According to the gastric biomarker test results, our patients were divided into the HS and NHS groups, following previous suggestions [19]. Using gastroscopic biopsies as the gold standard, the concordance between the biomarker testing and histology was substantial, with a kappa value of 0.68 and an overall agreement (across 5 categories) of 84.6%. These values favourably compete with those reported in previous validation studies [19, 23]. This is not unexpected because the biomarker test used (GastroPanel) is based on four biomarkers reflecting the function and structural integrity of the stomach mucosa [19, 22, 23, 25, 29]. Accordingly, Pepsinogen levels and their ratio are decreased in corpus atrophy, accompanied by elevated G-17. The G-17 level also gives indication of gastric acid secretion, being low with high acid output and high when stomach is acid-free (due to PPI treatment or AG). In antrum atrophy, G-17 is low and does not respond to protein stimulation (lack of G-cells). The two main indications of the GastroPanel test are: 1) first-line diagnostic test for dyspeptic complaints, and 2) screening of asymptomatic subjects for gastric cancer risk (HP and AG). Despite the fact that some minor abnormalities are not detected by the normal marker profile, GastroPanel is a test for stomach health, with an excellent longitudinal negative predictive value. On the other hand, abnormal test results implicating AG do predict a significantly increased long-term risk for gastric cancer.
The present study is the first where the utility of this biomarker test in the pre-operative management of bariatric surgery patients was evaluated in a 100% biopsy-confirmed clinical setting. One of the aims was to assess how many gastroscopies could be avoided by using the normal biomarker profile as a surrogate for healthy stomach (HS). The results are encouraging, while implicating that using this approach, the HS and NHS groups can be distinguished with high accuracy. Indeed, the serum levels of all 4 biomarkers were significantly different in the HS and NHS groups, being markedly higher in the latter (Table 3). Most remarkably, the markers of mucosal inflammation (PgII in particular) was almost three times as high in the NHS patients as in the HS patients.
HP is the key causative factor of severe gastric pathology, including peptic ulcer disease and gastric cancer. In the study cohort, the prevalence (66%) of HP in candidates for bariatric operation was significantly higher than that reported in many previous studies (3.4–17%) from Belgium, Finland and the USA [13, 15, 30], but similar to that (53–66%) reported from Greece and Brazil [31,32,33]. In the Estonian population, HP prevalence is closely associated with the birth cohort [34, 35]: HP has become more rare among younger generations. In our bariatric surgery cohort, the detected 66% prevalence of HP is equivalent to that (56–69%) reported in previous studies on the same birth cohorts (1970–1990) of the general population in Estonia [35].
Because HP is associated with severe clinical sequels [19, 36,37,38], its eradication is indicated [13] and leads to regression of the inflammatory process in the gastric mucosa and significantly reduces the risk for its known complications at the population’s level. Indeed, the reported preoperative endoscopic findings (hiatal hernia, 16–25%; esophagitis, 13–30%) from geographic regions with low HP prevalence [13, 15, 30], as well as from the the high-prevalence regions [31,32,33], are consistent with similar morbidity in our cohort (Table 4). Chronic inflammation of the stomach mucosa was detected in 75% (49/65) and atrophy in 6.2% (4/65) of the patients. As expected, gastric diseases (gastritis, 65.1%; AG, 16.7%) are more frequent in regions [31, 33] with high HP prevalence, like Estonia, as compared with the low-prevalence regions (gastritis, 9.1–28%; AG 0.9%) [13, 15, 30].
Most of the patients in the NHS group had HP -related gastritis without atrophy. In such cases, gastroscopy is optional if the patient requests it [19]. Gastroscopy is mandatory only in the cases with suspected AG or in patients with sustained symptoms. In the NHS group, only four patients had moderate AGA which requires regular monitoring by endoscopy to disclose eventual progression and increased risk of gastric cancer [37, 39]. Of these four AGA cases, only one was clearly confirmed and another one was suspected on the basis of biomarker testing. In the other two cases, AGA was only confirmed with biopsy. In GastroPanel, the G-17 values were within normal limits, implicating that abundant G-cells were still present to sustain the normal G-17 output. Most likely, these cases represent patchy mucosal atrophy instead of a diffuse disease. It is not well established how such patchy atrophy behaves in the long run, and whether regular endoscopic monitoring is indicated or whether biomarker testing is sufficient. It is likely that the gastric mucosa in these patients can significantly recover after HP eradication, while inflammation symptoms diminish or disappear and the process of mucosal atrophy can be arrested, as reported earlier [24, 39, 40].
In our series, AGA detected by the biomarkers was rare, which has been shown before [41]. A recent meta-/analysis of the published GastroPanel literature confirmed that the test works better for detection of AGC (PgI, PgI/PgII ratio) than AGA (G-17). A simple explanation is that low G-17 levels can result from two distinct causes: AGA and high acid output [19, 20, 42]. No biomarker that is regulated by more than one trigger can be a highly specific indicator of only the other [20]. To make distinction between these two (AGA, high acid output), it is mandatory to test G-17 after protein stimulation (G-17 s). Failure to increase G17 s output implicates lack of G-cells and presence of AGA [20].
