Clinical outcome using lansoprazole in acid hypersecretors with and without Zollinger-Ellison syndrome: A 13-year prospective study
2005; Elsevier BV; Volume: 3; Issue: 1 Linguagem: Inglês
10.1016/s1542-3565(04)00606-8
ISSN1542-7714
AutoresBasil I. Hirschowitz, Julie Simmons, Jean Mohnen,
Tópico(s)Tuberous Sclerosis Complex Research
ResumoBackground & Aims: Unremitting gastric acid and pepsin hypersecretion causes serious persistent and relapsing lesions, but the natural history with medical treatment alone has not been well-defined. The aims of this study were to heal and prevent relapse of acid/peptic lesions during acid suppression and to analyze benefits and risks during long-term lansoprazole treatment. Methods: Sixty-seven patients (49 with Zollinger-Ellison syndrome [ZES], 18 without), with basal acid output (BAO) >15 mmol/h or >5 mmol/h if post-antrectomy (n = 9, all ZES), were treated with individually optimized doses of lansoprazole (7.5–450 mg/day; median, 75 mg/day) to reduce BAO to <5 mmol/h or <1 mmol/h post-antrectomy and underwent endoscopy every 3–6 months for up to 13 years (median, 6.25 years). Results: Before treatment, 94% had duodenal ulcer, 64% had esophagitis, 60% had 1 or more bleeding episodes, 13% had perforated ulcers, 90% had pain, 60% had heartburn, and 40%–48% had diarrhea, vomiting, and/or weight loss. Forty-seven patients (70%) remained symptom- and lesion-free, whereas 13 (20%) had mild, transient relapses, and 7 (10%) had more complicated relapses. Overall, symptoms were reduced 90+%; ulcer or esophagitis relapsed in 4.8% of patients/year, unrelated to Helicobacter pylori, whereas complications declined to 5 mmol/h in intact patients, relative risk of relapse was 4.1, confidence interval 2.1–8.1, P < .001. Twenty patients died, 3 as a result of ZES (2 metastatic gastrinomas). Conclusions: With individually optimized medical suppression of acid secretion, 90% of patients had good to excellent long-term outcomes without surgery, with an annualized total relapse rate of 15 mmol/h or >5 mmol/h if post-antrectomy (n = 9, all ZES), were treated with individually optimized doses of lansoprazole (7.5–450 mg/day; median, 75 mg/day) to reduce BAO to <5 mmol/h or <1 mmol/h post-antrectomy and underwent endoscopy every 3–6 months for up to 13 years (median, 6.25 years). Results: Before treatment, 94% had duodenal ulcer, 64% had esophagitis, 60% had 1 or more bleeding episodes, 13% had perforated ulcers, 90% had pain, 60% had heartburn, and 40%–48% had diarrhea, vomiting, and/or weight loss. Forty-seven patients (70%) remained symptom- and lesion-free, whereas 13 (20%) had mild, transient relapses, and 7 (10%) had more complicated relapses. Overall, symptoms were reduced 90+%; ulcer or esophagitis relapsed in 4.8% of patients/year, unrelated to Helicobacter pylori, whereas complications declined to 5 mmol/h in intact patients, relative risk of relapse was 4.1, confidence interval 2.1–8.1, P < .001. Twenty patients died, 3 as a result of ZES (2 metastatic gastrinomas). Conclusions: With individually optimized medical suppression of acid secretion, 90% of patients had good to excellent long-term outcomes without surgery, with an annualized total relapse rate of 15 mmol/h) and pepsin secretion, whether or not caused by gastrinoma (Zollinger-Ellison syndrome [ZES] or idiopathic [non-ZES]),1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar, 2Hirschowitz B. Mohnen J. Shaw S. Long-term treatment with lansoprazole of patients with duodenal ulcer and basal acid output of more than 15 mmol/h.Aliment Pharmacol Ther. 1996; 10: 497-506Crossref PubMed Scopus (18) Google Scholar, 3Kirkpatrick P.M. Hirschowitz B.I. Duodenal ulcer with unexplained marked basal gastric acid hypersecretion.Gastroenterology. 