The interactions between Helicobacter pylori, acid, and

Transcription

1 GASTROENTEROLOGY 1999;116: EDITORIALS Helicobacter pylori, Acid, and Omeprazole Revisited: Bacterial Eradication and Rebound Hypersecretion See articles on pages 239 and 248. The interactions between Helicobacter pylori, acid, and drugs that suppress acid secretion remain of current interest. In the past 3 years, it has become clear that the bacterium is an acid-tolerant neutralophile with intracellular urease activity regulated by the extracellular ph. This mechanism allows the bacterium to survive even in the ph range between 4.0 and 2.5 by maintaining the periplasmic ph around 6. 1 Despite this ability to survive under strongly acidic conditions, the pattern of bacterial colonization quickly responds to changes in gastric acid secretion. If acid secretion is normal to high, bacterial colonization predominates in the antrum. However, if acid secretion is diminished, pangastric or corpuspredominant colonization patterns evolve in which the numbers of bacteria decrease in the antrum but remain the same in the corpus with the bacteria found closer to the mucosa and in the pits. This pattern is reversible if acid secretion is restored. 2 Effects of Acid and Omeprazole on H. pylori Suppressing acid production, for example by proton pump inhibitor therapy, has effects on the pattern of bacterial colonization but does not eradicate H. pylori even if the drug is continued for years. Nevertheless, acid suppression is part of most H. pylori eradication regimens. In a previous large international study, Lind et al. compared 5 omeprazole-based triple therapies using different combinations of amoxicillin, clarithromycin, and metronidazole. 3 The highest eradication rates were obtained with combinations of omeprazole with either amoxicillin and clarithromycin (OAC) or metronidazole and clarithromycin (OMC), which both led to an eradication success of approximately 95%. One of the strengths of this study was its size, allowing calculation of eradication rates within narrow confidence limits. Such studies are strongly needed in an era when many different regimens are still used for H. pylori eradication, when antibiotic resistance is increasingly common, and when indications for treatment may expand. 4 In this issue of GASTROENTEROLOGY, Lind et al. 5 examine whether omeprazole has any additional role in these two combinations of OMC and OAC, which is a logical follow-up to the MACH1 study. The authors are to be commended again to have completed such an elaborate and difficult international study. The eradication rate obtained with the OAC combination was similar to that of the MACH1, approximately 95%, whereas the success rate of the OMC combination (87%) was slightly lower than reported previously. This difference was in particular due to failure in patients with a preexistent metronidazole-resistant strain. The amoxicillin, 1000 mg, and clarithromycin, 500 mg (AC), and metronidazole, 400 mg, and clarithromycin, 250 mg (MC), combinations without omeprazole were found to be inadequate, with eradication rates of 26% and 69%, respectively. These results show that profound acid suppression is essential for the high eradication success of proton pump inhibitor triple therapy. This could in part be due to direct antibacterial effects of omeprazole but is more likely related to the creation of an intragastric ph at which the antibiotics are more effective. Omeprazole has a more pronounced effect on eradication rates when added to the AC combination than the MC combination, probably because metronidazole is the least sensitive of the three antibiotics to lower ph. The effectiveness of OMC therapy was seriously hampered by the presence of pretreatment metronidazole resistance, decreasing eradication success from 95% to 76%. The mechanism of such resistance has been elucidated recently and seems to be based on mutations of the rdxa gene. 6 The effect of pretreatment clarithromycin resistance appeared similar, although the number of patients with such strains was small. Clarithromycin resistance reduced the overall OAC and OMC success rates from 93% to 75%. If therapy failed with a metronidazole-containing regimen, secondary resistance to metronidazole was present in all but one case. Secondary resistance to clarithromycin was not that common after failed therapy. It only occurred in 8 (9%) of the 93 patients in whom MC or AC failed, probably because of lack of bacterial exposure to the rapidly disintegrating clarithromycin at low ph, and in 4 (33%) of 12 patients in whom OMC or OAC failed. The infrequent development of clarithromycin resistance is

