Background To establish optimal cutoff values for serologic diagnosis of fundic atrophy in a high-risk area for oesophageal squamous cell carcinoma and gastric cancer with high prevalence of Helicobacter pylori (H. pylori) in Northern Iran, we performed an endoscopy-room-based validation study. Methods We measured serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients in two major endoscopy clinics in northeastern Iran. Updated Sydney System was used as histology gold standard. Areas under curves (AUCs), optimal cutoff and predictive values were calculated for serum biomarkers against the histology. Results 309 persons were recruited (mean age: 63.5 years old, 59.5% female). 84.5% were H. pylori positive and 77.5% were CagA positive. 21 fundic atrophy and 101 nonatrophic pangastritis were diagnosed. The best cutoff values in fundic atrophy assessment were calculated at PGI<56 μg/l (sensitivity: 61.9%, specificity: 94.8%) and PGI/PGII ratio<5 (sensitivity: 75.0%, specificity: 91.0%). A serum G-17<2.6 pmol/l or G-17>40 pmol/l was 81% sensitive and 73.3% specific for diagnosing fundic atrophy. At cutoff concentration of 11.8 μg/l, PGII showed 84.2% sensitivity and 45.4% specificity to distinguish nonatrophic pangastritis. Exclusion of nonatrophic pangastritis enhanced diagnostic ability of PGI/PGII ratio (from AUC = 0.66 to 0.90) but did not affect AUC of PGI. After restricting study samples to those with PGII<11.8, the sensitivity of using PGI<56 to define fundic atrophy increased to 83.3% (95%CI 51.6–97.9) and its specificity decreased to 88.8% (95%CI 80.8–94.3). Conclusions Among endoscopy clinic patients, PGII is a sensitive marker for extension of nonatrophic gastritis toward the corpus. PGI is a stable biomarker in assessment of fundic atrophy and has similar accuracy to PGI/PGII ratio among populations with prevalent nonatrophic pangastritis.
References
[1]
Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, et al. (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345: 784–789.
[2]
Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, et al. (2004) Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst 96: 388–396.
[3]
Ren JS, Kamangar F, Qiao YL, Taylor PR, Liang H, et al. (2009) Serum pepsinogens and risk of gastric and oesophageal cancers in the General Population Nutrition Intervention Trial cohort. Gut 58: 636–642.
[4]
Gritti I, Banfi G, Roi GS (2000) Pepsinogens: physiology, pharmacology pathophysiology and exercise. Pharmacol Res 41: 265–281.
[5]
Graham DY, Nurgalieva ZZ, El-Zimaity HM, Opekun AR, Campos A, et al. (2006) Noninvasive versus histologic detection of gastric atrophy in a Hispanic population in North America. Clin Gastroenterol Hepatol 4: 306–314.
[6]
Vaananen H, Vauhkonen M, Helske T, Kaariainen I, Rasmussen M, et al. (2003) Non-endoscopic diagnosis of atrophic gastritis with a blood test. Correlation between gastric histology and serum levels of gastrin-17 and pepsinogen I: a multicentre study. Eur J Gastroenterol Hepatol 15: 885–891.
[7]
Adamu MA, Weck MN, Rothenbacher D, Brenner H (2011) Incidence and risk factors for the development of chronic atrophic gastritis: five year follow-up of a population-based cohort study. Int J Cancer 128: 1652–1658.
[8]
Miki K, Ichinose M, Shimizu A, Huang SC, Oka H, et al. (1987) Serum pepsinogens as a screening test of extensive chronic gastritis. Gastroenterol Jpn 22: 133–141.
[9]
McColl KE, el-Omar E, Gillen D, Banerjee S (1997) The role of Helicobacter pylori in the pathophysiology of duodenal ulcer disease and gastric cancer. Semin Gastrointest Dis 8: 142–155.
[10]
Sipponen P, Marshall BJ (2000) Gastritis and gastric cancer. Western countries. Gastroenterol Clin North Am 29: 579–592, v-vi.
[11]
Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52: 6735–6740.
[12]
Brenner H, Rothenbacher D, Weck MN (2007) Epidemiologic findings on serologically defined chronic atrophic gastritis strongly depend on the choice of the cutoff-value. Int J Cancer 121: 2782–2786.
