EDITORIAL Atrophic Gastritis in the Arctic A lmost 150 years after their first recorded use by Samuel Fenwick, 1 the terms gastric atrophy and atrophic gastritis remain incompletely defined. Is meta- plasia (intestinal, pyloric, or pseudopyloric) an essential part of gastric atrophy? Is gastric atrophy synonymous with atrophic gastritis? If not, what percentage of the gastric mucosa must be atrophic before it becomes atro- phic gastritis? Do we need histologic confirmation, or is an endoscopic appearance sufficient to declare a stomach atrophic? Recently as a consensus on the morphology of atrophy has been reached, a number of histopathologic guidelines have made their way into the collective con- science of gastrointestinal clinicians and pathologists. 2–4 In an article published in the current issue of Clinical Gastroenterology and Hepatology that might prompt a reconsideration of the established dynamics of atrophic gastritis, Song et al 5 from the Karolinska Institut in Stockholm have not addressed the morphology of atro- phy and have built their study on a purely functional definition. The authors evaluated the prevalence of low pepsinogen I (PG I) serologic levels, which they equate to atrophic corpus gastritis, in a well-characterized popu- lation from Norrebotten and Västerbotten, 2 large and sparsely inhabited provinces of arctic Sweden that include all of Swedish Lapland. In contrast to a reduction in the prevalence of atrophic gastritis in subjects aged 55 to 64 years, those between the ages of 35 and 44 years showed an unexpected substantial secular trend during the past 2 decades, which increased their prevalence from 22 to 64 per 1000. The significance of this increase in the prevalence of PG I-defined atrophic gastritis in a narrow age band of this population is difficult to fully appreciate without knowing some details of the pathol- ogy and physiology of these atrophic stomachs. Never- theless, the surprising surge in atrophic gastritis in a segment of the population in which a decline would be expected is a departure from the conventional paradigm that deserves our full attention. Low serum PG I levels are the functional counterpart of parietal cell impairment. This may be due to diminishing function (that is, the cells are still there, but their ability to secrete pepsinogen is impaired) or to a reduced oxyntic cell mass. Several studies have established a reasonable correlation between PG I level <28 mg/L and histopath- ologic evidence of oxyntic mucosa depleted of parietal cells, 6 as have PG I/PG II levels. 7,8 In the absence of his- topathologic data, the authors speculate that infection with CagA-positive Helicobacter pylori (which they found to be a predictor of atrophy with an odds ratio of 2.29), diabetes, obesity, and low educational levels (all associ- ated with atrophy in this population) may have contrib- uted to the increase in PG I-defined atrophy. At the risk of oversimplifying a complex issue, pa- thologists view patients with atrophic gastritis as con- sisting of 3 groups: those with “pure” H pylori infection, characterized by pangastritis, multifocal metaplastic at- rophy, and no autoantibodies; those with “pure” auto- immune gastritis, with corpus-restricted metaplastic atrophy, a normal or reactive antrum, and no evidence of past or present H pylori infection; and a third group that includes patients with a spectrum of corpus atro- phic metaplastic changes ranging from minimal to se- vere, a normal or mildly inflamed antrum, variable evidence of current or past H pylori infection, and au- toantibodies reactive to gastric tissue (specifically Hþ, Kþ-adenosine triphosphatase). This third group has been the major focus of attention in the search for a causal connection between H pylori infection and auto- immune gastritis. 9–11 The plausibility of an autoimmune pathway in a subgroup of patients with H pylori gastritis is supported by numerous lines of evidence, including increased B-cell or T-cell influx around glands and into the epithelium of the corpus mucosa, 12 the predominant severity of inflammatory and atrophic changes in the oxyntic compartment, 13,14 increased apoptosis in oxy- ntic glands, 14 and decreased gastric acid secretion coexisting with increased gastrin levels. 8 Furthermore, eradication of H pylori infection has been reported to arrest or reverse the early phases of autoimmune gastritis, further supporting the pathogenetic link with H pylori. 