1233
335
MEDICAL SCIENCE
Cure of duodenal ulcer associated with eradication of Helicobacter pylori
50 patients with intractable duodenal ulcer were randomly assigned to 4 weeks of treatment with colloidal bismuth subcitrate (CBS) alone (26 patients) or with amoxicillin and metronidazole (24 patients). 5 patients (all on triple therapy) withdrew because of side-effects. In 17 of the 45 patients who completed the treatment, Helicobacter pylori was eradicated, and there was no ulcer relapse during the first 12 months of follow-up. The ulcer relapse rate was significantly higher (17 of 21 [89%]) among patients who remained positive for H pylori. 9 patients who remained positive for H pylori and had ulcer relapses within 6 months of treatment with CBS alone, were subsequently given triple therapy. 7 of the 9 showed H pylori eradication and no relapses within the next 12 months. The 2 patients still H pylori-positive after triple therapy had further ulcer relapses. H pylori eradication, without altering acid output, will become the mainstay of duodenal ulcer treatment because it cures the disease.
Introduction
suppression for 4-8 weeks heals most duodenal ulcers,l,2 but 70-80% of healed ulcers relapse within the next year.3A Continuous low-dose maintenance therapy with Hz-receptor antagonists reduces the relapse rate,5,6 but it is expensive and there are problems with patient compliance and breakthrough ulcers. Hz-receptor antagonists heal ulcers, but do not reverse the tendency for ulcers to form. 7,8 The reasons why the rate of duodenal ulcer relapse is lower after healing with colloidal bismuth subcitrate (CBS) than after healing with Hz-receptor
Acid
clear. The identification of Helicobacter pylorz"13 and its associations with chronic and chronic active gastritis14 led to the hypothesis that it has a
antagonists9--12
are
not
pathogenetic role in the overall tendency to ulcer formation, because it causes inflammation. The links between H pylori and gastritis, and between gastritis and duodenal ulcer, led to treatment aimed at eradicating the microorganism. Five studiesl5-19 have shown that eradication of H pylori, by means of CBS or antibiotics, significantly lowers the 1-year ulcer relapse rate. It is not yet clear whether the lower relapse rate is directly related to the eradication of H pylori, to CBS-induced stimulation of prostaglandin production,2O or to an effect of bismuth accumulation in the body during long-term CBS treatment and its slow release.1O,21 Our prospective randomised study aimed to determine which of these theories was correct.
Patients and methods We chose
patients who had breakthrough ulcers on maintenance H,-receptor antagonists or who had had more than two ulcer relapses within 1 year. Most of the latter were non-compliant on, or had refused, maintenance therapy. All patients were H pylori positive. They were randomised in an open study to treatment with CBS, 1 tablet four times daily for 28 days (26 patients) or with CBS (same dose) plus amoxicillin 375 mg three times daily for 28 days and metronidazole 500 mg three times daily from day 18 to day 28 (24 patients). All the patients continued on ranitidine 150 mg after the trial period for a further 28 days, until their first control endoscopy in week 8. No antacids were prescribed, and no further maintenance therapy was given. 9 patients who relapsed after treatment with CBS alone and who were still H pylori positive were then given the CBS-antibiotic combination.
Endoscopy was repeated 1, 3, 6, and 12 months after treatment stopped, or if symptoms recurred. We excluded from the trial patients who needed emergency endoscopy, who had previously had gastric sugery or malignant
was
ADDRESS: Department of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands (E A. J. Rauws, MD, G N. J Tytgat, MD) Correspondence to Dr E A J Rauws
1234
DUODENAL ULCER HEALING AND RELAPSE RATES
*5 patients dropped out owing to side-effects. t6 by 3 months, 3 by 6 months (9 subsequently given
triple therapy), 7 by 12 months.