2 480 EDITORIALS GASTROENTEROLOGY Vol. 116, No. 2 somewhat remarkable because previous studies have shown that such resistance is easily induced both in vitro and in vivo resulting from a single point mutation, usually A to G, at positions 2142 or 2143 of the 23S recombinant RNA gene. 7,8 The authors used the low cutoff value of 1 µg/ml for the definition of clarithromycin resistance instead of the often used 2 µg/ml, so that clarithromycin resistance was certainly not underestimated in this study and its occurrence was indeed infrequent. Interestingly, clarithromycin resistance developed in particular if the drug was combined with metronidazole and much less when combined with amoxicillin. This is in agreement with previous findings and may be related to the mechanism of action of metronidazole, inducing DNA breaks and thus being mutagenic. 9 No primary or secondary amoxicillin resistance was observed. It has long been assumed that H. pylori would not develop amoxicillin resistance because it was never observed in clinical isolates and could not be induced in vitro by repeated passage under subminimum inhibitory concentrations of this drug. However, stable amoxicillin resistance was recently reported for the first time in a patient who had received 12 courses of amoxicillin in 6 years for chronic obstructive pulmonary disease. 10 Because this resistance was based on a stable genetic feature that could be transferred to other strains by natural transformation, it might potentially spread and become more common in the future. The MACH2 study shows that omeprazole increases the eradication success of AC and MC combinations. The side effects of these combinations are fairly similar, with diarrhea more common in the amoxicillin-containing regimens but liver function test abnormalities more common with metronidazole. The efficacy of OMC is insufficient in patients with primary metronidazole resistance, which does not affect the effect of OAC. The numbers are too small to make reliable statements on the effect of primary clarithromycin resistance on the efficacy of both regimens. OAC did not fail in the 2 patients with primary clarithromycin resistance treated with this combination, whereas OMC failed in 2 of 6 patients. A recent combined analysis of 3 large U.S. studies using OAC for 10 days reported H. pylori eradication in only 4 (27%) of 15 patients with a preexistent clarithromycin strain. 11 Finally, secondary clarithromycin resistance is more common after OMC than after OAC. These data suggest that OAC should be preferred over OMC, especially in patients infected with a metronidazole-resistant strain, or if such information is lacking, in areas where this resistance is common. Would replacement of omeprazole by ranitidine bismuth citrate (RBC) benefit the treatment of patients with resistant strains? To our knowledge, 6 studies directly compared OAC with RBC-AC, 2 of which have appeared as full papers. 12,13 Both studies reported similar efficacies for both regimens. A few studies that examined the effect of primary antibiotic resistance on the efficacy of RBCbased triple therapies suggested that the dual mode of action of RBC may help to overcome antibiotic resistance. 14 A direct comparison of omeprazole and RBC triple therapies is therefore needed in patients colonized with H. pylori strains with a primary resistance against imidazoles or macrolides. For now, the alternative in these patients is 1-week quadruple therapy with a proton pump inhibitor twice a day, a bismuth compound four times a day, 500 mg tetracycline four times a day, and mg metronidazole three times a day, because this regimen may overcome metronidazole resistance. 15 Effects of H. pylori on Acid and Omeprazole Therapy H. pylori is not only influenced by acid but, conversely, also has effects on acid. In most patients with duodenal ulcer, as well as in a proportion of H. pylori positive nonulcer subjects, basal and stimulated acid secretion are increased. 16 This effect seems to be due to increased basal and stimulus-induced release of gastrin, which in the presence of an unaltered sensitivity to this hormone leads to increased acid secretion. 