H. pylori gastritis

The most widely accepted hypothesis is that H. pylori is the initial etiological factor of chronic gastritis leading to GC. This infection is acquired in childhood and slowly progresses toward gastric atrophy, intestinal metaplasia, dysplasia and invasive adenocarcinoma of the intestinal type. Its rate of progress varies and is modulated over many years by genetic, dietary and environmental factors which offer broad opportunities for intervention. ^11,12

In 2002, Bedoya reported that 88% of children under 10 years of age showed some inflammatory changes of the gastric mucosa and changes that 5% presented chronic atrophic gastritis. ¹³

A review of gastric biopsies in a population aged one to 16 years by Archila et al. found H. pylori infections in 59% of these patients. There were small quantities of bacteria in 24.3%, moderate quantities in 20.1%, and abundant quantities in 14.6%. ¹³

H. pylori is the most important causative agent involved in the genesis of GC. The International Agency for Research on Cancer (IARC) has listed it as a Type I carcinogen since 1994. H. pylori is strongly associated with distal GC of the stomach although no relationship has been demonstrated with GC of the proximal and cardial regions. It has been estimated that more than 75% of gastric cancers worldwide are explained by H. pylori infections. There is also evidence that H. pylori infection is a necessary but not sufficient condition for gastric carcinogenesis. ¹⁵

Other etiological agents such as cigarettes, alcohol consumption and endogenous nitrosamine formation are recognized by the IARC as potential causal factors that in development of GC. Between 11% and 18% of cases may be associated with cigarettes. Diet and nutrition can also play a role in gastric oncogenesis. There is consistent evidence that consumption of fruit and vegetables is associated with decreased risks of GC (Figure 1). ¹⁵

Figure 1 GC risk factors. Taken from: Park JY et al. Clin Endosc. 2014; 47 (6): 478-89. 

GC’s association with family history (genetic component) has an odds ratio (OR) of 2.0 to 8.0, depending on the country. There are also studies that show higher prevalence of H. pylori infections and premalignant lesions in first-degree relatives of GC patients than in controls. ^9,16

Genetic susceptibility caused by a mutation in E-cadherin, a crucial molecule in maintaining epithelial architecture, is assumed to be related to diffuse GC. ¹⁵

The first crucial event in gastric carcinogenesis is H. pylori infection. It activates the inflammatory response, and there is a high prevalence of H. pylori infections in GC patients. ¹⁵ Nevertheless, only a very small proportion of people who are infected patients with H. pylori ever develop GC: only one out of every 100 infected patients will develop GC. ¹⁷

This forces one to wonder why and how the disease develops in this minority of infected patients. One reason is variation in the pathogenicity of the bacteria. Research in this field has focused on genetic susceptibility due to polymorphisms in genes that govern gastric inflammation responses, the heterogeneity of H. pylori, and environmental influences such as salt from the diet or the presence of other species of Helicobacter within the gastrointestinal microbiota. ¹²

Considering GC to be the consequence of an infection has created enthusiasm for diagnosing and treating H. pylori in areas of high GC prevalence, ¹² and it is clear that most GC is due to H. pylori infections rather than factors related to lifestyles. When it is suspected that cancer is caused by an infection, preventive measures are required in order to reduce both incidence and mortality. ¹²

HP infection is typically acquired in childhood, and mucosal transformation takes years and decades to pass through the chronic inflammatory process to states of atrophic gastritis and intestinal metaplasia. Consequently, eradication of the bacteria in young people could prevent this progression and reduce the risk of developing GC later in life. ¹¹

Based on the arguments, the strategy of diagnosing and treating patients with gastritis associated with H. pylori was validated in Japan in 2009 and 2103 and gained support from the health care insurance system. This largest part of this population has non-atrophic gastritis following eradication treatment so endoscopic monitoring is not necessary. ¹⁸

The prevalence of H. pylori is high on the island of Matsú in Taiwan, and the incidence of GC is 50 per 100,000 inhabitants, 3 to 5 times higher than the overall incidence in Taiwan. The age of 30 was chosen as the cut-off for accelerating elimination of GC. A pilot screening study to diagnose and treat H. pylori infections was begun on the island in 2004. Initial results were very promising: incidence of GC decreased by 25% and the incidence of gastric atrophy feel by 77% compared to historical data. ¹⁹ It has been calculated that it is necessary to diagnose and treat 15 men in China and 245 women in the United States to avoid one case of GC. ²⁰