1980; 79: 4-10PubMed Scopus (35) Google Scholar causes severe and often life-threatening lesions of the esophagus, duodenum, and proximal small bowel, but, surprisingly, not stomach, with debilitating symptoms. The only therapeutic option for this condition is the proper control of acid (and pepsin) secretion,1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar although the actual clinical outcome or the most desirable level of acid required to heal and prevent relapse of acid/peptic lesions has not been critically examined since more potent treatment with proton pump inhibitor (PPIs) has become standard.4O'Toole D. Mignon M. Ruszniewski P. The place of proton pump inhibitors in the management of the Zollinger-Ellison syndrome.in: Scarpignato C. Frontiers in gastroenterology proton pump inhibitors. Karger AG, Basel, Basel, Switzerland2004Google Scholar Despite extensive and important data in the literature5Weber H.C. Venzon D.J. 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Jensen R.T. et al.Studies on the interrelation between Zollinger-Ellison syndrome, Helicobacter pylori, and proton pump inhibitor therapy.Gastroenterology. 1997; 112: 84-91Abstract Full Text PDF PubMed Scopus (35) Google Scholar on survival of patients with ZES, there have been no good long-term data on clinical outcome (healing and recurrence of acid-related symptoms, lesions, or complications), either with PPI or after gastrinoma surgery.9Norton J.A. Fraker D.L. Alexander H.R. et al.Surgery to cure the Zollinger-Ellison syndrome.N Engl J Med. 1999; 341: 635-644Crossref PubMed Scopus (437) Google Scholar As a follow-up to our initial reports,2Hirschowitz B. Mohnen J. Shaw S. Long-term treatment with lansoprazole of patients with duodenal ulcer and basal acid output of more than 15 mmol/h.Aliment Pharmacol Ther. 1996; 10: 497-506Crossref PubMed Scopus (18) Google Scholar, 14Hirschowitz B. Mohnen J. Shaw S. Long-term treatment with lansoprazole for patients with Zollinger-Ellison syndrome.Aliment Pharmacol Ther. 1996; 10: 507-522Crossref PubMed Scopus (45) Google Scholar we present an additional 9 years of observation with double the number of hypersecretor patients, 49 with gastrinoma (ZES) and 18 without, in an open label prospective study currently in its 14th year, describing the favorable clinical outcome of effective, individually optimized acid suppression with lansoprazole1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar in the long-term nonsurgical management of acid/peptic lesions in acid hypersecretors with and without gastrinoma. The premise that ZES treatment could be entirely medical15Hirschowitz B.I. Clinical course of nonsurgically treated Zollinger-Ellison syndrome.in: Mignon M. Jensen R.T. Endocrine tumors of the pancreas. Volume 23. S Karger AG, Basel, Switzerland1994: 360-371Google Scholar was examined critically in this study. Sixty-seven patients with basal acid hypersecretion1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar were recruited and gave written consent for inclusion in this institutional review board–approved protocol using lansoprazole. Acid hypersecretion was defined as BAO >15 mmol/h in patients without prior antrectomy (40 intact ZES and 18 non-ZES hypersecretors) or >5 mmol/h after antrectomy (n = 9, all ZES). ZES was diagnosed by fasting and secretin-stimulated serum gastrin levels and/or by histologic identification of a gastrinoma.1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar, 16Hirschowitz B.I. Haber M.M. Helicobacter pylori effects on gastritis, gastrin and enterochromaffin-like cells in Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome acid hypersecretors treated long-term with lansoprazole.Aliment Pharmacol Ther. 2001; 15: 87-103Crossref PubMed Scopus (41) Google Scholar Forty-six of these patients had been treated for 17 ± 3 months with omeprazole (median, 40 mg/day) before entering this study. Gastric analysis measuring basal and maximal pentagastrin-stimulated acid and pepsin secretion1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar, 2Hirschowitz B. Mohnen J. Shaw S. Long-term treatment with lansoprazole of patients with duodenal ulcer and basal acid output of more than 15 mmol/h.Aliment Pharmacol Ther. 1996; 10: 497-506Crossref PubMed Scopus (18) Google Scholar, 14Hirschowitz B. Mohnen J. Shaw S. Long-term treatment with lansoprazole for patients with Zollinger-Ellison syndrome.Aliment Pharmacol Ther. 1996; 10: 507-522Crossref PubMed Scopus (45) Google Scholar, 17Hirschowitz B.I. Groarke J. Vagal effects on acid and pepsin secretion and serum gastrin in duodenal ulcer and controls.Dig Dis Sci. 1993; 38: 1874-1884Crossref PubMed Scopus (23) Google Scholar, 18Hirschowitz B.I. 