Alimentary Pharmacology and Therapeutics Letters to the Editors
Letter: effect of proton pump inhibitor use on invasive detection of Helicobacter pylori gastritis – authors’ reply R. M. Genta*,† & A. Sonnenberg‡ *Miraca Life Sciences Research Institute, Irving, TX, USA. † Departments of Medicine (Gastroenterology) and Pathology, UTSW – Dallas VAMC, Dallas, TX, USA. ‡ Department of Medicine (Gastroenterology) Portland VAMC, OHSU, Portland, OR, USA. E-mail: [email protected] doi:10.1111/apt.13093
SIRS, Dr Kilincalp and his colleagues lament the absence of information regarding use of proton pump inhibitors (PPIs) amongst patients included in our study of Helicobacter-negative gastritis.1, 2 They correctly note that prolonged PPI use can affect both the distribution of the bacteria and the intensity of the inflammation, reducing the diagnostic yield of biopsies, urea breath test, and stool antigen test. The typical patient with a PPI-altered Helicobacter infection tends to have an almost normal antrum with minimal chronic inflammation, no neutrophils, and no detectable bacteria; in contrast, the corpus has the characteristic chronic active gastritis, with bacteria often relegated to the deeper portions of the oxyntic glands.3–5 Thus, if such patients had only antral biopsies, they were diagnosed with chronic inactive gastritis; if sampling from the corpus was available, bacteria were detected by the immunohistochemical stain. Consequently, none of these patients would be included in the Helicobacter-negative gastritis group. The very different epidemiologic patterns of Helicobacter-positive and Helicobacter-negative
Letter: role of GNb3 polymorphisms in oesophageal adenocarcinoma and gastroesophageal reflux disease N. R. Brummond*, Y. A. Saito†, G. R. Locke III†, J. J. Larson‡, E. J. Atkinson‡, Y. Romero† & N. J. Talley†,§ *Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. † Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. ‡ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. § Faculty of Health and Medicine, University of Newcastle, New Lambton, NSW, Australia.
600
gastritis provide further support to our contention that the vast majority of the latter are not simply false negative cases. Real-time PCR, which can detect bacterial genes in a percentage of gastric biopsy specimens in which Helicobacters cannot be visualised, should be part of any future clinico-pathologic study of Helicobacter-negative gastritis. However, while PCR tests for antibiotic resistance and pathogenicity are well established and commercialised in Europe and Asia, the large numbers of apparent ‘false positives’ (positive PCR in histologically normal biopsies) has limited its clinical applications as markers of infection.6
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES € un Y, Akinci H, Coban S, Y€ 1. Kilincalp S, Ust€ uksel I. Letter: effect of proton pump inhibitor use on invasive detection of Helicobacter pylori gastritis. Aliment Pharmacol Ther 2015; 41: 599. 2. Genta RM, Sonnenberg A. Helicobacter-negative gastritis: a distinct entity unrelated to Helicobacter pylori infection. Aliment Pharmacol Ther 2015; 41: 218–26. 3. Graham DY, Genta R, Evans DG, et al. Helicobacter pylori does not migrate from the antrum to the corpus in response to omeprazole. Am J Gastroenterol 1996; 91: 2120–4. 4. Graham DY, Genta RM. Long-term proton pump inhibitor use and gastrointestinal cancer. Curr Gastroenterol Rep 2008; 10: 543–7. 5. Kumar KR, Iqbal R, Coss E, et al. Helicobacter gastritis induces changes in the oxyntic mucosa indistinguishable from the effects of proton pump inhibitors. Hum Pathol 2013; 44: 2706–10. 6. Patel SK, Pratap CB, Jain AK, et al. Diagnosis of Helicobacter pylori: what should be the gold standard? World J Gastroenterol 2014; 20: 12847–59.
