Letters to the Editor 105
Hosseini M, Amoueian S, Attaranzadeh A, Montazer M, Soltani G, Asadollahi K, Abangah G. Serum gastrin 17, pepsinogen I and pepsinogen II in atrophic gastritis patients living in North-East of Iran. J Res Med Sci 2013; 18:225–229. Shafaghi A, Mansour-Ghanaei F, Joukar F, Sharafkhah M, Mesbah A, Askari K, et al. Serum gastrin and the pepsinogen I/II ratio as markers for diagnosis of premalignant gastric lesions. Asian Pac J Cancer Prev 2013; 14:3931–3936.
thresholds have been proposed. As an example, Massarrat et al. [5] very recently obtained median PGI levels of 103 μg/l (interquartile range = 78–163) in a series of 107 patients with moderate or marked corpus atrophy. In this context our results are neither skewed nor impossible; in our study only one patient with atrophic gastritis (severe) showed PGI levels lower than 25 μg/l, and only two patients between 25 and 100 μg/l (one severe and one moderate).
Response to: Accuracy of GastroPanel test in detection of atrophic gastritis
As mentioned in our article, the Updated Sydney System (USS) was used as gold standard and all samples were evaluated and classified using that system (including the severity of each one of the variables measured with USS). It is true that GastroPanel diagnosis is based on the Gastrosoft software, and we used Gastrosoft, version 0.4b; however, we asked Biohit Oyj for the algorithm underlying the software programming (Fig. 1 of our article) for independent analysis. The output (diagnostic classification) of Gastrosoft for each patient was the value used in the GastroPanel section of our article (comparing Gastrosoft diagnosis to USS histological diagnosis). As the results were extremely poor (interassay agreement κ 0.089; slight/insignificant concordance) they were not included in the article; for example, 85% of patients diagnosed as corpus atrophy by Gastrosoft had normal mucosa by USS.
6
7
Adrian G. McNicholla, Julio Valleb and Javier P. Gisberta, aUniversity Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, Madrid and b Virgen de La Salud Hospital, Toledo, Spain Correspondence to Adrian G. McNicholl, PhD, MSc, University Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, 28006, Madrid, Spain Tel: +0034 913093911; fax: +0034 914022299; e-mail: [email protected] Received 5 November 2014 Accepted 6 November 2014
We thank Korpela et al. [1] for their comments regarding our study on the accuracy of GastroPanel for the diagnosis of atrophic gastritis [2]. We respect the interest of Biohit to defend its product that, we agree, is based on the best available noninvasive test for atrophy [pepsinogens (PGs)]. However, even the Maastricht IV Consensus states the low sensitivity of these tests, and the need of local validation before implementing their recommendation [3]. We agree with the correspondents that our study contradicts some previous experiences; however, as mentioned and exemplified in our response letter to Professor Di Mario, the debate on the real usefulness of PG and gastrin serologic marker panels is still ongoing, and conflicting results have been published [4]. Deltaclon (Helsinky, Finland) was, at the time of the study, the official distributer of Biohit in Spain, and Biohit Oyj (Helsinky, Finland) had full knowledge of this protocol and collaborated with the development of this project. Biohit Oyj provided the enzyme-linked immunosorbent assay kits, and the Gastrosoft (Helsinky, Finland), as well as giving information regarding the internal calculations of the algorithm. After contacting the Deltaclon staff in charge of the study samples, it has been confirmed that the use of chemiluminescent assay is a manuscript erratum, and that, as specified in the study protocol, the biomarkers were measured using the GastroPanel-Biohit Oyj validated enzyme-linked immunosorbent assay method (correction for this erratum has been sent to the European Journal of Gastroenterology & Hepatology editors). Although several series have proposed a PGI threshold for the diagnosis of atrophy at 25 μg/l, these values have been shown to be population specific and different