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Lippincott-Raven Publishers, Philadelphia1999: 9-31Google Scholar or <1 mmol/h post-antrectomy and contrary to the generally recommended 10 mmol/h.4O'Toole D. Mignon M. Ruszniewski P. The place of proton pump inhibitors in the management of the Zollinger-Ellison syndrome.in: Scarpignato C. Frontiers in gastroenterology proton pump inhibitors. Karger AG, Basel, Basel, Switzerland2004Google Scholar, 12Metz D.C. Benya R.V. Fishbeyn V.A. et al.Prospective study of the need for long-term antisecretory therapy in patients with Zollinger-Ellison syndrome following successful curative gastrinoma resection.Aliment Pharmacol Ther. 1993; 7: 247-257Crossref PubMed Scopus (29) Google Scholar, 13Weber H.C. Venzon D.J. Jensen R.T. et al.Studies on the interrelation between Zollinger-Ellison syndrome, Helicobacter pylori, and proton pump inhibitor therapy.Gastroenterology. 1997; 112: 84-91Abstract Full Text PDF PubMed Scopus (35) Google Scholar, 20Miller L.S. Vinayek R. Frucht H. et al.Reflux esophagitis in patients with Zollinger-Ellison syndrome.Gastroenterology. 1990; 98: 341-346Abstract Full Text PDF PubMed Google Scholar, 21Metz D.C. Strader D.B. Orbuch M. et al.Use of omeprazole in Zollinger-Ellison syndrome a prospective nine-year study of efficacy and safety.Aliment Pharmacol Ther. 1993; 7: 597-610Crossref PubMed Scopus (84) Google Scholar, 22Metz D.C. Pisegna J.R. Fishbeyn V.A. et al.Currently used doses of omeprazole in Zollinger-Ellison syndrome are too high.Gastroenterology. 1992; 103: 1498-1508PubMed Google Scholar, 23Maton P.N. Vinayek R. Frucht H. et al.Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome a prospective study.Gastroenterology. 1989; 97: 827-836Abstract PubMed Google Scholar, 24Frucht H. Maton P.N. Jensen R.T. Use of omeprazole in patients with Zollinger-Ellison syndrome.Dig Dis Sci. 1991; 36: 394-404Crossref PubMed Scopus (69) Google Scholar, 25Metz D.C. Pisegna J.R. Ringham G.L. et al.Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome.Dig Dis Sci. 1993; 38: 245-256Crossref PubMed Scopus (48) Google Scholar Optimal doses of lansoprazole in each patient were established in the first 3 weeks1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar and periodically adjusted as detailed before.1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar Patients were studied every 3 months for 1 year and then every 6 months with history, physical examination, endoscopy, and gastric biopsies,1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar, 16Hirschowitz B.I. Haber M.M. Helicobacter pylori effects on gastritis, gastrin and enterochromaffin-like cells in Zollinger-Ellison syndrome and non-Zollinger-Ellison syndrome acid hypersecretors treated long-term with lansoprazole.Aliment Pharmacol Ther. 2001; 15: 87-103Crossref PubMed Scopus (41) Google Scholar, 26Hirschowitz B.I. Simmons J. Mohnen J. Minor effects of Helicobacter pylori on gastric secretion and dose of lansoprazole during long-term treatment in ZE and non-ZE acid hypersecretors.Aliment Pharmacol Ther. 2002; 16: 303-313Crossref PubMed Scopus (5) Google Scholar gastric analysis,1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar, 17Hirschowitz B.I. Groarke J. Vagal effects on acid and pepsin secretion and serum gastrin in duodenal ulcer and controls.Dig Dis Sci. 1993; 38: 1874-1884Crossref PubMed Scopus (23) Google Scholar serum gastrin, and routine laboratory studies. Compliance was based on self-reporting and verified by pill counts. Unexpected increases in BAO suggested noncompliance. Patients were also seen and examined as necessary between scheduled visits for any significant symptoms or evidence of relapse. All patients were interviewed, examined, and underwent endoscopy by the same nurse (J.M.) and physician (B.I.H.) throughout the study. Esophageal manometry27Hirschowitz B.I. Simmons J.L. Johnson L.F. et al.Risk factors for esophagitis in extreme acid hypersecretors with and without Zollinger-Ellison syndrome.Clin Gastrol Hepatol. 