infection could have been made. In this tion, the CLO (rapid urease) test and carbon 14 urea study, a formal antiulcer procedure was performed in all breath analysis. The breath analysis is not uniformly avail- patients with no patient having recurrent bleeding. Post- able in many institutions; further, data suggest that in operative morbidity and mortality rates were 17.9% and those undergoing endoscopy for active bleeding, the CLO 5.1%, respectively. test lacks sensitivity with a substantial false-negative rate. Thus, in the emergency setting with significant bleed- Lee et al65 analyzed the diagnosis of HP infection in 55 ing, rapid diagnosis of HP infection is frequently impos- patients with bleeding duodenal ulcers and compared re- sible. Many patients require emergency surgery, which sults with 69 patients with uncomplicated ulcers. A va- does not allow any attempt at HP infection diagnosis. Sur- riety of diagnostic methods to assess HP infection were gery offers the lowest risk for rebleeding when com- used including the CLO test, serologic analysis, and mi- pared with repeat therapeutic endoscopy. However, mor- crobiologic and histologic evaluation. The false- bidity remains substantial in this cohort of patients with negative rate via the CLO test was significantly higher massive bleeding. in those with bleeding ulcers vs those without (18.2% The incidence of HP infection in those patients with vs 1.4%; PϽ.05). They further noted that those with bleed- significant upper gastrointestinal tract bleeding second- ing ulcers had HP infection rates significantly lower than ary to peptic ulcer disease is significantly lower than in those with uncomplicated disease (72.7% vs 92.8%; those with uncomplicated ulcers or minor degrees of hem- PϽ.05). These data would suggest that in the absence of orrhage. There are no data to substantiate a delay in sur- breath analysis, a rapid and reliable method to diagno- gical intervention to treat HP infection, and it would be sis HP infection in those with bleeding ulcers is lacking. anticipated that such a delay could be associated with an In addition, as will be discussed further, HP infection is increase in morbidity and mortality in this population less common in those with bleeding ulcers. with significant transfusion requirements. There is no role In 2 similarly designed and consecutively reported early for empirical treatment of HP infection in this cohort be- studies, Rokkas et al66 and Jaspersen et al67 examined the cause the incidence of infection is substantially re- impact of HP eradication in those patients with upper gas- duced. If HP infection is not present, the etiology of ul- trointestinal tract bleeding secondary to peptic ulcer dis- cer disease in this population is unknown but may be on ease. The presence of HP infection in both studies was the basis of acid hypersecretion. Thus, if surgery is to be assessed by both the CLO test and histologic evalua- performed, a definitive acid-reducing procedure should tion. Some 80 patients with bleeding ulcers and active strongly be considered. In contrast to the arguments of HP infection were randomized to HP infection treat- others, performing a less radical operation in the face of ment vs antacids alone. Neither study reported what per- massive bleeding with a known lower incidence of HP

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 infection would leave up to 50% of this population at risk no reported mortality to date.69,72 One must also con- for rebleeding.57,70 sider the surgical ramifications should pyloric dilation fail. Management of a difficult duodenal stump could be Gastric Outlet Obstruction more problematic because of advanced fibrosis from 1 or more prior pneumatic dilations. In addition, failed py- Benign GOO secondary to peptic ulcer disease remains loric dilation can lead to further weight loss and a high- prevalent and represents approximately 5% to 8% of ulcer- risk patient for surgical intervention because of nutri- related complications. Obstruction necessitates opera- tional depletion. tion in about 2000 patients per year in the United Surprisingly, despite these recent reports on the use States.71-73 Pathophysiologically, pyloric channel steno- of pyloric dilation in those with benign GOO, the