17 In the middle of the spectrum are subjects in whom antral gastritisinduced hypergastrinemia is counteracted by some degree of body gastritis impairing acid secretion. These subjects have little overall changes in acid secretion. On the other end of the spectrum are subjects in whom bacterial colonization induces acid hyposecretion. 18,19 This effect is strongly associated with the presence of corpus gastritis and can be caused by a combination of mechanisms. The latter include decreased gastrin response to reduced acid levels as a result of antral gland loss, direct inhibitory effects of H. pylori products such as the VacA and putative parietal cell inhibitory protein on the parietal cell, buffering of acid by bacterial urease activity, and parietal cell blocking by gastric autoantibodies or by cytokines, such as interleukin 1 and tumor necrosis factor impairing parietal cell function. Finally, the effect could also be due to a loss of body glands and specialized parietal cells as a result of the corpus gastritis. The acid-suppressive effect of corpus gastritis was already observed in the pre H. pylori era. 20 Recently, it was shown that this phenomenon is strongly associated with H. pylori colonization and that bacterial eradication leads to partial or complete restitution. 19,21 There is increasing evidence that the mechanism of acid suppres-

3 February 1999 EDITORIALS 481 sion by H. pylori, however small, may play a protective role against gastroesophageal reflux disease (GERD) in subjects with an insufficient lower esophageal sphincter; GERD patients are less often infected than healthy controls, in particular with caga strains that induce more severe gastritis and thus are supposed to have a larger effect on acid secretion. In addition, GERD patients who are colonized with H. pylori less often have serious long-term sequelae of this disease such as Barrett s esophagus and adenocarcinoma of the distal esophagus and proximal stomach. 22,23 The effect of H. pylori on intragastric acidity is not only present in subjects with corpus gastritis caused by atrophy or other causes but is also present if corpus gastritis occurs as a result of acid-suppressive drug treatment. H. pylori exaggerates the acid-suppressive effects of both H 2 -blockers and proton pump inhibitors. The 24-hour intragastric ph profile during treatment with these drugs is higher in H. pylori infected subjects than in noninfected subjects. 24 Bacterial eradication with resolution of corpus gastritis eliminates this effect, which is more pronounced during proton pump inhibitor treatment than during treatment with an H 2 -blocker. This is partially related to the negative log scale for ph, i.e., the closer the ph is to 7.0, the more pronounced is the effect of small changes in proton excretion on ph. However, it is likely to be also due to the more pronounced shift of H. pylori gastritis to a corpuspredominant type with the stronger proton pump inhibitors. Despite H. pylori mediated exaggeration of the effect of acid-suppressive drugs on intragastric ph, there is little evidence that this effect has any clinical relevance for the maintenance treatment of GERD with these drugs. H. pylori positive and negative GERD patients require the same dose of omeprazole during long-term maintenance treatment. 25,26 Both groups of GERD patients also have the same esophageal acid exposure during treatment with either ranitidine or omeprazole 27 and have very similar rates of recurrence of symptoms and esophagitis. 26 In addition, H. pylori colonization also has a very limited effect on healing rates of esophagitis during acid-suppressive therapy. In a very large study, German investigators observed a less than 5% difference in esophagitis healing rates and no differences in GERD symptoms between infected and noninfected patients treated with pantoprazole, 40 mg once daily for 8 weeks. 28 The previous studies compared groups of patients in whom the H. pylori status was not changed during follow-up; there is a need for randomized studies into the effect of bacterial eradication on GERD symptoms and relapse. There is little evidence that proton pump inhibitor maintenance therapy should be titrated dependent on H. pylori status. In this issue of GASTROENTEROLOGY, Gillen et al. 29 address a very interesting and important new subject related to the discussion on H. pylori and proton pump inhibitors: effect of H. pylori on rebound hypersecretion after withdrawal of omeprazole. The prevalence of GERD is high and increasing in Western societies, probably in part because of