2004; 2: 220-229Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar was performed in 46 of the patients during treatment. Twelve patients dropped out of the study for various reasons after 32 ± 15 months, mainly for other disabilities, relocation, dislike of procedures, and in 1 case because of pregnancy. Seven of these patients were followed outside the study without regular endoscopy or gastric analysis. Four deaths, none caused by ZES, among the dropouts are included in the 20 patients who died. The baseline data were analyzed with Fisher exact, Wilcoxon, and t tests. The appropriate univariate test, t test (paired and unpaired comparisons) or Wilcoxon signed rank test, and step-wise multivariate logistic regression was done with SAS (SAS Institute, Inc, Cary, NC) software. Means are expressed ± standard error of the mean. P value <.05 is considered significant. Intent-to-treat analysis was applied to include dropouts and cases with either high secretion or a relapse resulting from noncompliance. A history of aggressive acid/peptic disease was present in all 67 patients. Before diagnosis and treatment, 63 (94%) of the 67 patients had had endoscopically diagnosed duodenal ulcer (DU), 43 (64%) had grade 2 or worse esophagitis, and 39 of these 43 patients had a DU or jejunal ulcer (JU) as well (Table 1). There was a high rate of complications and symptoms (Table 1). Because the intact ZES and non-ZES patients had a very similar incidence of lesions and complications due to hypersecretion as previously reported,27Hirschowitz B.I. Simmons J.L. Johnson L.F. et al.Risk factors for esophagitis in extreme acid hypersecretors with and without Zollinger-Ellison syndrome.Clin Gastrol Hepatol. 2004; 2: 220-229Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar they were combined.Table 1Pre-entry HistoryAll intactZES antrectomyNumber of patients589 ZES: non-ZES40:189:0 Sex (M:F)41:174:5 Race (B:W)15:435:4 Age (y)43.6 ± 3.559.6 ± 4.1aP < .05.Symptoms Pain56 (97%)9 (100%) Heartburn With esophagitis28 (48%)3 (33%) No esophagitis9 (16%)1 (11%) Vomiting24 (41%)6 (67%) Diarrhea29 (50%)3 (33%) Weight loss 20–40 lb14 (24%)2 (22%) >40 lb8 (14%)3 (33%)Ulcer DU532bPost-antrectomy, B-I. JU17cPost-antrectomy, B-II. Bleed32 [19]d[] More than 1 episode.8 [4] Perforation5 [3]4 [4]Erosive esophagitis38 (66%)5 (56%) Grade 2231 Grade 3 or 4154 Stricture91Both esophagitis & ulcer345Other BMI26.3 ± 0.620.9 ± 1.8aP < .05. Hiatal hernia (positive:negative)33:253:6 H pylori H pylori eradicated before entry91 H pylori + at entry215Gastric secretion Gastrin (pg/mL) ZES737 ± 149645 ± 76 Non-ZES76 ± 12N/A BAO (mmol/h)28.2 ± 2.412.5 ± 2.3aP < .05. PAO (mmol/h)57.8 ± 3.025.8 ± 7.4aP < .05. BPO (pepsin units, 1000's/h)477 ± 45262 ± 62aP < .05. PPO (pepsin units, 1000's/h)911 ± 77447 ± 89aP < .05.Demographics, clinical presentation before treatment, and gastric secretion in 2 groups of hypersecretors with intact stomachs and 9 ZES patients who had antrectomy with or without vagotomy before surgery.a P < .05.b Post-antrectomy, B-I.c Post-antrectomy, B-II.d [] More than 1 episode. Open table in a new tab Demographics, clinical presentation before treatment, and gastric secretion in 2 groups of hypersecretors with intact stomachs and 9 ZES patients who had antrectomy with or without vagotomy before surgery. Nine ZES patients had undergone a partial gastrectomy for DU, and 5 of these underwent more than 1 operation, with presurgical and postsurgical recurrent bleeding in 7 of 9 and perforation in 3, one with a jejunocolonic fistula. All had active DUs (Billroth I [B-I]) or JUs (Billroth II [B-II]); 5 of 9 also had esophagitis (Table 1). Although clinically comparable to