Korpela et al. [1] in their letter mention that GastroPanel should always be used taking moderate or marked/severe atrophy as endpoints. However, GastroPanel, through its website and publicity, claims to be able to, among other things, identify normal mucosa and to diagnose gastric atrophy, it does not specify that is only valid for high-risk (moderate and marked) atrophy [6]. Our aim was not to evaluate, per se, the claims/conclusions published in other studies on serological biomarkers, but to evaluate the clinical utility of GastroPanel itself, and therefore the endpoint has to be the claims of the product on its brochure and website (as that is the information generally available to practitioners). Besides, in our study only one of the patients had mild corpus atrophy, and excluding it from the analysis or grouping it with the normal mucosa patients did not improve the results. Therefore, our results also invalidate the use of GastroPanel in our population for the diagnosis of moderate and severe atrophy. It is true that the number of atrophies found in our studied population is a limitation of our study, making our confidence intervals wider. Nevertheless, our results do not fall as outliers if compared with the studies evaluated by Dinis-Ribero et al. [7] in his meta-analysis (sensitivities ranging from 16 to 90%). Finally, we disagree with Biohit’s final remarks regarding the invalidity of our study to draw conclusions on the screening capacity of the product. It is GastroPanel’s publicity that claims its use not only for screening purposes but also in clinical practice for the diagnosis of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
106 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
gastric alterations in dyspeptic patients. In any case, regardless of the design, and the diagnostic intention behind the study, a method offering an area under the receiver operating characteristic curve lower than 0.70 is considered poor or failed. Even taking the higher range of the 95% confidence intervals for the sensitivity and specificity achieved by GastroPanel in our population, between 20 and 30% of patients would be misdiagnosed either in clinical or screening settings.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 Korpela S, Sipponen P, Härkonen M, Peetsalu A, Syrjänen K. Accuracy of GastroPanel test in detection of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 27:102–104. 2 McNicholl AG, Forné M, Barrio J, de la Coba C, González B, Rivera R, et al. Helicobacter pylori Study Group of the Asociación Española de Gastroenterología (AEG). Accuracy of GastroPanel for the diagnosis of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 26:941–948. 3 Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, et al. European Helicobacter Study Group. Management of Helicobacter pylori infection: the Maastricht IV/Florence Consensus Report. Gut 2012; 61:646–664. 4 McNicholl AG, Gisbert JP. Response to: Misleading results in diagnosis of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 27:104–105. 5 Massarrat S, Haj-Sheykholeslami A, Mohamadkhani A, Zendehdel N, Aliasgari A, Rakhshani N, et al. Pepsinogen II can be a potential surrogate marker of morphological changes in corpus before and after H. pylori eradication. Biomed Res Int 2014; 2014:481607. 6 Biohit Oyj; 2010. Available at: http://www.gastropanel.com. [Accessed 14 August 2014]. 7 Dinis-Ribeiro M, Yamaki G, Miki K, Costa-Pereira A, Matsukawa M, Kurihara M. Meta-analysis on the validity of pepsinogen test for gastric carcinoma, displasia or chronic atrophic gastritis screening. J Med Screen 2004; 11:141–147.
Criticism of: diagnostic accuracy of abdominal ultrasound in the screening of esophageal varices in patients with cirrhosis Abd Elrazek M.A. Abd Elrazek, Department of Gastroenterology and Hepatology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt Correspondence to Abd Elrazek M.A. Abd Elrazek, PhD, MD, Medicine of Liver Transplantation, Department of Gastroenterology and Hepatology, Al Azhar Faculty of Medicine, Al-Azhar University, Cairo, Egypt E-mail: [email protected] Received 9 August 2014 Accepted 12 August 2014
I recently came across an article entitled ‘Diagnostic accuracy of abdominal ultrasound in the screening of esophageal varices in patients with cirrhosis’ published in European Journal of Gastroenterology & Hepatology in August 2014 by Sort et al. [1]. I appreciate the effort of Sort and colleagues in their study. However, in this communication, I would like to put forth a critical analysis of several points that I hope will help everybody involved in the field.