inci- sis leads to stasis, which raises the gastric pH resulting dence of HP infection in this cohort was infrequently as- in pronounced gastrin release and excess acid produc- sessed. As such, its potential role in recurrent stricture tion. This is compounded by significant gastric disten- formation in those with an initially successful pyloric di- tion that further increases gastrin release. The combina- lation is unknown. Further, the impact on its eradica- tion exacerbates ongoing acid production resulting in a tion on the nonoperative management of benign peptic “vicious cycle.” The incidence of HP infection in this co- stricture can only be speculated. Only 19 of 42 patients hort has, until recently, not been well defined and con- in the series of pyloric dilation reported by Perng et al79 tinues to suffer from small numbers for analysis. How- had concurrent biopsy performed for HP infection. Of ever, our understanding of its role in those with GOO is these 19 patients, only 11 (57%) tested positive for HP improving. Most recently, therapy for GOO primarily fo- infection. Five of these 11 patients were treated for HP cused on 2 approaches, operative and nonoperative. Sur- infection following pyloric dilation, and all 5 remained gical intervention directed at a formal acid-reducing pro- asymptomatic at a median follow-up of 15 months. An- cedure has historically been the mainstay of therapy with other 5 of these 11 patients who tested positive for HP repeatedly good results and low associated morbidity and infection ultimately required surgical intervention. Un- mortality.72,74-78 Nonoperative management includes pneu- fortunately, it is unclear whether these patients were matic dilation with or without treatment directed at HP treated for HP infection or not. Gibson et al72 reported infection. In many instances, pneumatic dilation is used an HP infection incidence of only 33% in 24 patients un- primarily, and frequently repeatedly, before consider- dergoing surgery for GOO. In that series, 2 of 5 patients ation for surgical referral.79-83 receiving pneumatic dilation preoperatively tested posi- Pyloric dilation for benign peptic stricture was first tive for HP infection though none received treatment. As reported in 1982 and continues to be used, often as pri- previously noted, in the other 3, pyloric dilation failed, mary therapy.84 Its use, however, suffers from a lack of despite the concurrent use of antacid therapy. Very lim- published data, especially with respect to long-term symp- ited data suggest that treatment for active HP infection tomatic improvement. Early studies focused primarily on is an important adjunct to pyloric dilation if surgery is the feasibility, safety, and short-term results of this tech- to be avoided. In a series of 19 patients reported by Lam,88 nique.85-87 Studies with longer periods of follow-up have 9 (47%) had active HP infection. Six of these 9 patients yielded conflicting results. With a median follow-up of received both antimicrobial therapy directed at HP in- 23 months, Perng et al79 noted sustained symptomatic fection and concurrent dilation. No recurrent obstruc- improvement in 28 of 42 patients treated with pyloric tion was noted in these 6 patients at a median of 16 dilation. DiSario et al82 reported sustained relief in 24 of months. 30 patients, but 7 required repetitive dilation sessions. Case reports have noted total resolution of symptom- Kuwada and Alexander81 reported the longest follow-up atic and endoscopic outlet obstruction with medical treat- to date with a median of 45 months. In their series, 16 ment directed at HP infection without concurrent py- of 19 patients initially treated successfully with pyloric loric dilation.89 However, no large series has confirmed dilation had a recurrence of symptoms at a median of 9 this mode of therapy. In the series by Gibson et al,72 3 months following the index procedure. Similarly, Lau et patients received HP infection therapy alone without di- al80 noted a recurrence of obstruction in 18 of 41 pa- lation, and this was unsuccessful in avoiding operation. tients at a median of 39 months. These data would sug- Although medical treatment may eradicate an acute in- gest that pyloric dilation may offer excellent initial symp- flammatory