E-mail: [email protected] doi:10.1111/apt.13094
SIRS, The incidence of oesophageal adenocarcinoma (OAC) has risen dramatically although it may be levelling off.1 Barrett’s oesophagus (BO) is the precursor lesion; a higher than expected prevalence of BO occurs in first-degree relatives of patients with OAC2 and multiple genes may contribute.3 Acid reflux in BO is often silent.4, 5 The G-protein b3 subunit gene has been implicated in signal transduction of neurotransmitters6, 7 with Aliment Pharmacol Ther 2015; 41: 593–601 ª 2015 John Wiley & Sons Ltd
Letters to the Editors one study observing the heterozygote CT genotype was more prevalent in patients with gastro-oesophageal reflux disease (GERD) vs. healthy controls.8 We hypothesised that patients with GNb3 CC or CT genotype (vs. TT) would be less likely to sense acid reflux, and would be more susceptible to developing BO and OAC. In a case–control study (Mayo Clinic IRB approved), cases (n = 100) were randomly selected from the Oesophageal Adenocarcinoma and Barrett’s Oesophagus registry with long segment BO. Controls9, 10 were prospectively recruited from patients seen at Mayo Clinic (n = 100); none had BO or OAC. Genotyping9 used the Thermo Electron Hybrid MBS thermal cycler (Waltham, MA, USA). Median age of cases was higher than controls (68.8 and 57.7 years, respectively; P < 0.001). Each group had equal numbers by gender, and no significant difference between race, ethnicity, or weight, but PPI use was higher in cases (75% vs. 25%, P < 0.001). Genotype frequencies for the controls were in Hardy–Weinberg equi-
GNβ 825 C > T polymorphism 50 46
44
45
44
Controls Cases
# of subjects
40
30 P = 0.498 20 11 10
0
CC
CT
10
TT
Figure 1 | GNb3 allele frequencies observed in cases with long segment Barrett’s oesophagus and oesophageal adenocarcinoma vs. controls.
Table 1 | Heartburn symptoms by GNb3 genotype with no history of Barrett’s oesophagus Controls
CC
%
CT
%
No or rarely Occasionally Often/very often/almost always
23 15 6
52.3 34.1 13.6
22 16 7
48.9 35.6 15.7
Aliment Pharmacol Ther 2015; 41: 593–601 ª 2015 John Wiley & Sons Ltd
TT 2 6 3
librium. No statistically significant differences in allele frequencies were observed between cases and controls (Figure 1). Within controls, there was no difference in GNb3 between those with and without irritable bowel syndrome (P = 0.50). Testing different genetic models, the findings were not consistent with an ordinal, dominant, or recessive effect. Controls with the CC and CT allele were less likely to have symptoms of reflux compared to the controls with the TT allele (P = 0.098, Table 1). Further research into the genetics of silent GERD and BO is indicated.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Masclee GM, Coloma PM, de Wilde M, Kuipers EJ, Sturkenboom MC. The incidence of Barrett’s oesophagus and oesophageal adenocarcinoma in the United Kingdom and The Netherlands is levelling off. Aliment Pharmacol Ther 2014; 39: 1321–30. 2. Juhasz A, Mittal SK, Lee TH, Deng C, Chak A, Lynch HT. Prevalence of Barrett esophagus in first-degree relatives of patients with esophageal adenocarcinoma. J Clin Gastroenterol 2011; 45: 867–71. 3. Su Z, Gay LJ, Strange A, et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus. Nat Genet 2012; 44: 1131–6. 4. Krarup AL, Olesen SS, Funch-Jensen P, Gregersen H, Drewes AM. Proximal and distal esophageal sensitivity is decreased in patients with Barrett’s esophagus. World J Gastroenterol 2011; 17: 514–21. 5. Bennett C, Vakil N, Bergman J, et al. Consensus statements for management of Barrett’s dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012; 143: 336–46. 6. Jankowski JA, Talley NJ. Dissecting GI phenotype-genotype relationships in GERD and dyspepsia: an SNP here and an SNP there!. Am J Gastroenterol 2009; 104: 286–8. 7. Holtmann G, Siffert W, Haag S, et al. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 2004; 126: 971–9. 8. de Vries DR, ter Linde JJ, van Herwaarden MA, Smout AJ, Samsom M. Gastroesophageal reflux disease is associated with the C825T polymorphism in the G-protein beta3 subunit gene (GNB3). Am J Gastroenterol 2009; 104: 281–5. 9. Saito YA, Larson JJ, Atkinson EJ, et al. The role of 5-HTT LPR and GNbeta3 825C>T polymorphisms and gene-environment interactions in irritable bowel syndrome (IBS). Dig Dis Sci 2012; 57: 2650–7. 10. Saito YA, Petersen GM, Larson JJ, et al. Familial aggregation of irritable bowel syndrome: a family case-control study. Am J Gastroenterol 2010; 105: 833–41.
