Systematic review with meta-analysis: diagnostic performance of the combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies serum assays for the diagnosis of atrophic gastritis.

TLDR: The combination of pepsinogen, gastrin‐17 and anti‐H.

Abstract: Background The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays (panel test) is a non-invasive tool for the diagnosis of atrophic gastritis. However, the diagnostic reliability of this test is still uncertain. Aim To assess the diagnostic performance of the serum panel test for the diagnosis of atrophic gastritis. Methods Medline via PubMed, Embase, Scopus, Cochrane Library databases and abstracts of international conferences proceedings were searched from January 1995 to December 2016 using the primary keywords “pepsinogens,” “gastrin,” “atrophic gastritis,” “gastric precancerous lesions.” Studies were included if they assessed the accuracy of the serum panel test for the diagnosis of atrophic gastritis using histology according to the updated Sydney System as reference standard. Results Twenty studies with a total of 4241 subjects assessed the performance of serum panel test for the diagnosis of atrophic gastritis regardless of the site in the stomach. The summary sensitivity was 74.7% (95% confidence interval (CI), 62.0-84.3) and the specificity was 95.6% (95%CI, 92.6-97.4). With a prevalence of atrophic gastritis of 27% (median prevalence across the studies), the negative predictive value was 91%. Few studies with small sample size assessed the performance of the test in detecting the site of atrophic gastritis. Conclusions The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays appears to be a reliable tool for the diagnosis of atrophic gastritis. This test may be used for screening subjects or populations at high risk of gastric cancer for atrophic gastritis; however, a cost-effectiveness analysis is needed.

Figures

Table 1. Characteristics of the studies included.

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This is a repository copy of Systematic review with meta-analysis: diagnostic performance
of the combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies serum
assays for the diagnosis of atrophic gastritis.
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Version: Accepted Version
Article:
Zagari, RM, Rabitti, S, Greenwood, DC orcid.org/0000-0001-7035-3096 et al. (3 more
authors) (2017) Systematic review with meta-analysis: diagnostic performance of the
combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies serum
assays for the diagnosis of atrophic gastritis. Alimentary Pharmacology and Therapeutics,
46 (7). pp. 657-667. ISSN 0269-2813
https://doi.org/10.1111/apt.14248
© 2017 John Wiley & Sons Ltd. This is the peer reviewed version of the following article:
'Zagari, RM, Rabitti, S, Greenwood, DC et al (2017). Systematic review with
meta-analysis: diagnostic performance of the combination of pepsinogen, gastrin-17 and
anti-Helicobacter pylori antibodies serum assays for the diagnosis of atrophic gastritis.
Alimentary Pharmacology and Therapeutics, 46 (7). pp. 657-667', which has been
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1
Systematic review with meta-analysis: diagnostic performance of the
combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies
serum assays for the diagnosis of atrophic gastritis.
Short title: The panel test for the diagnosis of atrophic gastritis.
Rocco Maurizio Zagari
1
, Stefano Rabitti
1
, Darren C. Greenwood
2
, Leonardo H. Eusebi
1
, Amanda Vestito
3
,
Franco Bazzoli
1
.
1
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
2
Division of Biostatistics,
University of Leeds, Leeds, UK
3
Gastroenterology Unit, S. Orsola-Malpighi Hospital, Bologna, Italy
Corresponding author:
Prof. Rocco Maurizio Zagari,
Department of Medical and Surgical Sciences, University of Bologna,
Policlinico S. Orsola-Malpighi, Via Massarenti n. 9, 40138 Bologna, Italy.
Tel and Fax: +39 051 2144117
Email: roccomaurizio.zagari@unibo.it
Word count:

2
ABSTRACT
Background: The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays
(panel test) is a non invasive tool for the diagnosis of atrophic gastritis. However, the diagnostic reliability of
this test is still uncertain.
Aim: To assess the diagnostic performance of the serum panel test for the diagnosis of atrophic gastritis.
Methods: Medline via PubMed, Embase, Scopus, Cochrane Library databases and abstracts of international
conferences proceedings were searched from January 1995 to December 2016 using the primary keywords
“pepsinogens”, “gastrin”, “atrophic gastritis”, “gastric precancerous lesions”. Studies were included if they
assessed the accuracy of the serum panel test for the diagnosis of atrophic gastritis using histology according
to the updated Sydney System as reference standard.
Results: Twenty studies with a total of 4241 subjects assessed the performance of serum panel test for the
diagnosis of atrophic gastritis regardless of the site in the stomach. The summary sensitivity was 74.7% (95%
confidence interval (CI), 62.0-84.3) and the specificity was 95.6% (95%CI, 92.6-97.4). With a prevalence of
atrophic gastritis of 27% (median prevalence across the studies), the negative predictive value was 91%. Few
studies with small sample size assessed the performance of the test in detecting the site of atrophic gastritis.
Conclusions: The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays
appears to be a reliable tool for the diagnosis of atrophic gastritis. This test may be used for screening subjects
or populations at high risk of gastric cancer for atrophic gastritis; however, a cost-effectiveness analysis is
needed.