process, its success in resolving a chronic fi- tomatic relief. However, one can expect an unacceptably brotic process noted by surgeons at the time of opera- high rate of recidivism in this population. Certainly, long- tive intervention would seem doubtful. term antacid use is a necessary adjunct that would be Surgery for benign GOO remains an important treat- costly over the lifetime of a young patient. The impact ment modality either as initial therapy or following un- of antacid use on the prevention of recurrent GOO, how- successful pyloric dilation. Options for treatment in- ever, remains questionable. In a study from the Univer- clude highly selective vagotomy with some form of sity of Tennessee, 3 patients underwent successful py- pyloroplasty, truncal vagotomy with gastroenteros- loric dilation followed by antacid therapy.72 All 3 patients tomy, or truncal vagotomy with antrectomy. All have been eventually developed restenosis and underwent surgi- reported with good results.72,74-78 While vagotomy and an- cal management. Similar results were noted by Lam88 in trectomy may offer the lowest rate of ulcer recurrence, a subsequent study. Morbidity in the form of perfora- other modalities remain important, especially in those tion has been cited in 0% to 6% of patients undergoing with significant duodenal scarring. Short- and long- this procedure, necessitating emergency operation with term morbidity have been rare in reported series. Symp-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 tomatic control following surgical intervention remains 18. Levi S, Beardshall K, Swift I, et al. Antral Helicobacter pylori, hypergastrinemia, outstanding. In the series by Gibson et al,72 all but 1 of and duodenal ulcers: effect of eradicating the organism. BMJ. 1989;299:1504- 1505. 16 patients followed up long-term after surgery re- 19. Harris AW, Gummett PA, Misiewicz JJ, et al. Eradication of Helicobacter pylori ported Visick grade I or II symptoms (improved from Vis- in patients with duodenal ulcer lowers basal and peak acid outputs to gastrin ick IV), and no patients required antacid medication. releasing peptide and pentagastrin. Gut. 1996;38:663-667. Nonoperative management of benign GOO is ham- 20. Graham DY, Osato MS. H. pylori in the pathogenesis of duodenal ulcer: interac- pered by a lack of long-term follow-up data. The inci- tion between duodenal acid load, bile and H. pylori. Am J Gastroenterol. 2000; 95:87-91. dence of HP infection in this population appears to be 21. Shiotani A, Graham DY. Pathogenesis and therapy of gastric and duodenal ulcer substantially less than in populations with uncompli- disease. Med Clin North Am. 2002;86:1447-1466. cated ulcers and even less common than in those with 22. Gabriel SE, Jaakkimainen L, Bombardier C. Risks for serious gastrointestinal perforated or massively bleeding ulcers. In patients with complications related to the use of nonsteroidal anti-inflammatory drugs: a meta-analysis. Ann Intern Med. 1991;115:787-796. GOO and active HP infection, pyloric dilation com- 23. Feldman M, Cryer B, Mallet D, et al. Role of Helicobacter pylori infection in gas- bined with medical therapy directed at HP infection seems troduodenal injury and prostaglandin synthesis during long term/low dose as- reasonable, but one must recognize that no substantial pirin therapy: a prospective placebo-controlled, double-blind, randomized trial. data as yet exist to substantiate this mode of therapy. In Am J Gastroenterol. 2001;96:1751-1757. patients who test negative for HP infection, long-term suc- 24. Laine L, Sloane R, Ferretti M, et al. A randomized double-blind comparison of placebo, etodolac and naproxen on gastrointestinal injury and prostaglandin cess with pyloric dilation as reported in the literature re- production. Gastrointest Endosc. 1995;42:428-433. mains poor, especially in the absence of permanent ant- 25. Graham DY. Nonsteroidal anti-inflammatory drugs, Helicobacter pylori and ul- acid use. Surgical therapy for this ulcer complication cers: where we stand. Am J Gastroenterol. 1996;91:2080-2086. continues to offer definitive and durable symptomatic re- 26. Heresbach D, Raoul JL, Bretagne JF, et al. Helicobacter pylori: a risk and sever- lief in this patient population. ity factor of non-steroidal anti-inflammatory drug induced gastropathy. Gut. 1992; 33:1608-1611. 