the intact patients, the patients who had undergone antrectomy were older, had significantly lower gastric secretions and body mass index (BMI), and had a worse outcome. Lansoprazole was given for 3–156 months, median 75 months, representing a total of 419 patient-years of treatment. Acid (and pepsin) output was controlled to target levels by lansoprazole in 64 of the 67 (96%) patients within 3 weeks after entry into the study.1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar Later, as previously described in detail,1Hirschowitz B.I. Simmons J. Mohnen J. Long-term lansoprazole control of gastric acid and pepsin secretion in ZE and non-ZE hypersecretors a prospective 10-year study.Aliment Pharmacol Ther. 2001; 15: 1795-1806Crossref PubMed Scopus (39) Google Scholar lansoprazole doses were further adjusted for optimal acid control in half the patients either for elevated BAO or for dose reduction for presumed excessive suppression. Individual optimal effective doses of lansoprazole varied from 15 mg every other day to 450 mg/day, median 75 mg/day. Symptoms cleared rapidly, and most patients soon regained lost weight. By 3 months after starting therapy all ulcers had healed, but 5 patients had unhealed esophagitis or residual esophageal stricture that eventually resolved within 3–14 months. Marked reduction in symptoms reflected the major reduction in disease. Forty-six (70%) of the patients reported no significant symptoms. The number of visits in which, on systematic questioning, patients reported 1 or more moderate or severe symptoms since the prior visit as a proportion of 1050 follow-up visits was pain, 7.4%; heartburn, 2.7%; vomiting, 3.3%, and diarrhea, 4.1%. (Figure 1A). However, there was poor correlation between symptoms and lesion relapse; 89% of heartburn reports were not associated with esophagitis relapses, and 86% of visits in which patients reported pain were unrelated to relapse of either ulcer or esophagitis (Table 2). In half of those with pain unrelated to ulcer or esophagitis, pain was related to other known gastrointestinal pathology such as gallstones, irritable bowel, pancreatitis, or cancer. Conversely, there were no symptoms associated with 21 of 28 (75%) episodes of ulcer and 18 of 25 (72%) episodes of esophagitis (Table 2), suggesting that the pain of ulcer or esophagitis, or heartburn, normally acid related, is absent because of low acid. In 6 symptomatic relapse episodes, patients used supplemental antacids.Table 2Relation Between Relapse and Symptoms in Hypersecretors Treated With Lansoprazole (1050 Return Visits)SymptomNo. of patientsNo. of visitsWith lesionsWith no lesionsUlcerEsophagitisVisits with symptoms Pain28787467aHalf these patients had other causes for pain. (86%) Heartburn18280325 (89%) Vomiting22371432 (86%) Diarrhea23432140 (93%) None469102218870 (96%)LesionNo. of patientsNo. of visitsPainHeartburnWithout symptomsVisits with lesions UlcerbFour patients in each group had both.12bFour patients in each group had both.287021 (75%) EsophagitisbFour patients in each group had both.12bFour patients in each group had both.257418 (72%)Note. Top, frequency of moderate or severe symptoms reported during 1050 return visits and their relation to lesion relapses. Bottom, frequency of lesion relapses and associated symptoms.a Half these patients had other causes for pain.b Four patients in each group had both. Open table in a new tab Note. Top, frequency of moderate or severe symptoms reported during 1050 return visits and their relation to lesion relapses. Bottom, frequency of lesion relapses and associated symptoms. Frequency, severity, and complications of acid/peptic disease manifestations were dramatically reduced by treatment. On lansoprazole, 47 (70%) of the 67 patients were stable without relapse or symptoms during a median period of 84 months. These comprised 76% of the 58 intact patients (33/40 [82%] ZES and 11/18 [61%] non-ZES) who had no relapses of ulcer or esophagitis after first healing with lansoprazole, but only 3 of 9 (33%, P < .03) antrectomized