Studies dealing with esophageal varices, which report that approximately half of the patients with liver cirrhosis have esophageal varices and that one-third of all patients with varices will develop variceal hemorrhage, a major cause of morbidity and mortality in patients with cirrhosis, especially those waiting for liver transplantation, are highly important as many patient lives can be saved through surgery. Although Sort and colleagues have reported many noninvasive methods to predict varices, currently none can replace endoscopic screening; further, they did not mention the two important noninvasive studies cited in PubMed–NCBI and taken as references in the evidence-based clinical information resource UpToDate: Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis (http://www. uptodate.com/contents/primary-and-pre-primary-prophylaxisagainst-variceal-hemorrhage-in-patients-with-cirrhosis). (1) The ratio of platelet count to spleen size (expressed as a SD score) and clinical prediction rules that include platelet count, spleen size, and albumin have been shown to predict varices in children [2]. (2) In addition, a study using two-dimensional ultrasound (US) of the lower esophagus in patients with chronic liver disease found that patients with varices had a higher mean esophageal wall thickness compared with patients who did not have varices: 7.3 ± 3.3 mm in those with esophageal varices, 8.65 ± 1.98 mm in those with risky esophageal varices, and 3.7 ± 0.5 mm in those without varices. The overall accuracy was 95% [3]. Further, the second study mentioned that the sonographic image of portal hypertension (spleen size, portal vein diameter, splenic vein diameter, and the presence of collaterals) was not correlated with the degree of esophageal varices in many patients. However, in our study we performed examination of the esophagi of 673 patients to demonstrate esophageal wall thicknesses, which was very helpful in evaluation of the degree of esophageal varices. Moreover, in our experience and as per many published studies, portal vein (PV) pressure is not always correlated with PV diameter; the only method for evaluating PV pressure is by an intravascular invasive measure [4–7]. In addition, the spleen should be measured in two different spans, longitudinal × transverse diameters, and not only a longitudinal diameter greater than 12 cm could be indicative of splenomegaly, as reported in the study by Sort and colleagues. However, Sort and colleagues reported on page 3 of their article the following sentence: ‘The results indicate that if abdominal US were used to exclude patients at a low risk of LV from the endoscopic screening program, the number of endoscopies with this indication would decrease by 27%, but 14.9% of patients would be misclassified’. Accordingly,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Hosseini M, Amoueian S, Attaranzadeh A, Montazer M, Soltani G, Asadollahi K, Abangah G. Serum gastrin 17, pepsinogen I and pepsinogen II in atrophic gastritis patients living in North-East of Iran. J Res Med Sci 2013; 18:225–229. Shafaghi A, Mansour-Ghanaei F, Joukar F, Sharafkhah M, Mesbah A, Askari K, et al. Serum gastrin and the pepsinogen I/II ratio as markers for diagnosis of premalignant gastric lesions. Asian Pac J Cancer Prev 2013; 14:3931–3936.
thresholds have been proposed. As an example, Massarrat et al. [5] very recently obtained median PGI levels of 103 μg/l (interquartile range = 78–163) in a series of 107 patients with moderate or marked corpus atrophy. In this context our results are neither skewed nor impossible; in our study only one patient with atrophic gastritis (severe) showed PGI levels lower than 25 μg/l, and only two patients between 25 and 100 μg/l (one severe and one moderate).
Response to: Accuracy of GastroPanel test in detection of atrophic gastritis
As mentioned in our article, the Updated Sydney System (USS) was used as gold standard and all samples were evaluated and classified using that system (including the severity of each one of the variables measured with USS). It is true that GastroPanel diagnosis is based on the Gastrosoft software, and we used Gastrosoft, version 0.4b; however, we asked Biohit Oyj for the algorithm underlying the software programming (Fig. 1 of our article) for independent analysis. The output (diagnostic classification) of Gastrosoft for each patient was the value used in the GastroPanel section of our article (comparing Gastrosoft diagnosis to USS histological diagnosis). As the results were extremely poor (interassay agreement κ 0.089; slight/insignificant concordance) they were not included in the article; for example, 85% of patients diagnosed as corpus atrophy by Gastrosoft had normal mucosa by USS.
