Original publication in Finnish: BESTPRACTICE ONKOLOGIA / HEMATOLOGIA Lääketieteen asiantuntijoiden ammattilehti 2013;nro 4 helmikuu:26-33.
Published with the permission of publisher
Translation by Kari Syrjänen, Biohit
Electronical version and printable pdf (in Finnish)
MD, Ph.D., FIAC
Chief Medical Director, Biohit Oyj
GC remains one of the leading causes of cancer morbidity and mortality worldwide; approximately one million new cases and 736.000 annual cancer deaths.1 In Finland, the prevalence of GC has steadily declined during the past few decades; from the peaking years of the early 1960’s the number of new cases has decreased from 877 to 363 among males, and from 680 to 259 among women by 2010.1 The reasons for this steady decline are not entirely clear, but mainly attributed to the changes in the lifestyle, with concomitantly reduced exposure to the known risk factors.
The traditional risk factors of GC are numerous, and their different distribution in different populations may explain, at least in part, the observed geographic variations in the incidence of GC.2,3 The most common global risk factors include i) the male gender, ii) aging, and iii) poor socio-economic status. It is estimated that nearly 80% of GC cases among males and 70% of those in women are caused by various lifestyle and environmental factors. The known risk factors of GC in this group include smoking, alcohol consumption, dietary habits, occupational exposure, exposure to irradiation and/or radiation therapy used in the treatment of other cancer, as well as genetic susceptibility linked with certain rare hereditary syndromes.
Increased risk of GC is also associated with certain other diseases, including gastro-esophageal reflux disease (GERD), pernicious anemia, diabetes, HIV-related immunodeficiency, and Epstein-Barr virus. Also, gastric resection, blood group A, and certain drugs may be such risk factors. Estrogen replacement therapy, obesity, and early menopause may also have an impact on the risk of GC.
The role of diet as a risk factor of GC has been intensely studied, and there is evidence that a diet rich in fresh vegetables and fruits - especially citrus fruits - reduces the risk. Abundant use of salt and processed meat increases the risk, particularly in Asia, where the consumption of pickled vegetables is associated with particularly high risk of GC. In contrast, a Mediterranean diet has been claimed to be particularly healthy, and shown to be associated with markedly reduced risk.4
In addition to those listed above, there are two risk factors that play a key role in the development of GC: Helicobacter pylori (HP) infection of the stomach and atrophic gastritis (AG).5,6 Both of these major risk factors can be currently identified with a simple blood test, and this article briefly reviews the applicability of this test in a screening of the risk groups for GC.
International Agency for Research on Cancer (IARC, Lyon) decided in 1994 that the published evidence
is sufficient to conclude that HP-infection is carcinogenic to the humans.7 This bacterium causes inflammation of the gastric mucosa, of which approximately half of the patients will develop AG, if left non-eradicated. Although HP itself is not a directly carcinogenic agent, gastritis, and AG in particular are carcinogenic conditions. About 5-10% of all HP-infected subjects will develop a moderate to severe gastric atrophy, and the risk of GC is increased in parallel with the increasing atrophy; the risk is 2-5 fold among those with chronic HP-associated gastritis (without atrophy), but up to 90-fold in patients with severe AG.
Particularly the intestinal type of GC is known to develop from the atrophic stomach mucosa through a stepwise process including intestinal metaplasia and varying degrees of dysplasia (mild, moderate, severe); this sequence of events is known as the Correa cascade.2 It is important to remember that this process can be arrested by eradication of HP-infection quite often, but not nearly always.2,3,8,9 As stated above, HP-infection is a major risk factor of GC (WHO/IARC). A separate entity is known as auto-immune AG, which is most common among European and North-European populations. It is believed that some forms of atrophic autoimmune gastritis can develop without HP-infection, although this is a matter of dispute.