ZES patients were free of relapse (Figure 2). In the 20 patients who experienced relapse, 13 had a mild relapse and 7 had more complicated or multiple relapses (see below). During a period of 6.3 ± 0.5 years (median, 6.25 years), which includes the patients who experienced relapse, 20 patients (30% of all patients or 4.8%/y) had relapses either of ulcer (n = 8) or esophagitis, at least grade 2 (n = 8), or both ulcer and esophagitis, not necessarily concurrently (n = 4) (Figure 1B). Fourteen (24%) of the intact patients (7 ZES and 7 non-ZES) had 1 or more relapses, 14 of ulcer and 20 of esophagitis, for an annual rate of 3.9%. Time to first relapse of ulcer was 4–43 months (mean, 20.7 months), and for esophagitis it was 5–56 months (mean, 17 months). The 9 antrectomized ZES patients had a 3.6-fold higher rate of relapse than the unoperated ZES patients (67% [8.7%/y] vs 18% [2.4%/y], P < .01), with 5 of the 6 having 14 episodes of ulcer relapse with 7 episodes in 1 patient. Another of these patients had 4 relapses of esophagitis with stricture as well as a DU (Table 3). Mean time to first relapse in these 6 antrectomized patients was 23.5 months versus 20.1 months in intact patients.Table 3Complicated or Multiple RelapsesAt entryBefore treatmentRelapse during treatmentAge (y)SexOnset age (y)Esophagitis gradeUlcerBAOUlcera× no. of episodes.EsophagitisMonth of relapseH pyloriBAO at relapse (mmol/h)Follow-up after last lesion (mo)Non-ZES 122M19−DU15.5DU (×2)bBleed.−25, 31+0, 0DU (×2)bBleed.−37, 43−0.6, 7.6119ZES intact 245M412DUbBleed.1.5DU (× 3)bBleed.−4, 53, 73+0, 0.4, 4.7−+ (×3)12, 36, 53+0, 0.1, 0.4+91, 98−36, 0.122 334M314cEsophageal stricture.dBarrett's esophagus.DUbBleed.17.8DU−47−1.2−−cEsophageal stricture.0–14−0–2.4−+eEsophageal ulcer. (×2)18, 31−0−+cEsophageal stricture.42−9−−cEsophageal stricture.44–50−1.20 (died) 435M103JUbBleed.fPerforation.37.1JU (× 3)bBleed.fPerforation.−15, 20, 27−14.6, 0, 0−+5–11−27,3,8,7−+19–24−0gTotal gastrectomy.−−cEsophageal stricture.24–34−0gTotal gastrectomy.2 (died)ZES antrectomy 552, B-IIM37−DU→JUbBleed.8.3MU−43−0.8JUfPerforation.−52−Unknown0 (died) 659, B-IIF41−DUbBleed.→JUfPerforation.16.9MU−43−4.3JU (×6)−48, 85, 90−0–0.62099, 115, 1260–0.3 759, B-IM534bBleed.cEsophageal stricture.eEsophageal ulcer.DU→JUbBleed.15DU+cEsophageal stricture.dBarrett's esophagus.eEsophageal ulcer.8−1.9−+cEsophageal stricture.24–31−3.8+bBleed.47−0+651.29Note. Details of pretreatment status and relapses in 7 patients with multiple or complicated relapses.a × no. of episodes.b Bleed.c Esophageal stricture.d Barrett's esophagus.e Esophageal ulcer.f Perforation.g Total gastrectomy. Open table in a new tab Note. Details of pretreatment status and relapses in 7 patients with multiple or complicated relapses. Because some patients had more than 1 relapse, outcome might also be expressed as an annual rate of relapse episodes, counting all episodes regardless of multiple recurrences in some patients. Altogether there were 53 acid/peptic-related relapse episodes in these 20 patients, 28 of ulcer and 25 of esophagitis. Assuming that before treatment ulcers relapsed at least annually, if they healed at all, then by this measure, the ulcer attack rate fell more than 10-fold, from 94% to 6.7% per year, and esophagitis from 64% to 5.8% per year (P < .001). The rate of ulcer complications during treatment also fell steeply, bleeding to 1.2% per year and perforation to 0.5% per year (Figure 1, B). In 13 of the 20 patients relapses were mild; 10 patients had only a single relapse of ulcer (3 patients) or of esophagitis (7 patients), all of which healed rapidly. These 10 patients remained relapse-free up to the time of this analysis for another 3–89 months (mean, 40 months). Of the remaining three, 2 patients each had 2 relapses of ulcer that healed quickly with no further relapse for 27 and 72 months, respectively, on continuing treatment. One intact patient had one grade 1 and two grade 2 esophagitis relapses that healed rapidly, with
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