[13]
Islami F, Kamangar F, Aghcheli K, Fahimi S, Semnani S, et al. (2004) Epidemiologic features of upper gastrointestinal tract cancers in Northeastern Iran. Br J Cancer 90: 1402–1406.
[14]
Mahboubi E, Kmet J, Cook PJ, Day NE, Ghadirian P, et al. (1973) Oesophageal cancer studies in the Caspian Littoral of Iran: the Caspian cancer registry. Br J Cancer 28: 197–214.
[15]
Semnani S, Sadjadi A, Fahimi S, Nouraie M, Naeimi M, et al. (2006) Declining incidence of esophageal cancer in the Turkmen Plain, eastern part of the Caspian Littoral of Iran: a retrospective cancer surveillance. Cancer Detect Prev 30: 14–19.
[16]
Saidi F, Sepehr A, Fahimi S, Farahvash MJ, Salehian P, et al. (2000) Oesophageal cancer among the Turkomans of northeast Iran. Br J Cancer 83: 1249–1254.
[17]
Watabe H, Mitsushima T, Yamaji Y, Okamoto M, Wada R, et al. (2005) Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study. Gut 54: 764–768.
[18]
Broutet N, Plebani M, Sakarovitch C, Sipponen P, Megraud F (2003) Pepsinogen A, pepsinogen C, and gastrin as markers of atrophic chronic gastritis in European dyspeptics. Br J Cancer 88: 1239–1247.
[19]
Nardone G, Rocco A, Staibano S, Mezza E, Autiero G, et al. (2005) Diagnostic accuracy of the serum profile of gastric mucosa in relation to histological and morphometric diagnosis of atrophy. Aliment Pharmacol Ther 22: 1139–1146.
[20]
Storskrubb T, Aro P, Ronkainen J, Sipponen P, Nyhlin H, et al. (2008) Serum biomarkers provide an accurate method for diagnosis of atrophic gastritis in a general population: The Kalixanda study. Scand J Gastroenterol 43: 1448–1455.
[21]
Kang JM, Kim N, Yoo JY, Park YS, Lee DH, et al. (2008) The role of serum pepsinogen and gastrin test for the detection of gastric cancer in Korea. Helicobacter 13: 146–156.
[22]
Haj-Sheykholeslami A, Rakhshani N, Amirzargar A, Rafiee R, Shahidi SM, et al. (2008) Serum pepsinogen I, pepsinogen II, and gastrin 17 in relatives of gastric cancer patients: comparative study with type and severity of gastritis. Clin Gastroenterol Hepatol 6: 174–179.
[23]
He CY, Sun LP, Gong YH, Xu Q, Dong NN, et al. (2011) Serum pepsinogen II: a neglected but useful biomarker to differentiate between diseased and normal stomachs. J Gastroenterol Hepatol 26: 1039–1046.
[24]
Iijima K, Koike T, Abe Y, Ara N, Uno K, et al. (2009) Alteration of correlation between serum pepsinogen concentrations and gastric acid secretion after H. pylori eradication. J Gastroenterol 44: 819–825.
[25]
Chang YW, Oh HC, Jang JY, Hwangbo Y, Lee JW, et al. (2008) IL-1beta and IL-8, matrix metalloproteinase 3, and pepsinogen secretion before and after H. pylori eradication in gastroduodenal phenotypes. Scand J Gastroenterol 43: 1184–1193.
[26]
Abnet CC, Zheng W, Ye W, Kamangar F, Ji BT, et al. (2011) Plasma pepsinogens, antibodies against Helicobacter pylori, and risk of gastric cancer in the Shanghai Women's Health Study Cohort. Br J Cancer.
[27]
Mardh E, Mardh S, Mardh B, Borch K (2002) Diagnosis of gastritis by means of a combination of serological analyses. Clin Chim Acta 320: 17–27.
[28]
Knight T, Wyatt J, Wilson A, Greaves S, Newell D, et al. (1996) Helicobacter pylori gastritis and serum pepsinogen levels in a healthy population: development of a biomarker strategy for gastric atrophy in high risk groups. Br J Cancer 73: 819–824.