15 The prevalence of H pylori infection in Sweden is low, and there is no reason to believe that the subjects re- ported in this study were substantially different from the rest of the population in this respect. 16 Foreign-born residents of Norrebotten and Västerbotten (approxi- mately 7% of all inhabitants) are mostly of Finnish and Norwegian ancestry, which would have a risk compara- ble to that of native Swedes. Smaller numbers of immi- grants (likely in the age group in which the increase of atrophic gastritis has been observed) settled from areas of the former Soviet Union, and some were refugees from Middle Eastern countries. 17 Although the contribution of these individuals to the group with atrophic gastritis is not specifically addressed in the article, it is likely to be minimal. Thus, to the African 18 and Indian 19 enigma we can now add the Swedish enigma: why has a cohort of relatively young Swedes lost the ability to produce pepsinogen and apparently developed atrophic corpus gastritis? The only way to obtain a direct answer to this question would be by collecting gastric biopsies from a representative sample of the study subjects with low PG I levels and age-matched controls with normal PG I levels, clearly an impractical and unrealistic plan. However, there are ways to gather some powerful circumstantial evidence. One useful approach would be the study of Clinical Gastroenterology and Hepatology 2015;13:1601–1603
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Atrophic Gastritis in the ArcticAtrophic Gastritis in the Arctic
Almost 150 years after their first recorded use by Samuel Fenwick,1 the terms gastric atrophy and
atrophic gastritis remain incompletely defined. Is meta- plasia (intestinal, pyloric, or pseudopyloric) an essential part of gastric atrophy? Is gastric atrophy synonymous with atrophic gastritis? If not, what percentage of the gastric mucosa must be atrophic before it becomes atro- phic gastritis? Do we need histologic confirmation, or is an endoscopic appearance sufficient to declare a stomach atrophic? Recently as a consensus on the morphology of atrophy has been reached, a number of histopathologic guidelines have made their way into the collective con- science of gastrointestinal clinicians and pathologists.2–4
In an article published in the current issue of Clinical Gastroenterology and Hepatology that might prompt a reconsideration of the established dynamics of atrophic gastritis, Song et al5 from the Karolinska Institut in Stockholm have not addressed the morphology of atro- phy and have built their study on a purely functional definition. The authors evaluated the prevalence of low pepsinogen I (PG I) serologic levels, which they equate to atrophic corpus gastritis, in a well-characterized popu- lation from Norrebotten and Västerbotten, 2 large and sparsely inhabited provinces of arctic Sweden that include all of Swedish Lapland. In contrast to a reduction in the prevalence of atrophic gastritis in subjects aged 55 to 64 years, those between the ages of 35 and 44 years showed an unexpected substantial secular trend during the past 2 decades, which increased their prevalence from 22 to 64 per 1000. The significance of this increase in the prevalence of PG I-defined atrophic gastritis in a narrow age band of this population is difficult to fully appreciate without knowing some details of the pathol- ogy and physiology of these atrophic stomachs. Never- theless, the surprising surge in atrophic gastritis in a segment of the population in which a decline would be expected is a departure from the conventional paradigm that deserves our full attention.
Low serumPG I levels are the functional counterpart of parietal cell impairment. This may be due to diminishing function (that is, the cells are still there, but their ability to secrete pepsinogen is impaired) or to a reduced oxyntic cell mass. Several studies have established a reasonable correlation between PG I level <28 mg/L and histopath- ologic evidence of oxyntic mucosa depleted of parietal cells,6 as have PG I/PG II levels.7,8 In the absence of his- topathologic data, the authors speculate that infection with CagA-positive Helicobacter pylori (which they found to be a predictor of atrophy with an odds ratio of 2.29), diabetes, obesity, and low educational levels (all associ- ated with atrophy in this population) may have contrib- uted to the increase in PG I-defined atrophy.
