Taking the serological pathway to endoscopy
The risk of gastric cancer increases when a person suffers with atrophic gastritis – a pre-neoplastic condition of the gastric mucosa that is characterised by loss of normal antral or oxyntic glands. Recognised as a somewhat insidious condition, atrophic gastritis is associated with subtle or vague symptom presentation that’s difficult to distinguish, and therefore getting the right diagnosis early is very important. The gold standard for diagnosing atrophic gastritis is gastroscopy and biopsy histology where the extent and grade of atrophy can be confirmed – this is important when assessing risk of disease progression and helps clinicians plan their surveillance and management strategies for patients. But how do we know which patients to biopsy, or even endoscope, when a disease is obscured from clinical view? This is a real challenge for primary and secondary care clinicians.
In this blog we take a closer look at how serology supports endoscopy by helping identify atrophic gastritis before patients are referred. Let’s start by exploring the relationship between serological testing and histology.
Histological classification of gastric atrophy
Anyone who performs regular diagnostic gastroscopies will tell you how difficult it can be to identify gastric atrophy using standard white light endoscopy. In fact, experts report sensitivity figures of just 48-67% in picking up body atrophy using vascular visibility and loss of gastric folds as the key indicators.  Hence, in practice, when the endoscopist suspects atrophy based on gastroscopic appearances the gastric mucosa is biopsied according to a standardised system – the Updated Sydney System (USS), which directs the collection and histological analysis of biopsies from five gastric sites across the antrum and corpus including the greater and lesser curve of both the antrum and corpus, and the angularis incisura. 
This standardised and methodical approach to identify pathology of the gastric mucosa requires a high degree expertise from both the endoscopist and the histopathologist who applies specific scoring systems that quantify the extent of atrophy. However, the histologic reporting of atrophic gastritis using the USS is not without its flaws, for example, it is hampered by its inability to indicate the risk of gastric cancer, i.e., it reports a disease status, not risk of disease progression.
In 2006 a scoring system was developed that takes into account the degree of atrophy in biopsy samples named the Operative Link for Gastritis Assessment (OLGA) staging system.  OLGA combines the value of gastritis grading with a cancer risk score in order to help stratify patients according to cancer risk, thereby offering the clinician more of a prognostic report.
However, both systems share a common limitation – ultimately, a histological assessment can only be as good as the biopsy allows, that is, even the most highly skilled histopathologist can only report what they see, and, let’s remember a gastric mucosal biopsy is only a very, very, small sample (a 3-5um section of a ~5mm piece of tissue) from a surface area that covers up to 8m2, and is therefore seldom representative of the entire mucosa.
The role of serology
The role of serological markers in the diagnosis of atrophic gastritis is well documented and these highly specific blood tests are carried out routinely in other parts of the world to screen individuals for gastric cancer where the disease prevalence and risk are higher. The benefit being of course that serological tests are non-invasive, accurate, widely accessible, and low cost. Three serological markers that have repeatedly been shown to not only help identify chronic atrophic gastritis, but also to correlate well with histopathology, are Pepsinogen I, Pepsinogen II and Gastrin-17 – three markers of the GastroPanel® family. Let’s take a look at these markers.
Pepsinogen I (PGI)
PG I concentration in blood reflects the mucosal structure and function of the gastric body and when the mucosa is atrophied there is a fall in blood PG I levels below 30 µg/l due to the loss of gastric chief cells. Conversely, when the corpus mucosa is inflamed but there is no atrophy (superficial gastritis), the blood PG I concentration tends to increase. So PG I is a valid marker of the state and function of the corpus mucosa.
Pepsinogen II (PGII)
PG II is secreted by cells across the whole stomach mucosa as well as by Brunner’s glands in the duodenum, and its concentration in blood reflects the structure and function of whole stomach mucosa. Like PG I its concentration in blood increases in the case of mucosal inflammation and values of more than 10 µg/l often refer to inflammation.
Pepsinogen I/Pepsinogen II (PGI / PGII) ratio
The PG I/II ratio is used for diagnosis of atrophy of the gastric body mucosa (atrophic gastritis of corpus). In the case of atrophic corpus gastritis, the PG I/II ratio decreases below 3.