decreasing prevalence of H. pylori. Proton pump inhibitors are very effective and first choice for the treatment of GERD. A recent large survey of 40,000 subjects in the Amsterdam region found that 1% of that population used maintenance treatment with proton pump inhibitors, i.e., had used such a drug for at least 3 months in the previous year. 30 This wide use is also related to the difficulties to withdraw therapy. It was thought that this was largely due to the chronicity of GERD and the high efficacy of these drugs. However, another phenomenon, rebound hypersecretion, might also play an important role. Rebound hypersecretion of acid had been described after withdrawal of H 2 -blocker therapy, 31 but was thought not to occur after proton pump inhibitor therapy. However, it was recently also reported after withdrawal of proton pump inhibitor therapy. 32 Gillen et al. confirm this earlier observation and show that at day 15 after omeprazole, rebound hypersecretion in particular occurs in H. pylori negative patients. In these patients, basal acid output had increased by 82% and maximal acid output by 28% compared with before omeprazole. In contrast, in H. pylori positive subjects, basal acid output decreased by 32% and maximal acid output increased by 42% with large interindividual variation. Although the changes in basal acid output differed significantly for H. pylori positive and negative patients, the changes in maximal acid output were not significantly different. Gillen et al. suggest that the underlying mechanism is that of hypergastrinemia-induced hyperplasia of ECL and parietal cells. Parietal cell hypertrophy and hyperplasia has been described in patients undergoing long-term omeprazole therapy. 33 It occurs early in treatment and to the same extent in H. pylori positive and negative patients, 34 despite higher gastrin levels in H. pylori positive patients during omeprazole therapy. The absence of rebound increased basal output in H. pylori positive patients could be due to persistent corpus gastritis. Unfortunately, no gastric histology was obtained in these patients to support the mechanistic hypotheses. These interesting and important observations are likely to have clinical relevance. Rebound hypersecretion

4 482 EDITORIALS GASTROENTEROLOGY Vol. 116, No. 2 might play an important role in the difficulty to withdraw therapy, to which H. pylori negative patients might be more addicted than H. pylori positive patients. It should be noted that corpus gastritis in H. pylori positive patients quickly resolves after withdrawal of omeprazole. 2 It is unknown how long it takes for parietal cell hyperplasia to resolve; H. pylori positive patients might therefore also develop rebound hypersecretion later after withdrawal of therapy. As the investigators remark, further studies are needed at different posttherapy time points. Whether the magnitude of a rebound effect depends on the length of therapy also needs to be studied. It has been suggested that parietal cell hyperplasia increases with time. 33 However, we observed parietal cell hyperplasia in 70% of omeprazole-treated patients after 3 months of therapy with little further change after 12 months. 34 If rebound hypersecretion impairs withdrawal of therapy, further questions arise with respect to approaches of individual patients and adequate treatment withdrawal schemes. Finally, nocturnal breakthrough can occur during proton pump inhibitor therapy. 35 The mechanisms described also may play a role in this latter phenomenon, leading to more common nocturnal breakthrough H. pylori negative patients. In conclusion, this issue of GASTROENTEROLOGY contains two important further contributions to the topic of H. pylori, acid, and omeprazole. The MACH2 study shows that omeprazole contributes importantly to efficacy of the combinations of amoxicillin and clarithromycin or metronidazole and clarithromycin in eradicating H. pylori. The study confirms the high eradication rates with these combinations shown previously by the MACH1 study and others. This efficacy is especially important in patients with strains that are sensitive to the antibiotics used. For resistant strains, RBC-based triple therapy or alternatively quadruple therapy may be more effective, although direct comparisons are lacking. The study by Gillen et al. makes clinicians aware that rebound hypersecretion occurs after withdrawal of omeprazole. The phenomenon might be more important in H. pylori negative