At the risk of oversimplifying a complex issue, pa- thologists view patients with atrophic gastritis as con- sisting of 3 groups: those with “pure” H pylori infection, characterized by pangastritis, multifocal metaplastic at- rophy, and no autoantibodies; those with “pure” auto- immune gastritis, with corpus-restricted metaplastic atrophy, a normal or reactive antrum, and no evidence of past or present H pylori infection; and a third group that includes patients with a spectrum of corpus atro- phic metaplastic changes ranging from minimal to se- vere, a normal or mildly inflamed antrum, variable evidence of current or past H pylori infection, and au- toantibodies reactive to gastric tissue (specifically Hþ, Kþ-adenosine triphosphatase). This third group has been the major focus of attention in the search for a causal connection between H pylori infection and auto- immune gastritis.9–11 The plausibility of an autoimmune pathway in a subgroup of patients with H pylori gastritis is supported by numerous lines of evidence, including increased B-cell or T-cell influx around glands and into the epithelium of the corpus mucosa,12 the predominant severity of inflammatory and atrophic changes in the oxyntic compartment,13,14 increased apoptosis in oxy- ntic glands,14 and decreased gastric acid secretion coexisting with increased gastrin levels.8 Furthermore, eradication of H pylori infection has been reported to arrest or reverse the early phases of autoimmune gastritis, further supporting the pathogenetic link with H pylori.15
The prevalence of H pylori infection in Sweden is low, and there is no reason to believe that the subjects re- ported in this study were substantially different from the rest of the population in this respect.16 Foreign-born residents of Norrebotten and Västerbotten (approxi- mately 7% of all inhabitants) are mostly of Finnish and Norwegian ancestry, which would have a risk compara- ble to that of native Swedes. Smaller numbers of immi- grants (likely in the age group in which the increase of atrophic gastritis has been observed) settled from areas of the former Soviet Union, and some were refugees from Middle Eastern countries.17 Although the contribution of these individuals to the group with atrophic gastritis is not specifically addressed in the article, it is likely to be minimal. Thus, to the African18 and Indian19 enigma we can now add the Swedish enigma: why has a cohort of relatively young Swedes lost the ability to produce pepsinogen and apparently developed atrophic corpus gastritis?
The only way to obtain a direct answer to this question would be by collecting gastric biopsies from a representative sample of the study subjects with low PG I levels and age-matched controls with normal PG I levels, clearly an impractical and unrealistic plan. However, there are ways to gather some powerful circumstantial evidence. One useful approach would be the study of
Clinical Gastroenterology and Hepatology 2015;13:1601–1603
1602 Genta and Rugge Clinical Gastroenterology and Hepatology Vol. 13, No. 9
other populations. Song et al5 used a well-characterized set of sera from residents of Norrebotten and Väst- erbotten not because of any indication that these arctic dwellers had more atrophic gastritis than the residents of Värmland or Skåne but because the sera—to para- phrase Sir Edmund Hillary—were there, collected over several decades for a cardiovascular disease risk study.20
This atrophic trend could be affecting all of Sweden, Scandinavia, or Europe. Its causes could range from increased autoimmunity that is due to decreasing H py- lori infection (can anybody resist invoking the “hygiene hypothesis”?), or, as Song et al propose, increasing obesity (known to be associated with decreased PG I levels),21 or to some unknown factors that lower PG I levels irrespective of any oxyntic gland loss. Morphologic evidence to corroborate the serologic data could be gathered by a pathoepidemiologic study of the histo- pathologic diagnoses available in the hospitals of north- ern Sweden. Ludvigsson et al22,23 and Lebwohl et al24
have studied various aspects of celiac disease by using the biopsy results of small intestinal biopsies diagnosed in all 28 Swedish pathology departments, in some cases going back as far as 1969. We have used a similar approach (complicated by a lack of the accessible centralized data available in Sweden) to gather infor- mation about the relative prevalence of atrophic gastritis in northern Italy25 and the Rio Grande Valley in southern Texas.26 Thus, even without sampling the stomachs of specific individuals from the MONICA study, the authors may have the tools to determine whether PG I-defined atrophic gastritis is indeed histologic atrophic gastritis.
If such a study confirms that low PG I levels corre- spond to morphologic gastric atrophy with its inherent pre-neoplastic markers (loss of oxyntic glands, intestinal and spasmolytic polypeptide-expressing metaplasia), northern Sweden may experience an increased incidence of gastric cancer in the next 2 or 3 decades, as the affected subjects, now in their 40s, move toward an older age. On the other hand, if this serologic abnormality turns out to be the improbable epiphenomenon of con- ditions such as obesity or low educational levels, then there may be little reason to be alarmed by a looming risk of gastric cancer.