The G-17 concentration in blood reflects the integrity and function of the gastric antrum and since G-17 is secreted only from G-cells of the antrum and duodenum blood G-17 values fall when there is antral mucosal atrophy, when G-cells have disappeared. What’s really useful about this specific marker is that it can also be used to identify acid-related disorders because G-17 is directly involved in the normal acid-feedback mechanism of the stomach. In the absence of atrophy, low fasting G-17 values indicate high intra-gastric acidity which is a useful indicator of the risk of acid-related gastroesophageal reflux disease (GORD), erosive oesophagitis and Barrett’s oesophagus.
Low G-17 levels in blood during fasting may therefore indicate either an increased secretion of hydrochloric acid, or, antral mucosal atrophy. Antral mucosal atrophy, however, is dependent upon infection with Helicobacter pylori and can be differentiated from high acid output by determining the individual’s H. pylori status and by taking a measurement of G-17 after stimulating the stomach to produce acid using e.g. protein stimulation.
How does serology compare with histology in the diagnosis of atrophic gastritis?
Serology (specifically the measurement of PG I, PG II, G-17 and H. pylori IgG) and histology are in good agreement when it comes to diagnosing atrophic gastritis. Observational correlation studies from as early as 2002 have demonstrated how serum pepsinogens and gastrin-17 concentrations fall with increasing grade of histology-confirmed atrophy in the corpus and antral mucosa, and importantly, how the reference range of these serological markers reflect a normal and healthy mucosa. More recently, a meta-analysis demonstrated that the markers of GastroPanel® – a blood test that combines pepsinogen I, II, G-17 and H. pylori IgG antibodies, has negative- and positive-predictive values of 91% and 86% respectively in the diagnosis of chronic atrophic gastritis. 
This suggests that serology could be a very useful tool for ruling out, and, helping to identify atrophic gastritis non-invasively, thereby enabling endoscopy resources to be targeted to those at highest risk, and provide an entry point the endoscopic confirmation and management of atrophic gastritis.
Taking into consideration the challenges associated with histology (invasiveness, variability, trueness, sensitivity, subjectivity, turnaround time and cost), serology provides an accurate and objective means for assessing the entire gastric mucosa from a single blood sample. When Pepsinogens I, II, and Gastrin-17 have been compared against endoscopy and histology, the concordance is good making it an attractive proposition for pre-endoscopy testing in patients with dyspepsia in primary care, or at the point of referral at the primary/secondary care interface. GastroPanel is a test that combines these gastric markers and includes a H. pylori IgG test as well, which is ideally suited to a primary care setting. Not only does GastroPanel report on the risks associated with atrophic gastritis, it reports on the existent phenotype too, so that patients who are referred for endoscopy come complete with an unequivocal need for gastroscopy and biopsies.
Without serology and in the absence of guidelines explaining who and when to biopsy, there is a risk that primary care physicians miss the opportunity to refer patients for gastroscopy, and, when patients are referred there is additional pressure on endoscopists to identify atrophy endoscopically. At present, it is the endoscopist’s suspicion that remains the trigger for biopsy sampling, so if atrophic gastritis is difficult to identify both clinically, and visually by endoscopy, when to biopsy or when not to biopsy, is the somewhat controversial question. Serology helps bridge this gap and adds value to the pre-endoscopy probability of identifying atrophic gastritis and, therefore, the risk of gastric cancer. But we must remember that gastric cancer is not the only sequel to atrophic gastritis, there are other very important consequences too such as Vitamin B12 deficiency (e.g. pernicious anaemia, polyneuropathy) and hypochlorhydria (e.g. C. difficile, osteoporosis, iron-deficiency anaemia), Type I gastric neuroendocrine tumour (Type I NETs) and gastric ulcer, all of which are significant risks that require careful management, starting with an accurate and early diagnosis.
So could a combination of serology and endoscopy help close that gap between symptom presentation and diagnosis? Could pre-endoscopy serology help identify pre-cancerous lesions earlier? Could enhancing case selection en-route to endoscopy reduce the number of missed cases of atrophy at endoscopy? Perhaps there are additional benefits for recovering endoscopy services too? And economic advantages? It is highly likely that identifying patients with atrophic gastritis in a primary care setting, before referral to endoscopy, can benefit the patient, the endoscopist, and the economy.
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