6
7
Adrian G. McNicholla, Julio Valleb and Javier P. Gisberta, aUniversity Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, Madrid and b Virgen de La Salud Hospital, Toledo, Spain Correspondence to Adrian G. McNicholl, PhD, MSc, University Hospital of ‘La Princesa’ and Health Research Institute Princesa, Center for Network Biomedical Research on Hepatic and Digestive Diseases, 28006, Madrid, Spain Tel: +0034 913093911; fax: +0034 914022299; e-mail: [email protected] Received 5 November 2014 Accepted 6 November 2014
We thank Korpela et al. [1] for their comments regarding our study on the accuracy of GastroPanel for the diagnosis of atrophic gastritis [2]. We respect the interest of Biohit to defend its product that, we agree, is based on the best available noninvasive test for atrophy [pepsinogens (PGs)]. However, even the Maastricht IV Consensus states the low sensitivity of these tests, and the need of local validation before implementing their recommendation [3]. We agree with the correspondents that our study contradicts some previous experiences; however, as mentioned and exemplified in our response letter to Professor Di Mario, the debate on the real usefulness of PG and gastrin serologic marker panels is still ongoing, and conflicting results have been published [4]. Deltaclon (Helsinky, Finland) was, at the time of the study, the official distributer of Biohit in Spain, and Biohit Oyj (Helsinky, Finland) had full knowledge of this protocol and collaborated with the development of this project. Biohit Oyj provided the enzyme-linked immunosorbent assay kits, and the Gastrosoft (Helsinky, Finland), as well as giving information regarding the internal calculations of the algorithm. After contacting the Deltaclon staff in charge of the study samples, it has been confirmed that the use of chemiluminescent assay is a manuscript erratum, and that, as specified in the study protocol, the biomarkers were measured using the GastroPanel-Biohit Oyj validated enzyme-linked immunosorbent assay method (correction for this erratum has been sent to the European Journal of Gastroenterology & Hepatology editors). Although several series have proposed a PGI threshold for the diagnosis of atrophy at 25 μg/l, these values have been shown to be population specific and different
Korpela et al. [1] in their letter mention that GastroPanel should always be used taking moderate or marked/severe atrophy as endpoints. However, GastroPanel, through its website and publicity, claims to be able to, among other things, identify normal mucosa and to diagnose gastric atrophy, it does not specify that is only valid for high-risk (moderate and marked) atrophy [6]. Our aim was not to evaluate, per se, the claims/conclusions published in other studies on serological biomarkers, but to evaluate the clinical utility of GastroPanel itself, and therefore the endpoint has to be the claims of the product on its brochure and website (as that is the information generally available to practitioners). Besides, in our study only one of the patients had mild corpus atrophy, and excluding it from the analysis or grouping it with the normal mucosa patients did not improve the results. Therefore, our results also invalidate the use of GastroPanel in our population for the diagnosis of moderate and severe atrophy. It is true that the number of atrophies found in our studied population is a limitation of our study, making our confidence intervals wider. Nevertheless, our results do not fall as outliers if compared with the studies evaluated by Dinis-Ribero et al. [7] in his meta-analysis (sensitivities ranging from 16 to 90%). Finally, we disagree with Biohit’s final remarks regarding the invalidity of our study to draw conclusions on the screening capacity of the product. It is GastroPanel’s publicity that claims its use not only for screening purposes but also in clinical practice for the diagnosis of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
106 European Journal of Gastroenterology & Hepatology 2015, Vol 27 No 1
gastric alterations in dyspeptic patients. In any case, regardless of the design, and the diagnostic intention behind the study, a method offering an area under the receiver operating characteristic curve lower than 0.70 is considered poor or failed. Even taking the higher range of the 95% confidence intervals for the sensitivity and specificity achieved by GastroPanel in our population, between 20 and 30% of patients would be misdiagnosed either in clinical or screening settings.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1 Korpela S, Sipponen P, Härkonen M, Peetsalu A, Syrjänen K. Accuracy of GastroPanel test in detection of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 27:102–104. 2 McNicholl AG, Forné M, Barrio J, de la Coba C, González B, Rivera R, et al. Helicobacter pylori Study Group of the Asociación Española de Gastroenterología (AEG). Accuracy of GastroPanel for the diagnosis of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 26:941–948. 3 Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, et al. European Helicobacter Study Group. Management of Helicobacter pylori infection: the Maastricht IV/Florence Consensus Report. Gut 2012; 61:646–664. 4 McNicholl AG, Gisbert JP. Response to: Misleading results in diagnosis of atrophic gastritis. Eur J Gastroenterol Hepatol 2014; 27:104–105. 5 Massarrat S, Haj-Sheykholeslami A, Mohamadkhani A, Zendehdel N, Aliasgari A, Rakhshani N, et al. Pepsinogen II can be a potential surrogate marker of morphological changes in corpus before and after H. pylori eradication. Biomed Res Int 2014; 2014:481607. 6 Biohit Oyj; 2010. Available at: http://www.gastropanel.com. [Accessed 14 August 2014]. 7 Dinis-Ribeiro M, Yamaki G, Miki K, Costa-Pereira A, Matsukawa M, Kurihara M. Meta-analysis on the validity of pepsinogen test for gastric carcinoma, displasia or chronic atrophic gastritis screening. J Med Screen 2004; 11:141–147.