Preventing and eradicating H. pylori infections before atrophic gastritis develops is the best means of reducing and/or eliminating GC. ²¹

In 2005, the Nobel Prize in Physiology was awarded to Marshall and Warren for the discovery of H. pylori and its role in gastritis and peptic ulcer. In addition, chronic inflammation is a common risk factor for carcinogenesis, and it has been suggested that primary prevention of GC could be achieved through a strategy of screening and treating H. pylori infection. ¹¹

In 2013, an IARC working group reviewed the evidence accumulated in support of mass H. pylori eradication as a strategy for preventing GC. Based on the favorable results of controlled clinical studies and observational studies, a group of experts confirmed that this strategy is effective. ¹⁹ For this reason, the IARC recommended that health care agencies include this strategy in national cancer control programs.

In January 2014, a global consensus was reached in Kyoto, Japan for evaluation of the management of chronic gastritis associated with H. pylori. Its conclusions establish that H. pylori eradication could prevent GC and that all carriers of H. pylori should be treated in order to eradicate this pathogen. ²¹ Elimination of H. pylori from the population could eliminate approximately 75% of GC. ²²

Our attention should be focused on how this strategy is carried out, for example, by identification of H. pylori patientss within the asymptomatic population and eradication before GC develops. However, the current strategy must depend on H. pylori infections and the incidence of GC within that population. ²³

A metaanalysis of three studies (Forman, Parsonnet and Nomura) found that people infected with H. pylori had a great risk of developing GC than did uninfected people with an OR of 3.8. Uemura has shown that patients untreated H. pylori infections had a greater chance of progression to GC in the next 12 years than did uninfected patients. ¹²

Recent metaanalyses and studies with low statistical power indicate that the H. pylori eradication reduces the risk of GC developing by approximately 40% in primary prevention studies of asymptomatic individuals and by 54% as a tertiary prevention strategy against a second appearance of GC after endoscopic resection of early GC. It is not known if there is a cut-off time during the Correa cascade after which H. pylori eradication is no longer a deterrent to progression to GC. ^12,24

A study by Lee et al. which included 24 publications (14 primary prevention studies and 10 tertiary prevention studies) with more than 48,000 individuals with follow-ups of 34,000 people/years has shown that the benefit of H. pylori eradication were more evident in areas where the incidence of GC is higher. However, risk reduction was evident in almost every individual evaluated in the study. Presumably, high-risk populations in low-risk countries, including immigrants who have been infected since childhood, benefit significantly from eradication. ¹²

In another study, 544 patients who had undergone early GC endoscopic surgery were randomized to receive H. pylori eradication treatment. Metachronous GC was detected in nine patients in the group that received treatment and in twenty-four of the patients in the group that did not receive treatment, with p <0.01. This indicates that the preventive effect of H. pylori eradication therapy in these patients significantly reduced the risk of metachronous GC. ²⁵

One intervention strategy in the carcinogenic phase of GC’s natural history is the policy of diagnosing and treating H. pylori infections, especially before gastric atrophy and intestinal metaplasia occur. Nevertheless, patients with atrophy and metaplasia should also receive eradication therapy if bacterial infection is present even though there will be a time of no return after which therapy will have no justification because the mucosal damage will have already happened. ²⁴

Some researchers are trying to pinpoint the moment at which H. pylori generates changes in a person’s deoxyribonucleic acid (DNA) and when that damage leads to irreversible development of cancer even if the infection is eradicated. ²⁶ Determination of this point of no return will help define when eradicating the infection can guarantee the recovery of mucosal damage, stop the process and prevent the development of cancer.

A large number of medical professionals in Colombia do not have a clear, deep understandings of what gastritis implies in terms of risk, natural history, intervention and follow-up when faced with a pathology report of chronic atrophic gastritis with or without intestinal metaplasia. ¹⁴

The incidence of GC increases with age, and the impact of H. pylori eradication on the incidence of GC depends on the population studied. ²³

Evidence suggests that all individuals with H. pylori gastritis should be treated. In countries with high-risk populations for GC, this strategy is recommended for young people under 20 years of age given that the infection is acquired in childhood. This knowledge may have clinical utility for stratifying individuals with H. pylori infection into those who are at high risk and those who are at low risk for GC in order to create personalized follow-up schemes. ¹²

The question of how to prevent GC is addressed in Figure 2. The results support a strategy of eradicating the bacteria in countries where H. pylori and GC are common. Then, the current strategy should be carried out depending on the prevalence of H. pylori and GC. ²³ The participants in the 2014 Kyoto consensus unanimously recommended implementation of H. pylori eradication therapy before precancerous changes develop. ²¹ The reason is the risk of progression to gastric atrophy and to intestinal metaplasia would be reduced along with the later risk of GC.