% 18.2 54.5 27.3
601
Letter: effect of proton pump inhibitor use on invasive detection of Helicobacter pylori gastritis – authors’ reply R. M. Genta*,† & A. Sonnenberg‡ *Miraca Life Sciences Research Institute, Irving, TX, USA. † Departments of Medicine (Gastroenterology) and Pathology, UTSW – Dallas VAMC, Dallas, TX, USA. ‡ Department of Medicine (Gastroenterology) Portland VAMC, OHSU, Portland, OR, USA. E-mail: [email protected] doi:10.1111/apt.13093
SIRS, Dr Kilincalp and his colleagues lament the absence of information regarding use of proton pump inhibitors (PPIs) amongst patients included in our study of Helicobacter-negative gastritis.1, 2 They correctly note that prolonged PPI use can affect both the distribution of the bacteria and the intensity of the inflammation, reducing the diagnostic yield of biopsies, urea breath test, and stool antigen test. The typical patient with a PPI-altered Helicobacter infection tends to have an almost normal antrum with minimal chronic inflammation, no neutrophils, and no detectable bacteria; in contrast, the corpus has the characteristic chronic active gastritis, with bacteria often relegated to the deeper portions of the oxyntic glands.3–5 Thus, if such patients had only antral biopsies, they were diagnosed with chronic inactive gastritis; if sampling from the corpus was available, bacteria were detected by the immunohistochemical stain. Consequently, none of these patients would be included in the Helicobacter-negative gastritis group. The very different epidemiologic patterns of Helicobacter-positive and Helicobacter-negative
Letter: role of GNb3 polymorphisms in oesophageal adenocarcinoma and gastroesophageal reflux disease N. R. Brummond*, Y. A. Saito†, G. R. Locke III†, J. J. Larson‡, E. J. Atkinson‡, Y. Romero† & N. J. Talley†,§ *Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. † Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. ‡ Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. § Faculty of Health and Medicine, University of Newcastle, New Lambton, NSW, Australia.
600
gastritis provide further support to our contention that the vast majority of the latter are not simply false negative cases. Real-time PCR, which can detect bacterial genes in a percentage of gastric biopsy specimens in which Helicobacters cannot be visualised, should be part of any future clinico-pathologic study of Helicobacter-negative gastritis. However, while PCR tests for antibiotic resistance and pathogenicity are well established and commercialised in Europe and Asia, the large numbers of apparent ‘false positives’ (positive PCR in histologically normal biopsies) has limited its clinical applications as markers of infection.6
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES € un Y, Akinci H, Coban S, Y€ 1. Kilincalp S, Ust€ uksel I. Letter: effect of proton pump inhibitor use on invasive detection of Helicobacter pylori gastritis. Aliment Pharmacol Ther 2015; 41: 599. 2. Genta RM, Sonnenberg A. Helicobacter-negative gastritis: a distinct entity unrelated to Helicobacter pylori infection. Aliment Pharmacol Ther 2015; 41: 218–26. 3. Graham DY, Genta R, Evans DG, et al. Helicobacter pylori does not migrate from the antrum to the corpus in response to omeprazole. Am J Gastroenterol 1996; 91: 2120–4. 4. Graham DY, Genta RM. Long-term proton pump inhibitor use and gastrointestinal cancer. Curr Gastroenterol Rep 2008; 10: 543–7. 5. Kumar KR, Iqbal R, Coss E, et al. Helicobacter gastritis induces changes in the oxyntic mucosa indistinguishable from the effects of proton pump inhibitors. Hum Pathol 2013; 44: 2706–10. 6. Patel SK, Pratap CB, Jain AK, et al. Diagnosis of Helicobacter pylori: what should be the gold standard? World J Gastroenterol 2014; 20: 12847–59.