tBy6months
disorders, or who had taken steroids, non-steroidal antiinflammatory drugs, antibiotics, anticoagulants, or any of the drugs
study during the previous 4 weeks. Upper gastrointestinal endoscopy was done after the patient had fasted overnight. Four antral mucosal biopsy samples were taken with sterilised biopsy forceps (FB-26N, Olympus, Lake Success, New York, USA) from the lesser or greater curvature, 2 cm from the pylorus, from intact mucosa distant from any focal lesion, such as an ulcer or erosion. Two specimens were placed in 2 ml phosphate-buffered saline at 4°C for bacteriological examination, and two were fixed in 10% formalin for histopathology. The endoscopes (Olympus GIF Q10) were cleaned with detergent,
following 12 months, whereas 17 of the 21 patients who were positive for H pylori 1 month after stopping treatment had endoscopically confirmed duodenal ulcer relapse during that time. The difference in relapse rates between the groups positive and negative for H pylori was significant (p < 0-001). 9 patients initially given CBS alone, who had persistent H pylori and ulcer relapses, were subsequently given triple therapy. The ulcers were healed in all 9 a month after that treatment. In 7 of the 9, the triple therapy eradicated H pylori and there was no further gastritis or ulcer recurrence in the next 12 months. The 2 patients who remained positive for H pylori after triple therapy relapsed within 6 months.
under
disinfected with 70% ethanol, and rinsed with sterile water after each examination. Within 4 h of biopsy one culture of Colombia agar (Oxoid Ltd, London, UK) supplemented with horse blood (5 % by volume) and one of blood agar no 2 (Oxoid, containing horse blood and Skirrow selective supplement) were inoculated by rubbing the surface with one biopsy sample. All agars were incubated microaerobically at 35°C (Campy Pak; BBL Microbiology Systems, Cockeysville, Maryland, USA) for 7 days. Cultures were considered positive for H pylori if one or more colonies of gram-negative, oxidase-positive, catalase-positive, and urease-positive spiral or curved rods grew.22,23 The bacteriologist was unaware of the histology, the endoscopic findings, or the treatment regimen. Formalin-fixed biopsy samples were embedded in paraffin and 4 um sections were stained with haematoxylin and eosin. The presence, type, density, and location of the inflammatory infiltrate were assessed.24 The chi-square test was used for statistical analysis.
Results 66 subjects entered the study. 11 patients were withdrawn because they failed to attend follow-up appointments. 5 others were excluded after entry: 3 used Hz-receptor antagonists; 1 had a myocardial infarction; and in 1 sigmoid carcinoma developed. A further 5 patients (all on triple therapy) dropped out because of side-effects: 3 had nausea,1 diarrhoea, and 1 a rash. Their results were excluded from the analysis. Thus, 45 patients completed their treatment, and the ulcer had healed in 38, who were evaluated over the planned follow-up period of 12 months. Before treatment, all subjects with active duodenal ulcer had active chronic gastritis (neutrophil infiltration with chronic gastritis). At endoscopy 1 month after the study treatment period the ulcers had healed in 21 of the 26 (81 %) patients who completed treatment with CBS alone and in 17 of the 19 (89%) patients who completed the triple therapy regimen (see table). At that time histological and bacteriological examinations failed to find H pylori in 17 patients, 15 of whom had received triple therapy (table). As previously reported,24 the eradication of H pylori coincided with the disappearance of the inflammatory changes of the
gastric mucosa. There was no endoscopic evidence of ulcer relapse in any of the 17 patients who remained H pylori negative over the
Discussion
Hz-receptor antagonists for a year lower ulcer relapse rate than significantly produces does not the natural history of the but change placebo,s,6 disease. The relapse rate after stopping maintenance therapy is the same as that after initial ulcer healing not followed by maintenance therapy. 7,8 Maintenance with a
Extensive research has not found the cause of duodenal ulcer or its relapse. The isolation and culture of77)y/on and its association with gastritis led to the hypothesis that it may be the cause of the gastroduodenal inflammation and of duodenal ulcerp,14 H pylori meets Koch’s postulates for gastritis,2s6 but not for duodenal ulcer. The proof would involve prospective study of many H pylori-colonised subjects to await the development of an ulcer. The alternative approach is to eradicate H pylori from patients with duodenal ulcer and to study its relation with the expected ulcer relapse rate. In our study, both groups received the same dose of bismuth. However, the rate of H pylori eradication was lower with CBS alone than with the combination with amoxicillin and metronidazole. The dramatic reduction in relapse rate was solely associated with H pylori eradication. When H pylori was eradicated, duodenal ulcer relapse did not occur for at least 12 months: without such eradication, the duodenal ulcer relapse rate was as high as previously. In 7 of 9 patients who relapsed after CBS monotherapy and who were H pylori positive until they received the triple therapy, the effective eradication of the organism was followed by no further ulcer relapse over the next 12 months. This study does not prove that H pylori is the cause of duodenal ulcer disease. It does, however, strongly support a dominant role for H pylori in ulcer recurrence. Eradication of H pylori, and not the prolonged action of CBS after absorption, explains the lower ulcer relapse rate after CBS, with or without antibiotics, than after Hz-receptor
antagonists. We thank Dr M. L. Langenberg (Department of Microbiology) for carrying out the bacteriological cultures.