27. Kim JG, Graham DY. Helicobacter pylori infection and the development of gas- Accepted for Publication: December 17, 2003. tric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy: the Misoprostol Study Group. Am J Gastroenterol. 1994;89:203-207. Correspondence: Stephen W. Behrman, MD, Depart- 28. Taha AS, Sturrock RD, Russell RI. Mucosal erosions in longterm non-steroidal ment of Surgery, University of Tennessee Health Sci- anti-inflammatory drug users: predisposition to ulceration and relation to Heli- ence Center-Memphis, 956 Court Ave, Suite G218, Mem- cobacter pylori. Gut. 1995;36:334-336. phis, TN 38163 ([email protected]). 29. Chan FK, Sung JJ, Chung SC, et al. Randomised trial of eradication of Helico- bacter pylori before non-steroidal anti-inflammatory drug therapy to prevent pep- tic ulcers. Lancet. 1997;350:975-979. REFERENCES 30. Farrell JJ, Friedman LS. Gastrointestinal bleeding in older people. Gastroenterol Clin North Am. 2000;29:1-36. 1. Schwesinger WH, Page CP, Sirinek KR, et al. Operations for peptic ulcer dis- 31. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori ease: paradigm lost. J Gastrointest Surg. 2001;5:438-443. eradication and reduced duodenal and gastric ulcer recurrence: a review. 2. Christensen A, Bousfield R, Christiansen J. Incidence of perforated and bleed- Gastroenterology. 1996;110:1244-1252. ing peptic ulcers before and after the introduction of H2-receptor antagonists. 32. Van der Hulst RW, Rauws EAJ, Koycu B, et al. Prevention of ulcer recurrence Ann Surg. 1988;207:4-6. after eradication of Helicobacter pylori: a prospective long-term follow-up study. 3. Lau JY, Sung JJY, Lam Y, et al. Endoscopic retreatment compared with surgery Gastroenterology. 1997;113:1082-1086. in patients with recurrent bleeding after initial endoscopic control of bleeding 33. Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori ulcers. N Engl J Med. 1999;340:751-756. infection on the long-term recurrence of gastric or duodenal ulcer. Ann Intern 4. Pimpl W, Boeckl O, Heinerman M, et al. Emergency endoscopy: a basis for thera- Med. 1992;116:705-708. peutic decisions in the treatment of severe gastroduodenal bleeding. World J Surg. 34. Forbes GM, Glaser ME, Cullen DJE, et al. Duodenal ulcer treated with Helicobac- 1989;13:592-597. ter pylori eradication: seven year follow-up. Lancet. 1994;343:258-260. 5. Williams RA, Vartany A, Davis IP, et al. Impact of endoscopic therapy on out- 35. Labenz J, Borsch G. Highly significant change of the course of relapsing and com- come of operation for bleeding peptic ulcers. Am J Surg. 1993;166:712-715. plicated peptic ulcer disease after cure of Helicobacter pylori infection. Am J 6. Waisbren SJ, Modlin IM, Lester R. Dragstedt and his role in the evolution of thera- Gastroenterol. 1994;89:1785-1788. peutic vagotomy in the United States. Am J Surg. 1994;167:344-359. 36. Hennessy EJ, Chapman BJ, Duggan JM. Perforated peptic ulcer: long term 7. Farmer D, Smithwick R. Hemigastrectomy combined with resection of the va- follow-up. Med J Aust. 1976;1:50-53. gus nerves. N Engl J Med. 1952;247:1017-1022. 37. Hay JM, Lacaine F, Kohlmann G, et al. Immediate definitive surgery for perfo- 8. Edwards LW, Herrington JL. Efficacy of 40 per cent combined with rated duodenal ulcer does not increase operative mortality: a prospective con- vagotomy for duodenal ulcer. Surgery. 1957;41:346-348. trolled trial. World J Surg. 1988;12:705-709. 9. Warren JR. Unidentified curved bacilli on gastric epithelium in active chronic gas- 38. Griffin GE, Organ CH Jr. The natural history of the perforated duodenal ulcer treated tritis [letter]. Lancet. 1983;1:1273. by suture plication. Ann Surg. 1976;183:382-385. 10. Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gas- 39. Boey J, Lee NW, Koo J, et al. Immediate definitive surgery for perforated duo- tritis [letter]. Lancet. 1983;1:1273-1275. denal ulcers. Ann Surg. 1982;196:338-344. 11. Schwesinger WH. Is Helicobacter pylori a myth or the missing link? Am J Surg. 40. Illingworth CFW, Scott LDW, Jamieson RA. Progress after perforated peptic ulcer. 1996;172:411-417. BMJ. 1946;1:787-790. 12. Kokoska ER, Kaufffman GL. Helicobacter pylori and the gastroduodenal mucosa. 