3
INTRODUCTION
Atrophic gastritis is a loss of appropriate glands of the gastric mucosa, which are replaced by connective tissue
and/or intestinal type-epithelium (intestinal metaplasia) (1).
Atrophic gastritis, which is usually caused by
Helicobacter (H.) pylori or may have an autoimmune origin, predisposes to gastric cancer and impairs gastric
physiology leading to hypo- or achlorhydria, iron and vitamin B
12
malabsorption (2). It is well known that the
intestinal-type gastric adenocarcinoma develops in a stepwise manner with a sequence of events that evolves
from atrophic gastritis and intestinal metaplasia to dysplasia and carcinoma. International guidelines
recommend endoscopic follow-up and gastric biopsies for subjects with atrophic gastritis, even after H. pylori
eradication, in order to early detect gastric cancer and reduce mortality (2,3).
However, identifying subjects with an underlying atrophic gastritis is still an issue. Gastroscopy and histology
are the reference standard, but the use of endoscopy as a screening test is costly, uncomfortable and does not
have good patient’s compliance (2).
International guidelines and a recent global consensus report have agreed
that serological tests may be very useful in order to identify individuals with atrophic gastritis (2-4). A non-
invasive tool able to easily identify individuals with atrophic gastritis, or those who are very likely to carry
such precancerous lesion, is essential for improving the early diagnosis of gastric cancer. Such test would be
ideal for screening subgroups of subjects, such as those with a positive family history, or populations at high
risk of gastric cancer, to identify those patients which must undergo endoscopy. In addition, an accurate non-
invasive test would be very helpful to improve our knowledge on the epidemiology of atrophic gastritis in the
general population.
Over the last decade, the combination of serological assays including pepsinogen, gastrin-17 (G-17) and anti-
H. pylori antibodies (panel test) has been proposed as a non-invasive test for the diagnosis of atrophic gastritis
(2-4).
The rationale of this test is based on the fact that pepsinogen-I (PG-I) is secreted only by oxintic glands
of the corpus mucosa, while pepsinogen II (PG-II) is also produced in the gastric antrum and duodenum, and
that gastrin-17 is only secreted by the G cells of the antral mucosa. Serum PG-I levels and/or the PG-I/PG-II
ratio seem to be lower in patients with corpus atrophic gastritis, whereas a low G-17 serum level, in
combination with positive anti-H. pylori antibodies (HpAb), would indicate the presence of antrum atrophic

4
gastritis (5).
Thus the combination of the results of HpAb, PG-I or PGI/PGII ratio, and G-17 tests would allow
us to detect the presence and site of atrophic gastritis (5).
However, although the panel test is commercially available and used in many countries worldwide, in
particular in Europe, the diagnostic reliability of this test remains uncertain. Clarifying the diagnostic
performance of this test is essential for its use in individuals and in the general population for gastric cancer
screening and epidemiological studies on the prevalence and incidence of atrophic gastritis.
The aim of this study was to carry out a systematic review and meta-analysis to determine the diagnostic
performance of the combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serum assays for the
diagnosis of atrophic gastritis in adults. The primary outcome was to assess the diagnostic performance for
the diagnosis of atrophic gastritis regardless of the location. The secondary outcome was to determine the
accuracy in detecting the site of atrophic gastritis.
METHODS
We performed a systematic review and a meta-analysis following the recommendations of the Cochrane
Collaboration’s Diagnostic Test Accuracy Group (6).
Search strategy and study selection
We searched MEDLINE via PubMed, Ovid Embase, the Cochrane Library and Scopus databases up to 31
st
December 2016. The electronic search of literature was performed by using the following keywords:
“pepsinogens”, “pepsinogen I”, “pepsinogen II”, “gastrin”, “panel test” or “gastropanel”, and “atrophic
gastritis”, “gastric atrophy”, “intestinal metaplasia”, “gastric precancerous condition” or “gastric precancerous
lesion”. The search strategies are reported in the Supplementary Appendix 1. The first validation study of the
panel test was published in 2002 (7);
in order to identify earlier studies the search period was extended back
to January 1995. In addition, we searched electronically and by hands abstracts of the conferences proceedings
of Digestive Diseases Week, United European Gastroenterology Week, Asia Pacific Digestive Week and
International Workshop on Helicobacter and Microbiota for the same period. We searched the references lists

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Systematic review with meta-analysis: diagnostic performance of the combination of pepsinogen, gastrin-17 and anti-helicobacter pylori antibodies serum assays for the diagnosis of atrophic gastritis" ?