ROBERT M. GENTA, MDa
Miraca Life Sciences Research Institute Irving, Texas
University of Texas Southwestern Medical Center and Dallas VA Medical Center
Dallas, Texas
University of Padua Padua, Italy
References
1. Fenwick S. On atrophy of the stomach. Lancet 1870;ii:78.
2. Rugge M, Correa P, Dixon MF, et al. Gastric mucosal atro- phy: interobserver consistency using new criteria for classi- fication and grading. Aliment Pharmacol Ther 2002;16: 1249–1259.
3. Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Pathol 2005;36:228–233.
4. Rugge M, Correa P, Di Mario F, et al. OLGA staging for gastritis: a tutorial. Dig Liver Dis 2008;40:650–658.
5. Song H, Held M, Sandin S, et al. Increase in the prevalence of atrophic gastritis among adults age 35 to 44 years old in northern sweden between 1990 and 2009. Clin Gastroenterol Hepatol 2015;13:1592–1600.
6. Oksanen A, Sipponen P, Karttunen R, et al. Atrophic gastritis and Helicobacter pylori infection in outpatients referred for gastroscopy. Gut 2000;46:460–463.
7. Miki K, Ichinose M, Ishikawa KB, et al. Clinical application of serum pepsinogen I and II levels for mass screening to detect gastric cancer. Jpn J Cancer Res 1993;84:1086–1090.
8. Agreus L, Kuipers EJ, Kupcinskas L, et al. Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol 2012;47:136–147.
9. Negrini R, Lisato L, Zanella I, et al. Helicobacter pylori infection induces antibodies cross-reacting with human gastric mucosa. Gastroenterology 1991;101:437–445.
10. Appelmelk BJ, Simoons-Smit I, Negrini R, et al. Potential role of molecular mimicry between Helicobacter pylori lipopolysac- charide and host Lewis blood group antigens in autoimmunity. Infect Immun 1996;64:2031–2040.
11. Faller G, Winter M, Steininger H, et al. Decrease of antigastric autoantibodies in Helicobacter pylori gastritis after cure of infection. Pathol Res Pract 1999;195:243–246.
12. Claeys D, Faller G, Appelmelk BJ, et al. The gastric Hþ, Kþ- ATPase is a major autoantigen in chronic H. pylori gastritis with body mucosa atrophy. Gastroenterology 1998;115:340–347.
13. Negrini R, Savio A, Poiesi C, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology 1996;111:655–665.
14. Faller G, Steininger H, Kranzlein J, et al. Antigastric autoanti- bodies in Helicobacter pylori infection: implications of histolog- ical and clinical parameters of gastritis. Gut 1997;41:619–623.
15. Muller H, Rappel S, Wundisch T, et al. Healing of active, non- atrophic autoimmune gastritis by H. pylori eradication. Diges- tion 2001;64:30–39.
16. Thjodleifsson B, Asbjörnsdottir H, Sigurjonsdottir RB, et al. Seroprevalence of Helicobacter pylori and cagA antibodies in Iceland, Estonia and Sweden. Scand J Infect Dis 2007; 39:683–689.
17. Kotyrlo E. Labour market outcomes of migrant women in Väst- erbotten and Norrebotten. The Arctic Yearbook 2104. www. arcticyearbook.com. 2014.
18. Holcombe C. Helicobacter pylori: the African enigma. Gut 1992; 33:429–431.
19. Misra V, Pandey R, Misra SP, et al. Helicobacter pylori and gastric cancer: Indian enigma. World J Gastroenterol 2014; 20:1503–1509.
20. Peltonen M, Huhtasaari F, Stegmayr B, et al. Secular trends in social patterning of cardiovascular risk factor levels in Sweden: the Northern Sweden MONICA Study 1986-1994—multinational
September 2015 Editorial 1603
monitoring of trends and determinants in cardiovascular dis- ease. J Intern Med 1998;244:1–9.
21. Kutsuma A, Oshida H, Suwa K, et al. A possible association of low pepsinogen I and pepsinogen I/II with low and high body weight in Japanese men. Clin Biochem 2014;47:126–128.
22. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intes- tinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–1178.
23. Ludvigsson JF, Brandt L, Montgomery SM, et al. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009;9:19.
24. Lebwohl B, Murray JA, Rubio-Tapia A, et al. Predictors of persistent villous atrophy in coeliac disease: a population-based study. Aliment Pharmacol Ther 2014;39:488–495.