41. Dean AC, Clark CG, Sinclair-Geben AH. The late prognosis of perforated duode- Surgery. 2001;130:13-16. nal ulcers. Gut. 1962;3:60-64. 13. Peterson WL. Helicobacter pylori: and peptic ulcer disease. N Engl J Med. 1991; 42. Bornman PC, Theodorou NA, Jeffery PC, et al. Simple closure of perforated duo- 324:1043-1048. denal ulcer: a prospective evaluation of a conservative management policy. Br J 14. Graham DY. Helicobacter pylori: its epidemiology and its role in duodenal ulcer Surg. 1990;77:73-75. disease. J Gastroenterol Hepatol. 1991;6:105-113. 43. Boey J, Wong J. Perforated duodenal ulcers. World J Surg. 1987;11:319-324. 15. Parsonnet J, Shmuely H, Haggerty T. Fecal and oral shedding of Helicobacter 44. Lee HS, Lamaute HR, Pizzi WF, et al. Acute gastroduodenal perforations asso- pylori from healthy infected adults. JAMA. 1999;282:2240-2245. ciated with use of crack. Ann Surg. 1990;211:15-17. 16. Calam J. Helicobacter pylori, acid and gastrin. Eur J Gastroenterol Hepatol. 1995; 45. Abramson DL, Gertler JP, Lewis T, et al. Crack-related perforated gastropyloric 7:310-317. ulcer. J Clin Gastroenterol. 1991;13:17-19. 17. Peterson WL, Barnett CC, Evans DJ, et al. Acid secretion and serum gastrin in 46. Kram HB, Hardin E, Clark SR, et al. Perforated ulcers related to smoking ‘crack’ normal subjects and patients with duodenal ulcer: the role of Helicobacter pylori. cocaine. Am Surg. 1992;58:293-294. Am J Gastroenterol. 1993;88:2038-2043. 47. Sharma R, Organ CH, Hirvela ER, et al. Clinical observation of the temporal as-

(REPRINTED) ARCH SURG/ VOL 140, FEB 2005 WWW.ARCHSURG.COM 207

©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 sociation between crack cocaine and duodenal ulcer perforation. Am J Surg. 1997; the rate of rebleeding in ulcer hemorrhage. Gastrointest Endosc. 1995;41:5- 174:629-632. 7. 48. Feliciano DV, Ojukwo JC, Rozycki GS, et al. The epidemic of cocaine-related jux- 68. Fischer DR, Nussbaum MS, Pritts TA, et al. Use of omeprazole in the manage- tapyloric perforations. Ann Surg. 1999;229:801-806. ment of giant duodenal ulcer: results of a prospective study. Surgery. 1999; 49. Reinbach DH, Cruickshank G, McColl KEL. Acute perforated duodenal ulcer is 126:643-649. not associated with Helicobacter pylori infection. Gut. 1993;34:1344-1347. 69. Callicutt CS, Behrman SW. Incidence of Helicobacter pylori in operatively man- 50. Chu KM, Kwok KF, Law SYK, et al. Helicobacter pylori status and endoscopy fol- aged acute nonvariceal upper gastrointestinal bleeding. J Gastrointest Surg. 2001; low-up of patients having a history of perforated duodenal ulcer. Gastrointest 5:614-619. Endosc. 1999;50:58-62. 70. Millat B, Fingerhut A, Borie F. Surgical treatment of complicated duodenal ul- 51. Ng EK, Chung SC, Sung JJ, et al. High prevalence of Helicobacter pylori infec- cers: controlled trials. World J Surg. 2000;24:299-306. tion in duodenal ulcer perforations not caused by non-steroidal anti-inflam- 71. Ellis H. Pyloric stenosis complicating duodenal ulceration. World J Surg. 1987; matory drugs. Br J Surg. 1996;83:1779-1781. 11:315-318. 52. Matsukura N, Onda M, Tokunaga A, et al. Role of Helicobacter pylori infection in 72. Gibson JB, Behrman SW, Fabian TC, et al. Gastric outlet obstruction resulting perforation of peptic ulcer: an age and gender-matched case-control study. J Clin from peptic ulcer disease requiring surgical intervention is infrequently associ- Gastroenterol. 1997;25:S235-S239. ated with Helicobacter pylori infection. J Am Coll Surg. 2000;191:32-37. 53. Sebastian M, Chandran VP, Elashaal YI, et al. Helicobacter pylori infection in per- 73. Kozarek RA. Gastrointestinal dilation. In: Yamada T, Alpers DH, Owyang C, et al, forated peptic ulcer disease. Br J Surg. 1995;82:360-362. eds. Textbook of Gastroenterology. Philadelphia, Pa: Lippincott, Williams & Wilkins; 54. Tokunaga Y, Hata K, Ryo J, et al. Density of Helicobacter pylori infection in pa- 1990:2039-2053. tients with peptic ulcer perforation. J Am Coll Surg. 1998;186:659-663. 74. Lunde O-C, Liavag I, Roland M. Proximal gastric vagotomy and pyloroplasty for 55. Ng EK, Lam YH, Sung JJ, et al. Eradication of Helicobacter pylori prevents re- duodenal ulcer with pyloric stenosis: a thirteen year experience. World J Surg. currence of ulcer after simple closure of duodenal ulcer perforation. Ann Surg. 1985;9:165-170. 