patients, although it is not excluded that it will occur in H. pylori positive patients as well at a later stage after stopping treatment. These observations raise many questions for further research and may in the soon change our policies on withdrawal of acid-suppressive treatment in GERD. E. J. KUIPERS E. C. KLINKENBERG KNOL Department of Gastroenterology Free University Hospital Amsterdam, The Netherlands References 1. Rektorschek M, Weeks D, Sachs G, Melchers K. Influence of ph on metabolism and urease activity of Helicobacter pylori. Gastroenterology 1998;115: Solcia E, Villani I, Fiocca R, Luinetti O, Boldorini R, Trespi E, Perego M, Alvisi C, Lazzaroni M, Bianchi Porro G. Effects of eradication of Helicobacter pylori on gastritis in duodenal ulcer patients. Scand J Gastroenterol 1994;29(suppl 201): Lind T, Veldhuyzen van Zanten SJO, Unge P, Spiller R, Bayerdörffer E, O Morain C, Bardhan KD, Bradette M, Chiba N, Wrangstadh M, Cederberg C, Idström JP. The MACH-1 study optimal one-week treatment for H. pylori defined? Helicobacter 1996;1: McColl KEL, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wirz A, Kelman A, Penny C, Knill-Jones R, Hilditch T. Symptomatic benefit from eradicating Helicobacter pylori infection in non-ulcer dyspepsia. N Engl J Med 1998;339: Lind T, Mégraud F, Unge P, Bayerdörffer E, O Morain C, Spiller R, Veldhuyzen van Zanten SJO, Bardhan KD, Hellblom M, Wrangstadh M, Zeijlon L, Cederberg C. The MACH2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology 1999;116: Goodwin A, Kersulyte D, Sisson G, Veldhuyzen van Zanten SJO, Berg DE, Hoffman PS. Metronidazole resistance in Helicobacter pylori is due to null mutations in a gene (rdxa) that encodes an oxygenintensive NADPH nitroreductase. Mol Microbiol 1998;28: Debets-Ossenkopp YJ, Sparius M, Kusters JG, Kolkman JJ, Vandenbroucke-Grauls CMJE. Mechanism of clarithromycin resistance in clinical isolates of Helicobacter pylori. FEMS Microbiol Lett 1996;142: Debets-Ossenkopp YJ, Brinkman AB, Kuipers EJ, Vandenbroucke- Grauls CMJE, Kusters JG. Explaining the bias in the 23S rrna gene mutations associated with clarithromycin resistance in clinical isolates of Helicobacter pylori. Antimicrob Agents Chemother 1998;42: Buckley MJ, Xia HX, Hyde DM, Keane CT, O Morain CA. Metronidazole resistance reduces efficacy of triple therapy and leads to secondary clarithromycin resistance. Dig Dis Sci 1997;42: van Zwet AA, Vandenbroucke-Grauls CMJE, Thijs JC, van der Wouden EJ, Gerrits MM, Kusters JG. Stable amoxycillin resistance in Helicobacter pylori. Lancet 1998;352: Laine L, Suchower L, Frantz J, Connors A, Neil G. Twice-daily, 10-day triple therapy with omeprazole, amoxycillin, and clarithromycin for Helicobacter pylori eradication in duodenal ulcer disease: results of three multicenter, double-blind, United States trials. Am J Gastroenterol 1998;93: Catalaro F, Catanzaro R, Bentivegna C, Brogna A, Condorelli G, Cipolla R. Ranitidine bismuth citrate versus omeprazole triple therapy for the eradication of Helicobacter pylori and healing of duodenal ulcer. Aliment Pharmacol Ther 1998;12: Sung JY, Leung WK, Ling TKW, Yung MJ, Chan FKL, Lee YT, Cheng AFB, Chung SCS. One-week ranitidine bismuth citrate (RBC) triple therapy versus proton-pump inhibitor (PPI) triple therapy for the treatment of H. pylori associated duodenal ulcers. Aliment Pharmacol Ther 1998;12: van der Wouden EJ, Thijs JC, van Zwet AA, Kooy A, Kleibeuker JH. One week triple therapy with ranitidine bismuth citrate, clarithromycin and metronidazole versus two-week dual therapy with ranitidine bismuth citrate and clarithromycin for Helicobacter pylori: a randomized clinical trial. Am J Gastroenterol 1998;93: de Boer W, Driessen W, Jansz A, Tytgat GNJ. Effect of acid suppression on efficacy of treatment for Helicobacter pylori infection. Lancet 1995;345: El-Omar E, Penman I, Ardill JES, McColl KEL. A substantial proportion of non-ulcer dyspepsia patients have the same abnor-