25. Rugge M, Fassan M, Pizzi M, et al. Autoimmune gastritis: his- tology phenotype and OLGA staging. Aliment Pharmacol Ther 2012;35:1460–1466.
26. Genta RM, Allen R, Rugge M. Ethnic distribution of atrophic autoimmune gastritis in the United States. Gastrointest Endosc 2014;79(Suppl 5):AB148.
aAuthors share co-first authorship.
Most current article
References
Almost 150 years after their first recorded use by Samuel Fenwick,1 the terms gastric atrophy and
atrophic gastritis remain incompletely defined. Is meta- plasia (intestinal, pyloric, or pseudopyloric) an essential part of gastric atrophy? Is gastric atrophy synonymous with atrophic gastritis? If not, what percentage of the gastric mucosa must be atrophic before it becomes atro- phic gastritis? Do we need histologic confirmation, or is an endoscopic appearance sufficient to declare a stomach atrophic? Recently as a consensus on the morphology of atrophy has been reached, a number of histopathologic guidelines have made their way into the collective con- science of gastrointestinal clinicians and pathologists.2–4
In an article published in the current issue of Clinical Gastroenterology and Hepatology that might prompt a reconsideration of the established dynamics of atrophic gastritis, Song et al5 from the Karolinska Institut in Stockholm have not addressed the morphology of atro- phy and have built their study on a purely functional definition. The authors evaluated the prevalence of low pepsinogen I (PG I) serologic levels, which they equate to atrophic corpus gastritis, in a well-characterized popu- lation from Norrebotten and Västerbotten, 2 large and sparsely inhabited provinces of arctic Sweden that include all of Swedish Lapland. In contrast to a reduction in the prevalence of atrophic gastritis in subjects aged 55 to 64 years, those between the ages of 35 and 44 years showed an unexpected substantial secular trend during the past 2 decades, which increased their prevalence from 22 to 64 per 1000. The significance of this increase in the prevalence of PG I-defined atrophic gastritis in a narrow age band of this population is difficult to fully appreciate without knowing some details of the pathol- ogy and physiology of these atrophic stomachs. Never- theless, the surprising surge in atrophic gastritis in a segment of the population in which a decline would be expected is a departure from the conventional paradigm that deserves our full attention.
Low serumPG I levels are the functional counterpart of parietal cell impairment. This may be due to diminishing function (that is, the cells are still there, but their ability to secrete pepsinogen is impaired) or to a reduced oxyntic cell mass. Several studies have established a reasonable correlation between PG I level <28 mg/L and histopath- ologic evidence of oxyntic mucosa depleted of parietal cells,6 as have PG I/PG II levels.7,8 In the absence of his- topathologic data, the authors speculate that infection with CagA-positive Helicobacter pylori (which they found to be a predictor of atrophy with an odds ratio of 2.29), diabetes, obesity, and low educational levels (all associ- ated with atrophy in this population) may have contrib- uted to the increase in PG I-defined atrophy.
At the risk of oversimplifying a complex issue, pa- thologists view patients with atrophic gastritis as con- sisting of 3 groups: those with “pure” H pylori infection, characterized by pangastritis, multifocal metaplastic at- rophy, and no autoantibodies; those with “pure” auto- immune gastritis, with corpus-restricted metaplastic atrophy, a normal or reactive antrum, and no evidence of past or present H pylori infection; and a third group that includes patients with a spectrum of corpus atro- phic metaplastic changes ranging from minimal to se- vere, a normal or mildly inflamed antrum, variable evidence of current or past H pylori infection, and au- toantibodies reactive to gastric tissue (specifically Hþ, Kþ-adenosine triphosphatase). This third group has been the major focus of attention in the search for a causal connection between H pylori infection and auto- immune gastritis.9–11 The plausibility of an autoimmune pathway in a subgroup of patients with H pylori gastritis is supported by numerous lines of evidence, including increased B-cell or T-cell influx around glands and into the epithelium of the corpus mucosa,12 the predominant severity of inflammatory and atrophic changes in the oxyntic compartment,13,14 increased apoptosis in oxy- ntic glands,14 and decreased gastric acid secretion coexisting with increased gastrin levels.8 Furthermore, eradication of H pylori infection has been reported to arrest or reverse the early phases of autoimmune gastritis, further supporting the pathogenetic link with H pylori.15
The prevalence of H pylori infection in Sweden is low, and there is no reason to believe that the subjects re- ported in this study were substantially different from the rest of the population in this respect.16 Foreign-born residents of Norrebotten and Västerbotten (approxi- mately 7% of all inhabitants) are mostly of Finnish and Norwegian ancestry, which would have a risk compara- ble to that of native Swedes. Smaller numbers of immi- grants (likely in the age group in which the increase of atrophic gastritis has been observed) settled from areas of the former Soviet Union, and some were refugees from Middle Eastern countries.17 Although the contribution of these individuals to the group with atrophic gastritis is not specifically addressed in the article, it is likely to be minimal. Thus, to the African18 and Indian19 enigma we can now add the Swedish enigma: why has a cohort of relatively young Swedes lost the ability to produce pepsinogen and apparently developed atrophic corpus gastritis?