AG is the single most important condition associated with increased risk of GC.2,6,10,11 In the Sydney system for classification of gastritis, AG is defined according to its topographic location as i) AG of the antrum, ii) AG of the corpus, or iii) atrophic pan-gastritis.12 Diagnosis of AG is traditionally based on histological examination of the biopsies taken at gastroscopy. However, gastroscopy is an invasive diagnostic method, which requires appropriate facilities, relatively expensive equipment, and, above all, considerable experience. In other words, gastroscopy is a subjective diagnostic method, which, as such, is not suitable for population-based screening of the risk factors of GC. Given this, the need for a simple, reliable, and non-invasive diagnostic test increased in parallel with the growing body of evidence on HP and AG as the key risk factors of GC, e.g. from the long-term prospective cohort studies conducted in Finland during the past several decades.2-11
Based on these long-term cohort studies, researchers in Finland developed a simple ELISA-test performed on a plasma or serum sample and analyzing the structure and function of gastric mucosa with the aid of four stomach-specific biomarkers: pepsinogen I (PGI) and II (PGII), gastrin-17 (G17) and IgG and IgA antibodies for Helicobacter pylori.13,14 This combination (panel) of stomach-specific biomarkers is known as GastroPanel (GP), and the test results are interpreted by a software called GastroSoft (GS), both of which are proprietary trademarks of Biohit Oyj.14
When the mucosa of the gastric corpus undergoes atrophy, the functional cells and glands ultimately disappear completely. At the same time, hydrochloric acid (HCl) and pepsinogen (PGI and PGII) secretion is reduced, and the stomach is finally acid-free. The severity of mucosal atrophy closely correlates with the secretion of HCl as well as with the plasma and serum levels of PGI and PGII.11,13 While gastric antrum undergoes atrophy, the G-cells secreting G17 will be lost, resulting in low serum levels of fasting (basal) G17, and the level does not rise even after protein - or bombesin- stimulation.13 Through this negative feedback mechanism, G17 level remains low also in patients with increased acid output and highly acidic gastric fluid.
When the mucosal glands in the corpus are reduced and eventually disappear completely (total AG), also the secretion of so-called intrinsic factor (IF) decreases and finally ceases, the absorption of vitamin B12 in the small intestine is blocked and the patient develops pernicious anemia (PA). It is estimated that in Finland, there are close to 15.000 of these PA patients. When gastric acid content is reduced, also the absorption of iron, calcium and other trace elements such as zinc, will be impaired.
Except for the trace elements, also the absorption of many drugs, such as dipyridamole, some iron products and antifungals (fluconazole, itraconazole), thyroxine and atazanavir is considerably impaired in an acid-free stomach.14 In addition, it should be emphasized that a healthy stomach is sterile, whereas an acid-free stomach is not, but may be massively colonized by bacteria (and fungi) from the pharynx and intestines. Some of these can produce, e.g. nitrosamines and acetaldehyde. The latter was classified in 2009 by IARC as Group 1 carcinogen, and exposure to it should be avoided by any means. Indeed, these bacteria and fungi colonized in an atrophic stomach might be the missing factor that induces the gene errors in the mucosal cells that are the final trigger of the carcinogenic process.2
It is currently possible to reduce the exposure to acetaldehyde by a very simple means, oral Acetium capsule, which is another Biohit innovation classified as a medical device.14 Slowly released L-cystein from the Acetium capsules in the gastric fluid effectively binds acetaldehyde developed in an acid-free stomach, thus preventing the exposure to this Group 1 carcinogen and possibly the development of gastric and oesophageal cancers.