5 February 1999 EDITORIALS 483 mality of acid secretion as duodenal ulcer patients. Gut 1995;36: Gillen D, M. E-OE, Wirtz AA, Ardill JES, McColl KEL. The acid response to gastrin distinguishes duodenal ulcer patients from Helicobacter pylori infected healthy subjects. Gastroenterology 1998;114: Gutierrez O, Melo M, Segura AM, Angel A, Genta RM, Graham DY. Cure of Helicobacter pylori infection improves gastric acid secretion in patients with corpus gastritis. Scand J Gastroenterol 1997;32: Ruiz B, Correa P, Fontham ETH, Ramakrishnan T. Antral atrophy, Helicobacter pylori colonization, and gastric ph. Am J Clin Pathol 1996;105: Rohrer GV, Welsh JD. Correlative study: gastric secretion and histology. Gastroenterology 1967;52: El-Omar EM, Oien K, El-Nujumi A, Gillen D, Wirz A, Dahill S, Williams C, Ardill JES, McColl KEL. Helicobacter pylori infection and chronic acid hyposecretion. Gastroenterology 1997;113: Blaser MJ. Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modern era. Gut 1998;43: Richter JE, Falk GW, Vaezi MF. Helicobacter pylori and gastroesophageal reflux disease: the bug may not all be bad. Am J Gastroenterol 1998;10: Verdú E, Armstrong D, Fraser R, Viani F, Idström J-P, Cederberg C, Blum AL. Effect of H. pylori status on intragastric ph during treatment with omeprazole. Gut 1995;36: Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, Eskes SA, Meuwissen SGM. H. pylori and the efficacy of omeprazole for gastroesophageal reflux disease. Am J Gastroenterol 1999 (in press). 26. Klinkenberg-Knol EC. Eleven years experience of continuous maintenance treatment with omeprazole in GERD patients (abstr). Gastroenterology 1998;114:A Peters FTM, Kuipers EJ, Ganesh S, Sluiter WJ, Klinkenberg-Knol EC, Lamers CBHW, Kleibeuker JH. Helicobacter pylori and esophageal acid exposure in GERD (abstr). Gastroenterology 1998;114:A Holtmann G, Cain C, Malfertheiner P. Helicobacter pylori accelerates healing of reflux esophagitis during treatment with the proton pump inhibitor pantoprazole (abstr). Gastroenterology 1998;114:A Gillen D, Wirz AA, Ardill JE, McColl KEL. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999;116: Hurenkamp GJB, Grundmeyer HGLM, Bindels PJE, Tytgat GNJ, van der Hulst RWM. A population-based inventarisation of longterm acid suppressant use in 24 general practices in the Netherlands. Digestion 1998;59(suppl 3): Fullarton GM, McLaughlan G, MacDonald A, et al. Rebound nocturnal hypersecretion after four weeks treatment with an H 2 receptor antagonist. Gut 1989;30: Waldum HL, Arnestad JS, Brenna E, Eide I, Syversen U, Sandvik AK. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut 1996;29: Driman DK, Wright C, Tougas G, Riddell RH. Omeprazole produces parietal cell hypertrophy and hyperplasia in humans. Dig Dis Sci 1996;41: Cats A, Bloemena E, Schenk BE, Lindeman J, Klinkenberg-Knol EC, Meuwissen SGM, Kuipers EJ. Parietal cell protrusion (PCP) and fundic gland cysts (FGC) in GERD in relation to omeprazole and H. pylori (abstr). Gastroenterology (submitted). 35. Katz PO, Anderson C, Khoury R, Castell DO. Gastro-oesophageal reflux associated with nocturnal breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998;12: Address requests for reprints to: E. J. Kuipers, M.D., Ph.D., Department of Gastroenterology, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. kuipers@azvu.nl; fax: (31) by the American Gastroenterological Association /99/$10.00 p16 INK4 : Involvement Early and Often in Gastrointestinal Malignancies See article on page 394. In this issue, Matsuda et al. report that p16 INK4 is inactivated by extensive CpG methylation in human hepatocellular carcinoma. 1 The authors first examined expression of p16 INK4 protein in 60 hepatocellular carcinomas and found complete loss in nearly 50% of these primary tumors. Similar rates of protein loss have been reported in hepatocellular carcinoma, 2 but the mechanism for the loss of expression in this tumor type has not been directly shown. Homozygous deletion and point mutation were excluded as the primary mechanism. Although four somatic sequence changes were detected, none of these would be expected to result in loss of protein, confirming other previously negative data for p16 INK4 inactivation. However, hypermethylation of the CpG island of p16 INK4 was found in most tumors completely lacking p16 INK4 protein and a high fraction of those with diminished p16 INK4 expression. p16 INK4 methylation was specific for the tumors and not observed in normal liver or benign hepatic diseases. This epigenetic change has been found in a number of tumor suppressor genes in recent years as an alternative mechanism for loss of function. We can now add hepatocellular cancer to the growing number of tumor types in which p16 INK4 hypermethylation has been found. However, more than just extending initial studies 3 5 of this event to another malignancy, this report raises some interesting points concerning the relationship of p16 INK4 methylation to tumorigenesis in