REFERENCES 1. Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987; 28: 1120-27. 2. McIsaac RL, McCanless I, Summers K, Wood JR. Ranitidine and cimetidine in the healing of duodenal ulcer: meta-analysis of comparative clinical trials. Aliment Pharmacol Therap 1987; 1: 369-81. 3. Wormsley KG. Relapse of duodenal ulcer. Br Med J 1986; 293: 1501. 4. Boyd EJS, Wilson JA, Wormsley KG. Recurrent ulcer disease. In: Misiewicz JJ, Wood JR, eds. Ranitidine: therapeutic advances. Amsterdam: Excerpta Medica, 1984: 14-42.
1235
Gough KR, Bardhan KD, Crowe JR, et al. Ranitidine and cimetidine in prevention of duodenal ulcer relapse. Lancet 1984; i: 659-62. 6. Silvis SE. Final report on the United States Multicentre Trial comparing ranitidine to cimetidine as maintenance therapy following healing of duodenal ulcer. J Clin Gastroenterol 1985; 7: 482-87. 7. Gudmand Hoyer E, Jensen BK, Kray E, et al. Prophylactic effect of cimetidine on duodenal ulcer disease. Br Med J 1978; i: 1095-97. 8. Bardhan K, Cole DS, Hawkins BW, Franks CR. Does treatment with cimetidine extended beyond initial healing of duodenal ulcer reduce the subsequent relapse rate? Br Med J 1982; 284: 621-23. 9. Martin DF, Way SJ, Tweedle DEF, Hollanders D, Ravenscroft MM, Miller JP. Difference in relapse rates of duodenal ulcer after healing with cimetidine or tripotassium dicitrate bismuthate. Lancet 1981; i: 5.
7-10. 10. Hamilton I, O’Connor HJ, Wood NC, Bradbury I, Axon ATR. Healing and recurrence of duodenal ulcer after treatment with tripotassium citrato bismuthate (TBD) tablets or cimetidine. Gut 1986; 27: 106-10. 11. Lane MR, Lee SP. Recurrence of duodenal ulcer after medical treatment. Lancet 1988; i: 1147-49. 12. Chiverton SG, Hunt RH. Initial therapy and relapse of duodenal ulcer: possible and secretory mechanisms. Gastroenterology 1989; 96: 632-39. 13. Marshall BJ, Royce H, Annear DI, et al. Original isolation of Campylobacter pyloridis from human gastric mucosa. Microbios Lett 1984; 25: 83-88. 14. Marshall BJ, Warren JR, Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; i: 1311-15. 15. Coghlan JG, Gilligan D, Humphries H, et al. Campylobacter pylori and recurrence of duodenal ulcers—a 12 month follow-up study. Lancet 1987; ii: 1109-11. 16. Lambert JR, Borremeo M, Korman MG, Hansky J, Eaves ER. Effect of colloidal bismuth (De-Nol) and healing relapse of duodenal ulcer-role
Effect of
a
22.
23.
24.
25.