Although the prevalence of HP-infection is declining, it is still detected in 30 to 70% of the population in Finland, depending on the sample and its age.14 Moderate or severe AG is detected in about 2.5-10% of asymptomatic individuals over 50 years of age in this country.11 It is well established that approximately one half of HP-infected patients will develop AG (of any degree), 15,16 and from an estimated 2.5-5% of the subjects with moderate to severe AG, a GC or its precursor lesion can be detected in histological examination of gastric biopsies.11
In contrast, among the individuals with healthy stomach mucosa, the risk of GC is practically non-existent, except for the rare cases where the cancer linked with a hereditary genetic defect. HP-infection is the main cause of AG and therefore also the main cause of GC.2,3,7-9 Ongoing HP-infection is detected by antibody measurements among 70-80% of the patients who suffer from AG of the corpus.16,17 After successful eradication of HP, both antibodies and inflammatory reaction will subside within a few months, and AG as well as the gastric mucosal function start recovering towards normal, at least in part of the patients.17,18 Incidence of GC rises sharply with age, but age itself is not an independent predictor of GC.6 As early as in the 1980’s, it was demonstrated that stomach cancer linked with aging is associated specifically with AG, not with the age itself. The risk of GC among individuals with healthy stomach is as low at the age of 70 years as it is among healthy 30-year-old subjects.14
The main indications of the biomarker test (GP) include i) a screening of the risk conditions for GC and AG, and ii) first-line diagnosis (triage) of the patients with dyspeptic complaints. This applies particularly to the groups of individuals in whom HP-associated gastritis or AG is a possible cause of the disease or its risk factor.14 GP is a quantitative ELISA-based diagnostic test in which each of the four biomarkers (PGI, PGII, G17, HP) have their normal cut-off values that will not be reached or are exceeded, whenever the gastric mucosa is not healthy.14 The clinical performance of the GP test is excellent; its sensitivity, specificity and accuracy are around (or over) 95%, using the distinction between healthy and non-healthy (HP, AG) stomach as the endpoint. The test results are interpreted by the GastroSoft program, and the patient and/or physician will receive the GP-report (interpreted by a specialist) in a simple format (A, B, C) of recommendations:19
A. The patient does not have an HP-infection or AG, i.e., the GP-examination is normal. In this case, gastroscopy does not provide any significant additional diagnostic information about the stomach, because the risk of GC or gastric- and/or duodenal ulcer (GU, DU) is virtually non-existent, provided that the patient does not use anti-inflammatory drugs, or have any family history of GC. In symptomatic patients, further examinations can and should be focused elsewhere, irrespective of the patient’s age.
B. The patient has a non-atrophic gastritis associated with HP, i.e., only the HP-antibody test is positive, but the other markers are within normal range. Also in these cases, gastroscopy rarely gives any significant additional clinical information. The risk of GC is very low, albeit not completely non-existing. All HP-associated non-neoplastic conditions (GU, DU) will recover, and the risk will disappear after successful eradication of H. pylori infection.
C. The patient has AG, caused either (most frequently) by HP or being of autoimmune origin. In such a case, all biomarker levels are low, irrespective whether the HP antibody test is positive or negative. A consultation by a gastroenterologist and gastroscopy are mandatory because of an increased risk of GC. All HP-positive subjects should undergo bacterial eradication therapy. Proton pump inhibitors (PPI) are of no use, because all these AG-patients have an acid-free stomach by definition.
Like in most of the developed countries, also in Finland, approximately one half of the patients who attend to a general practitioner due to stomach complaints belong to Group A, and only up to 5-10% of those belong to category C.20 Because of the fact that gastroscopy is clinically indicated only for this group of patients, the cost savings will be substantial, when the GP test is used as the first-line diagnostic test for all patients with dyspeptic complaints instead of systematic gastroscopy.
Diagnosis of infectious diseases is usually based on direct demonstration of the pathogen (by culture) or on serological testing. This is not the routine procedure with HP-induced gastritis, however, although it is clearly a bacterial disease. The widely publicized 13C-urea breath test (UBT) is commonly used in Finland, even though it is more expensive and more complex to use than the HP-antibody test. The result of UBT is dependent on the amount of HP colonized in the gastric mucosa, and this test will give false negative results in up to one half of the patients, especially when the stomach is acid-free or hypo-acidic, e.g. due to AG, or prolonged use of PPIs. Furthermore, UBT, stool antigen test and HP-antibody tests do not reliably diagnose AG of the corpus caused by HP or of autoimmune origin, or of HP-associated AG in the antrum. None of the three tests provides accurate information on the high acid output of the stomach, which among patients with gastro-oesophageal reflux disease (GERD) may cause often asymptomatic complications, such as ulcerative oesophagitis or Barrett's esophagus, both of which can lead to esophageal cancer if left untreated.21,22