This is the peer reviewed version of the following article: 'Zagari, RM, Rabitti, S, Greenwood, DC et al ( 2017 ). This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. 

Q2. What is the effect of the gastrin on the antrum atrophic gas?

It is well known that PPIs increase serum levels of G-17 through the reduction of hydrochloric acid; in addition, the trophic effect of the gastrin on parietal cells increases serum levels of pepsinogens (5,29); 

Q3. how many studies are needed to confirm the diagnosis of atrophic gastritis?

well-designed high quality studies with a large sample size are needed to confirm the performance of the panel test in the diagnosis of atrophic gastritis, especially in Asia and America. 

Q4. What is the strength of this study?

Another strength of this study is the use of a multilevel statistical approach with a bivariate model, that is recommended for meta-analysis of diagnostic accuracy studies (6,9). 

Q5. What is the strength of this review?

A strength of this review is the comprehensive search of literature without restrictions on the language of publications; the authors also identified and included unpublished studies, which were reported as abstracts in international conferences proceedings, minimizing the risk of missing relevant studies. 

Q6. How many studies were performed in a single centre?

Fourteen studies were performed in a single centre (7,15,18,20,23,30,33,38,48-53), and six were multicentre studies (12,19,26,35,42,47). 

Q7. How many studies assessed the performance of the serum panel test for the diagnosis of atrophic?

Twenty studies with a total of 4241 subjects assessed the performance of serum panel test for the diagnosis of atrophic gastritis regardless of the site in the stomach. 

Q8. What is the way to diagnose atrophic gastritis?

The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays appears to be a reliable tool for the diagnosis of atrophic gastritis. 

Q9. What was the primary keyword used in the search?

Methods: Medline via PubMed, Embase, Scopus, Cochrane Library databases and abstracts of international conferences proceedings were searched from January 1995 to December 2016 using the primary keywords “pepsinogens”, “gastrin”, “atrophic gastritis”, “gastric precancerous lesions”. 

Q10. How many studies were conducted in Europe?

Fifteen studies were conducted in Europe (7,12,15,19,20,23,26,33,35,42,49-53), three in Russia (18,47,48), one in Japan (30), and one in Africa (38). 

Q11. What system is the widely accepted for classifying and grading gastritis?

The Updated Sydney System is the most widely accepted system for classifying and grading gastritis both in clinical practice and research (2). 

Q12. What is the way to identify atrophic gastritis?

International guidelines recommend endoscopic follow-up and gastric biopsies for subjects with atrophic gastritis, even after H. pylori eradication, in order to early detect gastric cancer and reduce mortality (2,3). 

Q13. How many full text articles were assessed for eligibility?

The electronic search identified 3924 records after duplicates were removed, of which 38 full text articles were assessed for eligibility (5,7,12-47). 

Q14. How many studies did not include all participants in the final analysis?

In addition, about half of studies did not include all participants in the final analysis or did not report the time interval between gastroscopy and blood sampling, thus having a high or unclear risk of bias in the flow and timing domain. 

Q15. What was the summary sensitivity of the panel test?

Pooling data from seven studies produced a summary sensitivity of the panel test of 65.4% for the diagnosis of antrum atrophic gastritis, 70.4% for the diagnosis of corpus atrophic gastritis and 42.6% for both antrum and corpus atrophic gastritis; the summary specificity was higher than 95% for any site of atrophic gastritis. 

Q16. What criteria were used to select studies for inclusion in the review?

For the inclusion in the review, the authors selected studies if they met the following pre-specified criteria: diagnostic studies evaluating the accuracy of the combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays for the diagnosis of atrophic gastritis in adults using the histological diagnosis of atrophic gastritis according to the updated Sydney System as reference standard (1). 

Q17. What was the effect of the use of PPIs on the summary estimates?

The use of PGI/PGII ratio (p=0.12), moderate-severe atrophic gastritis as target condition (p=0.22), setting (p=0.80), study design (p=0.09), country (p=0.29) and the type of publication (p=0.36), on the other hand, had not effect on the summary estimates. 

Q18. What is the cost-effectiveness analysis of the panel test?

This test may be used for screening subjects or populations at high risk of gastric cancer for atrophic gastritis; however, a cost-effectiveness analysis is needed. 

Q19. What is the use of the combination of pepsinogen, gastrin-17 and?

The combination of pepsinogen, gastrin-17 and anti-H. pylori antibodies serological assays (panel test) is a non invasive tool for the diagnosis of atrophic gastritis.