26.
accumulates in the body during treatment with tripotassium dicitrato bismuthate. Aliment Pharmacol Therap 1989; 3: 21-28. Cowan ST. Cowan and Steele’s manual for the identification of medical bacteria, 2nd ed. Cambridge: Cambridge University Press, 1974: 22-41. Langenberg ML, Tytgat GNJ, Schipper MEI, Rietra PJGM, Zanen HC. Campylobacter-like organisms in the stomach of patients and healthy individuals. Lancet 1984; i: 1348. Rauws EAJ, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GNJ. Campylobacter-pyloridis-associated chronic active antral gastritis. Gastroenterology 1988; 94: 33-40. Marshall BJ, Amstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulates for pyloric campylobacter. Med J Aust 1985; 142: 436-39. Morris A, Nicholson G. Ingestion of Campylobater pyloridis causes gastritis and raised fasting gastric pH. Am J Gastroenterol 1987; 82: 192-99.
Scandinavian-style boiled coffee, which
cholesterol
raises
cholesterol, was found to contain more lipid material than drip filter coffee, which does not.
serum
Ten volunteers consumed a lipid-enriched fraction from boiled coffee for six weeks: the supplement provided 77 g of water, 1·3 g of lipid, and 1·6 g of other solids per day. Serum cholesterol rose in every subject; the mean rise was 0·74 mmol/l after three weeks (range - 0·09 to 1·48 mmol/l) and 1 ·06 SD 0·37 mmol/l or 23% after six weeks (range 0·48 to 1·52 mmol/l). The increase was mainly due to low-density-lipoprotein cholesterol, which rose by 29%, but very-low-density lipoprotein cholesterol was also raised, as evidenced by a 55% rise in triglycerides. High-density-lipoprotein After cholesterol was unchanged. supplementation had ended, lipid levels returned to baseline. Boiled coffee thus contains a lipid that powerfully raises serum cholesterol.
Introduction Scandinavians have traditionally made their coffee by coffee beans and
(abstr). 19. Marshall BJ, Goodwm CS, Warren JR, et al. Prospective double-blind trial of duodenal relapse after eradication of Campylobacter pylori. Lancet 1988; ii: 1437-42. 20. Konturek SJ, Radecki T, Piastucki I, et al. Studies on the gastroprotective and ulcer-healing effects of colloidal bismuth subcitrate. Digestion 1987; 37 (suppl): 8-15. 21. Gavey CJ, Szeto ML, Nwokolo CU, Sercombe J, Pounder RE. Bismuth
lipid-rich fraction from boiled coffee on serum
boiling ground
of Campylobacter pyloridis. Gastroenterology 1987; 92: 1489 (abstr). Borody TJ, Cole P, Noonan S, et al. Long term Campylobacter pylori recurrence post-eradication. Gastroenterology 1988; 94: 43 (abstr). 18. Smith AC, Price AB, Borriello P, Levi AJ. A comparison of ranitidine and tripotassium dicitrato-bismuth (TDB) in relapse rate of duodenal ulcer. The role of Campylobacter pylori. Gastroenterology 1988; 94: 431
17.
water
in
a
saucepan, and
decanting the fluid into a cup. In 1983, a study from Norway showed a strongly significant relation between the amount of coffee ingested and serum total cholestero1.1 Recently it was found that this association is specifically due to boiled coffee.2 Controlled experiments3A showed that abstaining from boiled coffee caused large decreases in serum cholesterol in and in volunteers3 healthy hypercholesterolaemic men.4 In a Finnish trials volunteers showed a rise in cholesterol of 0-64 mmol/1 after four weeks of consumption of 8 cups of boiled coffee per day but a fall after consumption of regular drip filter coffee or tea. A similar cholesterol-raising effect of boiled but not of drip coffee was found in a Dutch experiment.6 A switch from boiled to drip coffee consumption is believed to have contributed to the fall in serum cholesterol and coronary heart disease observed in Finland in the past 20 years.z However, it is totally unclear why boiled coffee should cause hypercholesterolaemia. Nor do we know to what extent other types of coffee such as Turkish, Greek, or espresso ADDRESS. Department of Human Nutrition, Agricultural University, Bomenweg 2, 6703 HD Wageningen, The Netherlands (P L Zock, MSc, Prof M B Katan, PhD, M P Merkus, M. van
Dusseldorp, MSc, J. L. Harryvan). Correspondence
Katan
to
Prof M. B.