E-mail: [email protected] doi:10.1111/apt.13094
SIRS, The incidence of oesophageal adenocarcinoma (OAC) has risen dramatically although it may be levelling off.1 Barrett’s oesophagus (BO) is the precursor lesion; a higher than expected prevalence of BO occurs in first-degree relatives of patients with OAC2 and multiple genes may contribute.3 Acid reflux in BO is often silent.4, 5 The G-protein b3 subunit gene has been implicated in signal transduction of neurotransmitters6, 7 with Aliment Pharmacol Ther 2015; 41: 593–601 ª 2015 John Wiley & Sons Ltd
Letters to the Editors one study observing the heterozygote CT genotype was more prevalent in patients with gastro-oesophageal reflux disease (GERD) vs. healthy controls.8 We hypothesised that patients with GNb3 CC or CT genotype (vs. TT) would be less likely to sense acid reflux, and would be more susceptible to developing BO and OAC. In a case–control study (Mayo Clinic IRB approved), cases (n = 100) were randomly selected from the Oesophageal Adenocarcinoma and Barrett’s Oesophagus registry with long segment BO. Controls9, 10 were prospectively recruited from patients seen at Mayo Clinic (n = 100); none had BO or OAC. Genotyping9 used the Thermo Electron Hybrid MBS thermal cycler (Waltham, MA, USA). Median age of cases was higher than controls (68.8 and 57.7 years, respectively; P < 0.001). Each group had equal numbers by gender, and no significant difference between race, ethnicity, or weight, but PPI use was higher in cases (75% vs. 25%, P < 0.001). Genotype frequencies for the controls were in Hardy–Weinberg equi-
GNβ 825 C > T polymorphism 50 46
44
45
44
Controls Cases
# of subjects
40
30 P = 0.498 20 11 10
0
CC
CT
10
TT
Figure 1 | GNb3 allele frequencies observed in cases with long segment Barrett’s oesophagus and oesophageal adenocarcinoma vs. controls.
Table 1 | Heartburn symptoms by GNb3 genotype with no history of Barrett’s oesophagus Controls
CC
%
CT
%
No or rarely Occasionally Often/very often/almost always
23 15 6
52.3 34.1 13.6
22 16 7
48.9 35.6 15.7
Aliment Pharmacol Ther 2015; 41: 593–601 ª 2015 John Wiley & Sons Ltd
TT 2 6 3
librium. No statistically significant differences in allele frequencies were observed between cases and controls (Figure 1). Within controls, there was no difference in GNb3 between those with and without irritable bowel syndrome (P = 0.50). Testing different genetic models, the findings were not consistent with an ordinal, dominant, or recessive effect. Controls with the CC and CT allele were less likely to have symptoms of reflux compared to the controls with the TT allele (P = 0.098, Table 1). Further research into the genetics of silent GERD and BO is indicated.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Masclee GM, Coloma PM, de Wilde M, Kuipers EJ, Sturkenboom MC. The incidence of Barrett’s oesophagus and oesophageal adenocarcinoma in the United Kingdom and The Netherlands is levelling off. Aliment Pharmacol Ther 2014; 39: 1321–30. 2. Juhasz A, Mittal SK, Lee TH, Deng C, Chak A, Lynch HT. Prevalence of Barrett esophagus in first-degree relatives of patients with esophageal adenocarcinoma. J Clin Gastroenterol 2011; 45: 867–71. 3. Su Z, Gay LJ, Strange A, et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus. Nat Genet 2012; 44: 1131–6. 4. Krarup AL, Olesen SS, Funch-Jensen P, Gregersen H, Drewes AM. Proximal and distal esophageal sensitivity is decreased in patients with Barrett’s esophagus. World J Gastroenterol 2011; 17: 514–21. 5. Bennett C, Vakil N, Bergman J, et al. Consensus statements for management of Barrett’s dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012; 143: 336–46. 6. Jankowski JA, Talley NJ. Dissecting GI phenotype-genotype relationships in GERD and dyspepsia: an SNP here and an SNP there!. Am J Gastroenterol 2009; 104: 286–8. 7. Holtmann G, Siffert W, Haag S, et al. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 2004; 126: 971–9. 8. de Vries DR, ter Linde JJ, van Herwaarden MA, Smout AJ, Samsom M. Gastroesophageal reflux disease is associated with the C825T polymorphism in the G-protein beta3 subunit gene (GNB3). Am J Gastroenterol 2009; 104: 281–5. 9. Saito YA, Larson JJ, Atkinson EJ, et al. The role of 5-HTT LPR and GNbeta3 825C>T polymorphisms and gene-environment interactions in irritable bowel syndrome (IBS). Dig Dis Sci 2012; 57: 2650–7. 10. Saito YA, Petersen GM, Larson JJ, et al. Familial aggregation of irritable bowel syndrome: a family case-control study. Am J Gastroenterol 2010; 105: 833–41.
% 18.2 54.5 27.3
601