In contrast, the HP-antibody test included in the GP is free of these limitations. International Helicobacter Pylori Study Group stated in their report of the Maastricht IV consensus conference appeared in April 2012, that a blood biomarker tests are a reliable means to detect and screen for gastric disorders and their risk conditions.21 Researchers recommend the use of biomarker tests for detection and follow-up of all acid-free stomach cases associated with HP-infection and particularly AG among dyspeptic patients as well as for screening of asymptomatic subjects. The same recommendations were included in the statement of the Healthy Stomach Initiative (HSI; www.hsinitiative.org) launched by 16 experts from 12 countries, according to which the biomarker tests are particularly suitable for screening of both asymptomatic subjects and those suffering from dyspeptic symptoms, to disclose the individuals at increased risk for GC due to AG.22
The plasma levels of PGI and PGII, and their ratio, together with G17 and HP-antibodies (IgA and IgG) build up a marker panel that enables a highly accurate diagnosis of HP-induced gastritis and AG. 13,14,19,21,22 Measurement of G17 in combination with PGI and PGII allows a more accurate assessment of the structure of antrum as well as physiological functions of the whole stomach by the GP test. The level of G17 gives indirect evidence on the acid output of the stomach, because G17 concentration is low (<1pmol/l) and does not increase after protein stimulation in cases where also the antrum has severe AG. In contrast, G17 levels rise over 5 pmol/l after protein stimulation, if the stomach is highly acidic, but there is no atrophy in the antrum. On the other hand, G17 level is high whenever the stomach is hypo-acidic, i.e., the patient has AG or is a regular user of PPI drugs.
The most important risk conditions preceding gastric cancer (GC) are HP-infection and AG. As a result of long-term research and development, a Finnish biotechnology company, Biohit HealthCare has launched the GastroPanel test, a panel of four stomach-specific biomarkers that give accurate information on both the structure and function of gastric mucosa.
Since the risk of GC and peptic ulcer disease among individuals with healthy stomach is very low, it is essential to distinguish between subjects with healthy stomach and those with gastric disorders. With GP - a simple blood test - it is now possible to detect the patients who are at high risk for GC because they harbor either HP-infection or AG or both in their stomach mucosa. HP-infection alone increases the risk of GC several-fold, and this risk is over 90-fold among patients with HP-related severe AG of both the corpus and antrum (pangastritis).14,21,22
Another area of use for the GP test are the dyspeptic complaints, which in western countries appear in 20-40% of the population. According to the orthodox medical practice, the assessment of these complaints should invariably include examination by gastroscopy, for which the existing resources are clearly insufficient, and for which there is actually no real need. The same applies to the costly and risky “test” medications with PPIs, because using the GP test, it is now possible to screen the patients at true risk and for whom, gastroscopy is indicated. With this approach, we can release approximately 40-70% of the limited and expensive endoscopy capacity to be focused on colonoscopies, i.e., for screening and early detection of colorectal cancer. Because of the fact that particularly among the older people, dyspeptic complaints are frequently of large intestinal origin, it is cost-effective to supplement the examinations of these dyspeptic patients with ColonView test, based on detection of Hb and Hb/Hp complex in the stools, and intended for screening of colorectal cancer.
The safe and cost-effective GP test enables early detection of many different disorders, and thus helps avoiding the majority of subsequent health problems. Undetected AG of the corpus - acid-free stomach - can eventually lead, except to gastric and oesophageal cancer, also to malabsorption of vitamin B12, iron, magnesium, calcium, and some drugs. AG of the antrum, in turn, increases the risk of peptic ulcer disease and GC.
Concomitant AG of the antrum and corpus (pangastritis) is the single most important risk condition for GC. A minority of GCs can develop directly from HP-induced gastritis, without recognizable stages of mucosal atrophy. It is well known that vitamin B12 deficiency can lead to pernicious anemia (PA), dementia, depression, and injuries of the peripheral nervous system. Calcium deficiency, in turn, leads to osteoporosis. The absorption of many drugs is impaired in acid-free stomach. The risk of serious intestinal infections (giardiasis, malaria, Clostridium difficile and E. coli EHEC) can be increased particularly among the senior citizens with AG.
Within public health care, it is possible to achieve substantial cost savings by replacing the systematic use of gastroscopy with a simple and inexpensive GP test as the first-line diagnostic tool for all patients complaining dyspeptic symptoms.
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