335
MEDICAL SCIENCE
Cure of duodenal ulcer associated with eradication of Helicobacter pylori
50 patients with intractable duodenal ulcer were randomly assigned to 4 weeks of treatment with colloidal bismuth subcitrate (CBS) alone (26 patients) or with amoxicillin and metronidazole (24 patients). 5 patients (all on triple therapy) withdrew because of side-effects. In 17 of the 45 patients who completed the treatment, Helicobacter pylori was eradicated, and there was no ulcer relapse during the first 12 months of follow-up. The ulcer relapse rate was significantly higher (17 of 21 [89%]) among patients who remained positive for H pylori. 9 patients who remained positive for H pylori and had ulcer relapses within 6 months of treatment with CBS alone, were subsequently given triple therapy. 7 of the 9 showed H pylori eradication and no relapses within the next 12 months. The 2 patients still H pylori-positive after triple therapy had further ulcer relapses. H pylori eradication, without altering acid output, will become the mainstay of duodenal ulcer treatment because it cures the disease.
Introduction
suppression for 4-8 weeks heals most duodenal ulcers,l,2 but 70-80% of healed ulcers relapse within the next year.3A Continuous low-dose maintenance therapy with Hz-receptor antagonists reduces the relapse rate,5,6 but it is expensive and there are problems with patient compliance and breakthrough ulcers. Hz-receptor antagonists heal ulcers, but do not reverse the tendency for ulcers to form. 7,8 The reasons why the rate of duodenal ulcer relapse is lower after healing with colloidal bismuth subcitrate (CBS) than after healing with Hz-receptor
Acid
clear. The identification of Helicobacter pylorz"13 and its associations with chronic and chronic active gastritis14 led to the hypothesis that it has a
antagonists9--12
are
not
pathogenetic role in the overall tendency to ulcer formation, because it causes inflammation. The links between H pylori and gastritis, and between gastritis and duodenal ulcer, led to treatment aimed at eradicating the microorganism. Five studiesl5-19 have shown that eradication of H pylori, by means of CBS or antibiotics, significantly lowers the 1-year ulcer relapse rate. It is not yet clear whether the lower relapse rate is directly related to the eradication of H pylori, to CBS-induced stimulation of prostaglandin production,2O or to an effect of bismuth accumulation in the body during long-term CBS treatment and its slow release.1O,21 Our prospective randomised study aimed to determine which of these theories was correct.
Patients and methods We chose
patients who had breakthrough ulcers on maintenance H,-receptor antagonists or who had had more than two ulcer relapses within 1 year. Most of the latter were non-compliant on, or had refused, maintenance therapy. All patients were H pylori positive. They were randomised in an open study to treatment with CBS, 1 tablet four times daily for 28 days (26 patients) or with CBS (same dose) plus amoxicillin 375 mg three times daily for 28 days and metronidazole 500 mg three times daily from day 18 to day 28 (24 patients). All the patients continued on ranitidine 150 mg after the trial period for a further 28 days, until their first control endoscopy in week 8. No antacids were prescribed, and no further maintenance therapy was given. 9 patients who relapsed after treatment with CBS alone and who were still H pylori positive were then given the CBS-antibiotic combination.
Endoscopy was repeated 1, 3, 6, and 12 months after treatment stopped, or if symptoms recurred. We excluded from the trial patients who needed emergency endoscopy, who had previously had gastric sugery or malignant
was
ADDRESS: Department of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands (E A. J. Rauws, MD, G N. J Tytgat, MD) Correspondence to Dr E A J Rauws
1234
DUODENAL ULCER HEALING AND RELAPSE RATES
*5 patients dropped out owing to side-effects. t6 by 3 months, 3 by 6 months (9 subsequently given
triple therapy), 7 by 12 months.