2000;231:153-158. 75. Donahue PE, Yoshida J, Richter HM, et al. Proximal gastric vagotomy with drain- 56. Jordan PH, Thornby J. Perforated pyloroduodenal ulcers: long term results with age for obstructing duodenal ulcer. Surgery. 1988;104:757-764. omental patch closure and parietal cell vagotomy. Ann Surg. 1995;221:479- 76. Bowden TA, Hooks VH III, Rogers DA. Role of highly selective vagotomy and 488. duodenoplasty in the treatment of postbulbar duodenal obstruction. Am J Surg. 57. Ohmann C, Imhof M, Roher H. Trends in peptic ulcer bleeding and surgical 1990;159:15-19, discussion 19-20. management. World J Surg. 2000;24:284-293. 77. Weiland D, Dunn DH, Humphrey EW, et al. Gastric outlet obstruction in peptic 58. Kurata J, Corboy E. Current peptic ulcer time trends: an epidemiological profile. ulcer disease: an indication for surgery. Am J Surg. 1982;143:90-93. J Clin Gastroenterol. 1988;10:259-268. 78. Hermann RE. Obstructing duodenal ulcer. Surg Clin North Am. 1976;56:1403-1411. 59. Gustavsson S, Kelly KA, Melton LJ III, et al. Trends in peptic ulcer surgery: a 79. Perng C, Lin H, Lo W, et al. Characteristics of patients with benign gastric outlet population-based study in Rochester, Minnesota, 1956-1985. Gastroenterology. obstruction requiring surgery after endoscopic balloon dilation. Am J Gastroenterol. 1988;94:688-694. 1996;91:987-990. 60. Miller AR, Farnell MB, Kelly KA, et al. Impact of therapeutic endoscopy on the 80. Lau JY, Chung SCS, Sung JJY, et al. Through-the-scope balloon dilation for py- treatment of bleeding duodenal ulcers: 1980-1990. World J Surg. 1995;19: loric stenosis: long-term results. Gastrointest Endosc. 1996;43:98-101. 89-95. 81. Kuwada SK, Alexander GL. Long-term outcome of endoscopic dilation of non- 61. Sacks H, Chalmers T, Blum A, et al. Endoscopic hemostasis: an effective therapy malignant pyloric stenosis. Gastrointest Endosc. 1995;41:15-17. for bleeding peptic ulcers. JAMA. 1990;264:494-499. 82. DiSario JA, Fennerty MB, Tietze CC, et al. Endoscopic balloon dilation for ulcer- 62. Kubba A, Choudaari C, Rajhopal C, et al. The outcome of urgent surgery for ma- induced gastric outlet obstruction. Am J Gastroenterol. 1994;89:868-871. jor peptic ulcer hemorrhage following failed endoscopic therapy. Eur J Gastro- 83. Kozarek RA, Botomn VA, Patterson DJ. Long-term follow-up in patients who have enterol Hepatol. 1996;8:1175-1182. undergone balloon dilation for gastric outlet obstruction. Gastrointest Endosc. 63. Rockall TA, Logan RFA, Devlin HB, et al. Incidence of and mortality from acute 1990;36:558-561. upper gastrointestinal hemorrhage in the United Kingdom. BMJ. 1995;311: 84. Benjamin SB, Cattau EL, Glass RL. Balloon dilation of the pylorus: therapy for 222-226. gastric outlet obstruction. Gastrointest Endosc. 1982;28:253-254. 64. Silverstein F, Gilbert D, Tedesco F, et al. The national ASGE survey on upper gas- 85. Lindor KD, Ott BJ, Hughes RW. Balloon dilation of upper digestive tract strictures. trointestinal bleeding, I: study design and baseline data. Gastrointest Endosc. Gastroenterology. 1985;89:545-548. 1981;27:73-79. 86. Hogan RB, Hamilton JK, Patter DE. Preliminary experience with hydrostatic bal- 65. Lee JM, Breslin NP, Fallon C, et al. Rapid urease tests lack sensitivity in Helico- loon dilation of gastric outlet obstruction. Gastrointest Endosc. 1986;32:71-74. bacter pylori diagnosis when peptic ulcer disease presents with bleeding. Am J 87. Griffin SM, Chung SCS, Leung JWC, et al. Peptic pyloric stenosis treated by en- Gastroenterol. 2000;95:1166-1170. doscopic balloon dilation. Br J Surg. 1989;76:1147-1148. 66. Rokkas T, Karameris A, Mavrogeorgis A, et al. Eradication of Helicobacter pylori 88. Lam Y. Endoscopic balloon dilation and Helicobacter pylori eradication in the treat- reduces the possibility of rebleeding in peptic ulcer disease. Gastrointest Endosc. ment of gastric outlet obstruction. Gastrointest Endosc. 1997;46:379-380. 1995;41:1-4. 89. de Boer WA, Driesson WMM. Resolution of gastric outlet obstruction after eradi- 67. Jaspersen D, Koerner T, Schorr W, et al. Helicobacter pylori eradication reduces cation of Helicobacter pylori. J Clin Gastroenterol. 1995;21:329-330.

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