The only way to obtain a direct answer to this question would be by collecting gastric biopsies from a representative sample of the study subjects with low PG I levels and age-matched controls with normal PG I levels, clearly an impractical and unrealistic plan. However, there are ways to gather some powerful circumstantial evidence. One useful approach would be the study of
Clinical Gastroenterology and Hepatology 2015;13:1601–1603
1602 Genta and Rugge Clinical Gastroenterology and Hepatology Vol. 13, No. 9
other populations. Song et al5 used a well-characterized set of sera from residents of Norrebotten and Väst- erbotten not because of any indication that these arctic dwellers had more atrophic gastritis than the residents of Värmland or Skåne but because the sera—to para- phrase Sir Edmund Hillary—were there, collected over several decades for a cardiovascular disease risk study.20
This atrophic trend could be affecting all of Sweden, Scandinavia, or Europe. Its causes could range from increased autoimmunity that is due to decreasing H py- lori infection (can anybody resist invoking the “hygiene hypothesis”?), or, as Song et al propose, increasing obesity (known to be associated with decreased PG I levels),21 or to some unknown factors that lower PG I levels irrespective of any oxyntic gland loss. Morphologic evidence to corroborate the serologic data could be gathered by a pathoepidemiologic study of the histo- pathologic diagnoses available in the hospitals of north- ern Sweden. Ludvigsson et al22,23 and Lebwohl et al24
have studied various aspects of celiac disease by using the biopsy results of small intestinal biopsies diagnosed in all 28 Swedish pathology departments, in some cases going back as far as 1969. We have used a similar approach (complicated by a lack of the accessible centralized data available in Sweden) to gather infor- mation about the relative prevalence of atrophic gastritis in northern Italy25 and the Rio Grande Valley in southern Texas.26 Thus, even without sampling the stomachs of specific individuals from the MONICA study, the authors may have the tools to determine whether PG I-defined atrophic gastritis is indeed histologic atrophic gastritis.
If such a study confirms that low PG I levels corre- spond to morphologic gastric atrophy with its inherent pre-neoplastic markers (loss of oxyntic glands, intestinal and spasmolytic polypeptide-expressing metaplasia), northern Sweden may experience an increased incidence of gastric cancer in the next 2 or 3 decades, as the affected subjects, now in their 40s, move toward an older age. On the other hand, if this serologic abnormality turns out to be the improbable epiphenomenon of con- ditions such as obesity or low educational levels, then there may be little reason to be alarmed by a looming risk of gastric cancer.
ROBERT M. GENTA, MDa
Miraca Life Sciences Research Institute Irving, Texas
University of Texas Southwestern Medical Center and Dallas VA Medical Center
Dallas, Texas
University of Padua Padua, Italy
References
1. Fenwick S. On atrophy of the stomach. Lancet 1870;ii:78.
2. Rugge M, Correa P, Dixon MF, et al. Gastric mucosal atro- phy: interobserver consistency using new criteria for classi- fication and grading. Aliment Pharmacol Ther 2002;16: 1249–1259.
3. Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Pathol 2005;36:228–233.