tBy6months
disorders, or who had taken steroids, non-steroidal antiinflammatory drugs, antibiotics, anticoagulants, or any of the drugs
study during the previous 4 weeks. Upper gastrointestinal endoscopy was done after the patient had fasted overnight. Four antral mucosal biopsy samples were taken with sterilised biopsy forceps (FB-26N, Olympus, Lake Success, New York, USA) from the lesser or greater curvature, 2 cm from the pylorus, from intact mucosa distant from any focal lesion, such as an ulcer or erosion. Two specimens were placed in 2 ml phosphate-buffered saline at 4°C for bacteriological examination, and two were fixed in 10% formalin for histopathology. The endoscopes (Olympus GIF Q10) were cleaned with detergent,
following 12 months, whereas 17 of the 21 patients who were positive for H pylori 1 month after stopping treatment had endoscopically confirmed duodenal ulcer relapse during that time. The difference in relapse rates between the groups positive and negative for H pylori was significant (p < 0-001). 9 patients initially given CBS alone, who had persistent H pylori and ulcer relapses, were subsequently given triple therapy. The ulcers were healed in all 9 a month after that treatment. In 7 of the 9, the triple therapy eradicated H pylori and there was no further gastritis or ulcer recurrence in the next 12 months. The 2 patients who remained positive for H pylori after triple therapy relapsed within 6 months.
under
disinfected with 70% ethanol, and rinsed with sterile water after each examination. Within 4 h of biopsy one culture of Colombia agar (Oxoid Ltd, London, UK) supplemented with horse blood (5 % by volume) and one of blood agar no 2 (Oxoid, containing horse blood and Skirrow selective supplement) were inoculated by rubbing the surface with one biopsy sample. All agars were incubated microaerobically at 35°C (Campy Pak; BBL Microbiology Systems, Cockeysville, Maryland, USA) for 7 days. Cultures were considered positive for H pylori if one or more colonies of gram-negative, oxidase-positive, catalase-positive, and urease-positive spiral or curved rods grew.22,23 The bacteriologist was unaware of the histology, the endoscopic findings, or the treatment regimen. Formalin-fixed biopsy samples were embedded in paraffin and 4 um sections were stained with haematoxylin and eosin. The presence, type, density, and location of the inflammatory infiltrate were assessed.24 The chi-square test was used for statistical analysis.
Results 66 subjects entered the study. 11 patients were withdrawn because they failed to attend follow-up appointments. 5 others were excluded after entry: 3 used Hz-receptor antagonists; 1 had a myocardial infarction; and in 1 sigmoid carcinoma developed. A further 5 patients (all on triple therapy) dropped out because of side-effects: 3 had nausea,1 diarrhoea, and 1 a rash. Their results were excluded from the analysis. Thus, 45 patients completed their treatment, and the ulcer had healed in 38, who were evaluated over the planned follow-up period of 12 months. Before treatment, all subjects with active duodenal ulcer had active chronic gastritis (neutrophil infiltration with chronic gastritis). At endoscopy 1 month after the study treatment period the ulcers had healed in 21 of the 26 (81 %) patients who completed treatment with CBS alone and in 17 of the 19 (89%) patients who completed the triple therapy regimen (see table). At that time histological and bacteriological examinations failed to find H pylori in 17 patients, 15 of whom had received triple therapy (table). As previously reported,24 the eradication of H pylori coincided with the disappearance of the inflammatory changes of the
gastric mucosa. There was no endoscopic evidence of ulcer relapse in any of the 17 patients who remained H pylori negative over the
Discussion
Hz-receptor antagonists for a year lower ulcer relapse rate than significantly produces does not the natural history of the but change placebo,s,6 disease. The relapse rate after stopping maintenance therapy is the same as that after initial ulcer healing not followed by maintenance therapy. 7,8 Maintenance with a
Extensive research has not found the cause of duodenal ulcer or its relapse. The isolation and culture of77)y/on and its association with gastritis led to the hypothesis that it may be the cause of the gastroduodenal inflammation and of duodenal ulcerp,14 H pylori meets Koch’s postulates for gastritis,2s6 but not for duodenal ulcer. The proof would involve prospective study of many H pylori-colonised subjects to await the development of an ulcer. The alternative approach is to eradicate H pylori from patients with duodenal ulcer and to study its relation with the expected ulcer relapse rate. In our study, both groups received the same dose of bismuth. However, the rate of H pylori eradication was lower with CBS alone than with the combination with amoxicillin and metronidazole. The dramatic reduction in relapse rate was solely associated with H pylori eradication. When H pylori was eradicated, duodenal ulcer relapse did not occur for at least 12 months: without such eradication, the duodenal ulcer relapse rate was as high as previously. In 7 of 9 patients who relapsed after CBS monotherapy and who were H pylori positive until they received the triple therapy, the effective eradication of the organism was followed by no further ulcer relapse over the next 12 months. This study does not prove that H pylori is the cause of duodenal ulcer disease. It does, however, strongly support a dominant role for H pylori in ulcer recurrence. Eradication of H pylori, and not the prolonged action of CBS after absorption, explains the lower ulcer relapse rate after CBS, with or without antibiotics, than after Hz-receptor
antagonists. We thank Dr M. L. Langenberg (Department of Microbiology) for carrying out the bacteriological cultures.