Criticism of: diagnostic accuracy of abdominal ultrasound in the screening of esophageal varices in patients with cirrhosis Abd Elrazek M.A. Abd Elrazek, Department of Gastroenterology and Hepatology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt Correspondence to Abd Elrazek M.A. Abd Elrazek, PhD, MD, Medicine of Liver Transplantation, Department of Gastroenterology and Hepatology, Al Azhar Faculty of Medicine, Al-Azhar University, Cairo, Egypt E-mail: [email protected] Received 9 August 2014 Accepted 12 August 2014
I recently came across an article entitled ‘Diagnostic accuracy of abdominal ultrasound in the screening of esophageal varices in patients with cirrhosis’ published in European Journal of Gastroenterology & Hepatology in August 2014 by Sort et al. [1]. I appreciate the effort of Sort and colleagues in their study. However, in this communication, I would like to put forth a critical analysis of several points that I hope will help everybody involved in the field.
Studies dealing with esophageal varices, which report that approximately half of the patients with liver cirrhosis have esophageal varices and that one-third of all patients with varices will develop variceal hemorrhage, a major cause of morbidity and mortality in patients with cirrhosis, especially those waiting for liver transplantation, are highly important as many patient lives can be saved through surgery. Although Sort and colleagues have reported many noninvasive methods to predict varices, currently none can replace endoscopic screening; further, they did not mention the two important noninvasive studies cited in PubMed–NCBI and taken as references in the evidence-based clinical information resource UpToDate: Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis (http://www. uptodate.com/contents/primary-and-pre-primary-prophylaxisagainst-variceal-hemorrhage-in-patients-with-cirrhosis). (1) The ratio of platelet count to spleen size (expressed as a SD score) and clinical prediction rules that include platelet count, spleen size, and albumin have been shown to predict varices in children [2]. (2) In addition, a study using two-dimensional ultrasound (US) of the lower esophagus in patients with chronic liver disease found that patients with varices had a higher mean esophageal wall thickness compared with patients who did not have varices: 7.3 ± 3.3 mm in those with esophageal varices, 8.65 ± 1.98 mm in those with risky esophageal varices, and 3.7 ± 0.5 mm in those without varices. The overall accuracy was 95% [3]. Further, the second study mentioned that the sonographic image of portal hypertension (spleen size, portal vein diameter, splenic vein diameter, and the presence of collaterals) was not correlated with the degree of esophageal varices in many patients. However, in our study we performed examination of the esophagi of 673 patients to demonstrate esophageal wall thicknesses, which was very helpful in evaluation of the degree of esophageal varices. Moreover, in our experience and as per many published studies, portal vein (PV) pressure is not always correlated with PV diameter; the only method for evaluating PV pressure is by an intravascular invasive measure [4–7]. In addition, the spleen should be measured in two different spans, longitudinal × transverse diameters, and not only a longitudinal diameter greater than 12 cm could be indicative of splenomegaly, as reported in the study by Sort and colleagues. However, Sort and colleagues reported on page 3 of their article the following sentence: ‘The results indicate that if abdominal US were used to exclude patients at a low risk of LV from the endoscopic screening program, the number of endoscopies with this indication would decrease by 27%, but 14.9% of patients would be misclassified’. Accordingly,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