Another explanation for the rarity of AGA in our series could be the relatively young age of the patients. In fact, GastroPanel was not primarily designed for testing bariatric surgery patients but for diagnosis and screening of elderly patients with AG and for screening increased risk of gastric cancer [29]. However, bariatric surgery can be safely performed also in patients aged 60 years or more [43]. In this sub-group, the potential role of the gastric biomarker test can be particularly important as the incidence of atrophy and gastric cancer increases with age. Furthermore, using the biomarker test, we could easily diagnose almost all HP-infections and administer a timely treatment to diminish the risk of AG and gastric cancer.
There was also one false positive “panatrophy” (according to GP) in our series while histologically only superficial H.pylori related gastritis was confirmed. Rather, this fact could be related to technical issues.
In patients with AG, follow-up EGDS is still needed. Thus the gastric sleeve method (SG) would be preferable, because routine EGDS after bypass operation (GBP) is unfeasible. In large series of operated patients, however, practically no post-operative problems have been reported in the bypass group. Only a few case reports are available on postoperative cancer [44].
Regarding the use of the normal GastroPanel profile as a surrogate for healthy stomach (HS), 22/65 subjects were categorised into this group according to its criteria. Clinically, 20 of them were asymptomatic, had no history of abdominal complaints, and only 2 had reflux symptoms. On EGDS, only minor abnormalities were detected that were considered clinically insignificant: non-HP gastritis, mild or moderate degree esophagitis, or gastric mucosa erosions. It is clear that management of these disorders does not require a delay in elective surgery, nor is it a contraindication for operation [11]. In 4 cases, esophagitis (LA grade A/B) was found to be associated with hiatal hernia, and 2 of these reported reflux complaints. According to international consensus [17, 18], for patients with upper abdominal complaints, endoscopic investigation is indicated. In patients with symptomatic esophagitis, the recommended surgical procedure could be gastric bypass rather than gastric sleeve. Although the opinions on the use of gastric sleeve in esophagitis are controversial [45], the probability of complicated esophagitis has been shown to increase postoperatively [46]. Such cases respond poorly to medical treatment [47], despite the fact that a major portion of the gastric corpus is resected, which results in a significant reduction of parietal cell mass and a decline in acid output.
There is yet no unanimous agreement on the need and technical methods for simultaneous gastric sleeve and hiatal hernia repair, although most authors agree that posterior hiatus repair is necessary when hiatal hernia is diagnosed pre- or intraoperatively [47, 48]. It has been shown earlier that low basal G-17 levels in the general population are a marker of high basal acid output, which in turn predisposes to gastric acid reflux and esophagitis [42]. In this series, however, we failed to find correlation between esophagitis and low G17b levels, as only one out of the 4 patients in the HS group and 2/10 in the NHS group showed G-17b levels below the cut-off value. Although some studies have obtained results similar to ours [49, 50], there are also reports about such correlation between G-17 and esophagitis [51].
In the light of the above data, it is evident that in symptomatic esophagitis, endoscopy plays a role also in guiding the selection of the surgical method (i.e., preferring gastric bypass over gastric sleeve), which is crucial to ensure optimal treatment outcome. In our series, 3 asymptomatic patients in the HS group had, despite the normal marker profile, erosions in the stomach (antrum), with a Lanza score of less than 4 (i.e. not severe). Recently, some authors have reported gastric erosions in bariatric surgery patients [48] and others have reported them also in asymptomatic volunteers in population studies, more frequently in HP-negative than HP-positive subjects [40]. Although the cause of such erosions may be multifactorial, all 3 patients in our study took several medications known to damage the gastric mucosa. Yet the erosions seen in the HS group can be considered clinically insignificant: the patients were asymptomatic, and no complications like haemorrhage were found on EGDS. Accordingly, we cannot consider minor erosions in patients with the normal biomarker profile as an indication for changing treatment practices in such bariatric surgery patients.
Summing up for the HS group, our data demonstrate that the gastric biomarker test can definitely help select this particular patient group of asymptomatic patients (20/22 in this series) with minor but clinically non-significant gastric mucosa alterations for whom preoperative endoscopic investigation can be safely replaced by the non-invasive biomarker test. Endoscopy should only be reserved for symptomatic patients to confirm the diagnosis and opt for the surgical method, as has been pointed out earlier [17, 18].
Regarding the NHS patients, the rationale should be the same as for the HS patients: those with reflux complaints should undergo endoscopic investigation to confirm the diagnosis and to plan possible preoperative treatment. Endoscopic findings in bariatric surgery patients can be highly variable [52]. To avoid postoperative complications, including ulcer [52], it is important to evaluate the patients pre-operatively to detect (by using GastroPanel) [19] and eradicate HP infection. Although there were no cases of ulcer disease in our material, these steps are always important in this special group of patients. In the case of suspected peptic ulcer, EGDS is essential; the same applies to patients with a family history of gastric cancer.
The present results confirm that the normal biomarker profile in the GastroPanel test is an excellent surrogate for healthy stomach, and this non-invasive test could replace EGDS in the pre-operative management of bariatric surgery patients. Indeed, using the biomarker test, it could have been possible to avoid EGDS in 20/22 patients in the HS group, i.e., in 31% (20/65) of all bariatric patients in our cohort. These asymptomatic patients with the normal biomarker profile are at very low risk to develop a clinically significant disease in the gastric mucosa, including peptic ulcer and gastric cancer [19, 53].