REFERENCES 1. Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987; 28: 1120-27. 2. McIsaac RL, McCanless I, Summers K, Wood JR. Ranitidine and cimetidine in the healing of duodenal ulcer: meta-analysis of comparative clinical trials. Aliment Pharmacol Therap 1987; 1: 369-81. 3. Wormsley KG. Relapse of duodenal ulcer. Br Med J 1986; 293: 1501. 4. Boyd EJS, Wilson JA, Wormsley KG. Recurrent ulcer disease. In: Misiewicz JJ, Wood JR, eds. Ranitidine: therapeutic advances. Amsterdam: Excerpta Medica, 1984: 14-42.
1235
Gough KR, Bardhan KD, Crowe JR, et al. Ranitidine and cimetidine in prevention of duodenal ulcer relapse. Lancet 1984; i: 659-62. 6. Silvis SE. Final report on the United States Multicentre Trial comparing ranitidine to cimetidine as maintenance therapy following healing of duodenal ulcer. J Clin Gastroenterol 1985; 7: 482-87. 7. Gudmand Hoyer E, Jensen BK, Kray E, et al. Prophylactic effect of cimetidine on duodenal ulcer disease. Br Med J 1978; i: 1095-97. 8. Bardhan K, Cole DS, Hawkins BW, Franks CR. Does treatment with cimetidine extended beyond initial healing of duodenal ulcer reduce the subsequent relapse rate? Br Med J 1982; 284: 621-23. 9. Martin DF, Way SJ, Tweedle DEF, Hollanders D, Ravenscroft MM, Miller JP. Difference in relapse rates of duodenal ulcer after healing with cimetidine or tripotassium dicitrate bismuthate. Lancet 1981; i: 5.
7-10. 10. Hamilton I, O’Connor HJ, Wood NC, Bradbury I, Axon ATR. Healing and recurrence of duodenal ulcer after treatment with tripotassium citrato bismuthate (TBD) tablets or cimetidine. Gut 1986; 27: 106-10. 11. Lane MR, Lee SP. Recurrence of duodenal ulcer after medical treatment. Lancet 1988; i: 1147-49. 12. Chiverton SG, Hunt RH. Initial therapy and relapse of duodenal ulcer: possible and secretory mechanisms. Gastroenterology 1989; 96: 632-39. 13. Marshall BJ, Royce H, Annear DI, et al. Original isolation of Campylobacter pyloridis from human gastric mucosa. Microbios Lett 1984; 25: 83-88. 14. Marshall BJ, Warren JR, Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; i: 1311-15. 15. Coghlan JG, Gilligan D, Humphries H, et al. Campylobacter pylori and recurrence of duodenal ulcers—a 12 month follow-up study. Lancet 1987; ii: 1109-11. 16. Lambert JR, Borremeo M, Korman MG, Hansky J, Eaves ER. Effect of colloidal bismuth (De-Nol) and healing relapse of duodenal ulcer-role
Effect of
a
22.
23.
24.
25.