4. Rugge M, Correa P, Di Mario F, et al. OLGA staging for gastritis: a tutorial. Dig Liver Dis 2008;40:650–658.
5. Song H, Held M, Sandin S, et al. Increase in the prevalence of atrophic gastritis among adults age 35 to 44 years old in northern sweden between 1990 and 2009. Clin Gastroenterol Hepatol 2015;13:1592–1600.
6. Oksanen A, Sipponen P, Karttunen R, et al. Atrophic gastritis and Helicobacter pylori infection in outpatients referred for gastroscopy. Gut 2000;46:460–463.
7. Miki K, Ichinose M, Ishikawa KB, et al. Clinical application of serum pepsinogen I and II levels for mass screening to detect gastric cancer. Jpn J Cancer Res 1993;84:1086–1090.
8. Agreus L, Kuipers EJ, Kupcinskas L, et al. Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol 2012;47:136–147.
9. Negrini R, Lisato L, Zanella I, et al. Helicobacter pylori infection induces antibodies cross-reacting with human gastric mucosa. Gastroenterology 1991;101:437–445.
10. Appelmelk BJ, Simoons-Smit I, Negrini R, et al. Potential role of molecular mimicry between Helicobacter pylori lipopolysac- charide and host Lewis blood group antigens in autoimmunity. Infect Immun 1996;64:2031–2040.
11. Faller G, Winter M, Steininger H, et al. Decrease of antigastric autoantibodies in Helicobacter pylori gastritis after cure of infection. Pathol Res Pract 1999;195:243–246.
12. Claeys D, Faller G, Appelmelk BJ, et al. The gastric Hþ, Kþ- ATPase is a major autoantigen in chronic H. pylori gastritis with body mucosa atrophy. Gastroenterology 1998;115:340–347.
13. Negrini R, Savio A, Poiesi C, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology 1996;111:655–665.
14. Faller G, Steininger H, Kranzlein J, et al. Antigastric autoanti- bodies in Helicobacter pylori infection: implications of histolog- ical and clinical parameters of gastritis. Gut 1997;41:619–623.
15. Muller H, Rappel S, Wundisch T, et al. Healing of active, non- atrophic autoimmune gastritis by H. pylori eradication. Diges- tion 2001;64:30–39.
16. Thjodleifsson B, Asbjörnsdottir H, Sigurjonsdottir RB, et al. Seroprevalence of Helicobacter pylori and cagA antibodies in Iceland, Estonia and Sweden. Scand J Infect Dis 2007; 39:683–689.
17. Kotyrlo E. Labour market outcomes of migrant women in Väst- erbotten and Norrebotten. The Arctic Yearbook 2104. www. arcticyearbook.com. 2014.
18. Holcombe C. Helicobacter pylori: the African enigma. Gut 1992; 33:429–431.
19. Misra V, Pandey R, Misra SP, et al. Helicobacter pylori and gastric cancer: Indian enigma. World J Gastroenterol 2014; 20:1503–1509.
20. Peltonen M, Huhtasaari F, Stegmayr B, et al. Secular trends in social patterning of cardiovascular risk factor levels in Sweden: the Northern Sweden MONICA Study 1986-1994—multinational
September 2015 Editorial 1603
monitoring of trends and determinants in cardiovascular dis- ease. J Intern Med 1998;244:1–9.
21. Kutsuma A, Oshida H, Suwa K, et al. A possible association of low pepsinogen I and pepsinogen I/II with low and high body weight in Japanese men. Clin Biochem 2014;47:126–128.
22. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intes- tinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–1178.
23. Ludvigsson JF, Brandt L, Montgomery SM, et al. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol 2009;9:19.
24. Lebwohl B, Murray JA, Rubio-Tapia A, et al. Predictors of persistent villous atrophy in coeliac disease: a population-based study. Aliment Pharmacol Ther 2014;39:488–495.
25. Rugge M, Fassan M, Pizzi M, et al. Autoimmune gastritis: his- tology phenotype and OLGA staging. Aliment Pharmacol Ther 2012;35:1460–1466.
26. Genta RM, Allen R, Rugge M. Ethnic distribution of atrophic autoimmune gastritis in the United States. Gastrointest Endosc 2014;79(Suppl 5):AB148.
aAuthors share co-first authorship.
Most current article
References
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