[29]
Sipponen P, Ranta P, Helske T, Kaariainen I, Maki T, et al. (2002) Serum levels of amidated gastrin-17 and pepsinogen I in atrophic gastritis: an observational case-control study. Scand J Gastroenterol 37: 785–791.
[30]
Shimatani T, Inoue M, Iwamoto K, Hyogo H, Yokozaki M, et al. (2005) Gastric acidity in patients with follicular gastritis is significantly reduced, but can be normalized after eradication for Helicobacter pylori. Helicobacter 10: 256–265.
[31]
Imagawa S, Yoshihara M, Ito M, Yoshida S, Wada Y, et al. (2008) Evaluation of gastric cancer risk using topography of histological gastritis: a large-scaled cross-sectional study. Dig Dis Sci 53: 1818–1823.
[32]
Song HJ, Jang SJ, Yun SC, Park YS, Kim MJ, et al. (2010) Low Levels of Pepsinogen I and Pepsinogen I/II Ratio are Valuable Serologic Markers for Predicting Extensive Gastric Corpus Atrophy in Patients Undergoing Endoscopic Mucosectomy. Gut Liver 4: 475–480.
[33]
Shiotani A, Iishi H, Uedo N, Kumamoto M, Nakae Y, et al. (2005) Histologic and serum risk markers for noncardia early gastric cancer. Int J Cancer 115: 463–469.
[34]
Bodger K, Wyatt JI, Heatley RV (2001) Variation in serum pepsinogens with severity and topography of Helicobacter pylori-associated chronic gastritis in dyspeptic patients referred for endoscopy. Helicobacter 6: 216–224.
[35]
Di Mario F, Moussa AM, Cavallaro LG, Caruana P, Merli R, et al. (2004) Clinical usefulness of serum pepsinogen II in the management of Helicobacter pylori infection. Digestion 70: 167–172.
[36]
Gatta L, Di Mario F, Vaira D, Rugge M, Franze A, et al. (2011) Quantification of serum levels of pepsinogens and gastrin to assess eradication of Helicobacter pylori. Clin Gastroenterol Hepatol 9: 440–442.
[37]
Ricci C, Vakil N, Rugge M, Gatta L, Perna F, et al. (2004) Serological markers for gastric atrophy in asymptomatic patients infected with Helicobacter pylori. American Journal of Gastroenterology 99: 1910–1915.
[38]
Malekzadeh R, Sotoudeh M, Derakhshan MH, Mikaeli J, Yazdanbod A, et al. (2004) Prevalence of gastric precancerous lesions in Ardabil, a high incidence province for gastric adenocarcinoma in the northwest of Iran. J Clin Pathol 57: 37–42.
[39]
Pakseresht M, Forman D, Malekzadeh R, Yazdanbod A, West RM, et al. (2011) Dietary habits and gastric cancer risk in north-west Iran. Cancer Causes Control 22: 725–736.
[40]
Weck MN, Gao L, Brenner H (2009) Helicobacter pylori infection and chronic atrophic gastritis: associations according to severity of disease. Epidemiology 20: 569–574.
[41]
Gao L, Weck MN, Nieters A, Brenner H (2009) Inverse association between a pro-inflammatory genetic profile and Helicobacter pylori seropositivity among patients with chronic atrophic gastritis: enhanced elimination of the infection during disease progression? Eur J Cancer 45: 2860–2866.
[42]
Parente F, Lazzaroni M, Sangaletti O, Baroni S, Bianchi Porro G (1985) Cigarette smoking, gastric acid secretion, and serum pepsinogen I concentrations in duodenal ulcer patients. Gut 26: 1327–1332.
[43]
Kikuchi S, Kurosawa M, Sakiyama T, Tenjin H (2002) Long-term effect of smoking on serum pepsinogen values. J Epidemiol 12: 351–356.
[44]
Tatemichi M, Kabuto M, Tsugane S (2001) Effect of smoking on serum pepsinogen I level depends on serological status of Helicobacter pylori. Jpn J Cancer Res 92: 243–248.
[45]
Dixon MF, Genta RM, Yardley JH, Correa P (1996) Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 20: 1161–1181.
[46]
Pepe M, Longton G, Janes H (2009) Estimation and Comparison of Receiver Operating Characteristic Curves. Stata J 9: 1.