26.
accumulates in the body during treatment with tripotassium dicitrato bismuthate. Aliment Pharmacol Therap 1989; 3: 21-28. Cowan ST. Cowan and Steele’s manual for the identification of medical bacteria, 2nd ed. Cambridge: Cambridge University Press, 1974: 22-41. Langenberg ML, Tytgat GNJ, Schipper MEI, Rietra PJGM, Zanen HC. Campylobacter-like organisms in the stomach of patients and healthy individuals. Lancet 1984; i: 1348. Rauws EAJ, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GNJ. Campylobacter-pyloridis-associated chronic active antral gastritis. Gastroenterology 1988; 94: 33-40. Marshall BJ, Amstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulates for pyloric campylobacter. Med J Aust 1985; 142: 436-39. Morris A, Nicholson G. Ingestion of Campylobater pyloridis causes gastritis and raised fasting gastric pH. Am J Gastroenterol 1987; 82: 192-99.
Scandinavian-style boiled coffee, which
cholesterol
raises
cholesterol, was found to contain more lipid material than drip filter coffee, which does not.
serum
Ten volunteers consumed a lipid-enriched fraction from boiled coffee for six weeks: the supplement provided 77 g of water, 1·3 g of lipid, and 1·6 g of other solids per day. Serum cholesterol rose in every subject; the mean rise was 0·74 mmol/l after three weeks (range - 0·09 to 1·48 mmol/l) and 1 ·06 SD 0·37 mmol/l or 23% after six weeks (range 0·48 to 1·52 mmol/l). The increase was mainly due to low-density-lipoprotein cholesterol, which rose by 29%, but very-low-density lipoprotein cholesterol was also raised, as evidenced by a 55% rise in triglycerides. High-density-lipoprotein After cholesterol was unchanged. supplementation had ended, lipid levels returned to baseline. Boiled coffee thus contains a lipid that powerfully raises serum cholesterol.
Introduction Scandinavians have traditionally made their coffee by coffee beans and
(abstr). 19. Marshall BJ, Goodwm CS, Warren JR, et al. Prospective double-blind trial of duodenal relapse after eradication of Campylobacter pylori. Lancet 1988; ii: 1437-42. 20. Konturek SJ, Radecki T, Piastucki I, et al. Studies on the gastroprotective and ulcer-healing effects of colloidal bismuth subcitrate. Digestion 1987; 37 (suppl): 8-15. 21. Gavey CJ, Szeto ML, Nwokolo CU, Sercombe J, Pounder RE. Bismuth
lipid-rich fraction from boiled coffee on serum
boiling ground
of Campylobacter pyloridis. Gastroenterology 1987; 92: 1489 (abstr). Borody TJ, Cole P, Noonan S, et al. Long term Campylobacter pylori recurrence post-eradication. Gastroenterology 1988; 94: 43 (abstr). 18. Smith AC, Price AB, Borriello P, Levi AJ. A comparison of ranitidine and tripotassium dicitrato-bismuth (TDB) in relapse rate of duodenal ulcer. The role of Campylobacter pylori. Gastroenterology 1988; 94: 431
17.
water
in
a
saucepan, and
decanting the fluid into a cup. In 1983, a study from Norway showed a strongly significant relation between the amount of coffee ingested and serum total cholestero1.1 Recently it was found that this association is specifically due to boiled coffee.2 Controlled experiments3A showed that abstaining from boiled coffee caused large decreases in serum cholesterol in and in volunteers3 healthy hypercholesterolaemic men.4 In a Finnish trials volunteers showed a rise in cholesterol of 0-64 mmol/1 after four weeks of consumption of 8 cups of boiled coffee per day but a fall after consumption of regular drip filter coffee or tea. A similar cholesterol-raising effect of boiled but not of drip coffee was found in a Dutch experiment.6 A switch from boiled to drip coffee consumption is believed to have contributed to the fall in serum cholesterol and coronary heart disease observed in Finland in the past 20 years.z However, it is totally unclear why boiled coffee should cause hypercholesterolaemia. Nor do we know to what extent other types of coffee such as Turkish, Greek, or espresso ADDRESS. Department of Human Nutrition, Agricultural University, Bomenweg 2, 6703 HD Wageningen, The Netherlands (P L Zock, MSc, Prof M B Katan, PhD, M P Merkus, M. van
Dusseldorp, MSc, J. L. Harryvan). Correspondence
Katan
to
Prof M. B.