Figure 2 Primary GC prevention strategies. Taken from: Lee YC et al. Gut Liver 2016; 10 (1): 12-26. 

This strategy of screening for and treating H. pylori infections seems to be the best approach for reducing cancer risk. However, the implementation of this strategy at the population level requires a systematic approach. The program must also be integrated into national health care priorities so that limited resources are effectively allocated and used. Implementation may require adoption of an appropriate strategy. Within the population there are subgroups that vary in risk, so that it is impossible for the approach to be the same for everyone. ¹¹

Treating all patients with infections documented by histology or rapid urease test would not be justified because it would not be cost-effective. It is necessary to define a high-risk group within that population.

High Risk Group

High risk individuals might be defined as those from high-risk areas, especially in populations with an incidence greater than 20/100,000 inhabitants, who have a first degree family member with a history of GC, and who have histories of heavy smoking, and heavy salt and alcohol consumption (Figure 3). ^24,27

Figure 3 Summary of primary prevention strategies. 

Cost Analysis

The literature shows that diagnostic and treatment programs for H. pylori patients are more cost-effective in countries where the incidence of GC is higher than in low incidence countries. ^30,31 Two studies have shown that the optimal screening age is between 20 and 30 years because screening in older cohorts was less cost-effective. ³²

H. pylori screening is cost-effective because of the relatively low cost of H. pylori testing and treatment and the fact that screening is done only once. The estimated costs for detection and treatment of H. pylori are less than 1% of the costs of GC treatment in all studies. This means that the strategy of diagnosing and treating H. pylori entails considerable cost savings. GC consensus recommends blood test screening. In high prevalence populations, blood tests are used more frequently than the breath test while in low prevalence populations, the fecal antigen test is used more than the other two options. It should be taken into account that acceptability of the test is one of the requirements for introduction of this strategy in a study population. It has been found that blood tests and fecal antigen tests are more cost-effective than the breath test. Repeating screening and/or treatment and limiting treatment to those with CagA strains do not appear to be cost-effective policies. ³²

A large-scale study for the prevention of colon cancer and gastric cancer through the detection of fecal occult blood and fecal antigen for H. pylori is being carried out in Taiwan. Patients infected with H. pylori receive treatment. The results of this study are not yet known. ¹¹

Gastric Atrophy

Because GC develops over a long period of years to decades, the frequency of gastric atrophy is very low before the age of 40 (<5%). Only 5.9% of GC patients are younger than 40. ^33,34

A study by Pelayo Correa in an area of ​​high GC incidence reported that, in individuals over 40 years of age, the prevalence of chronic atrophic gastritis was 57%, the prevalence of intestinal metaplasia was 38%, and the prevalence of dysplasia was 10%. ³⁵ This means that development of precancerous lesions and then identification of lesions can also take several years. Therefore, endoscopic follow-up of high risk patients can help identify malignant lesions early when they are still operable and there is a high probability of curing the patient. A 10-year follow-up study has reported that the figures for progression to GC for patients with atrophic gastritis, intestinal metaplasia, mild dysplasia and severe dysplasia are 0.8%, 1.8%, 4% and 33%, respectively. ³⁶

Patients with atrophy or extensive intestinal metaplasia should be followed up with endoscopy every three years. Patients with moderate atrophy or intestinal metaplasia limited only to the antrum do not need follow-up. ³⁷ Management should be individualized according to other factors such as family history of GC, geographic origin, smoking and salt consumption.

Dysplasia is a high risk indicator for GC and should be confirmed and classified by two pathologists due to interobserver variability.

European guidelines recommend that patients with extensive atrophic gastritis or extensive intestinal metaplasia should have endoscopic follow-ups every 3 years. The incidence of GC in 10 years of follow-up for patients with atrophic gastritis is 0.8%. For patients with intestinal metaplasia, it is 1.8%, so the endoscopic follow-up of these 2 groups should be different. ³⁷

The operative link for gastritis assessment (OLGA) was established to evaluate the degree and location of atrophy. During diagnosis and follow-up of premalignant lesions, it is recommended that at least 5 samples be taken from patients undergoing endoscopy. Samples should include two from the antrum, two from the corpus, and one from the incisure. A biopsy sample from the incisure is needed because the prevalence of intestinal metaplasia is higher at this site than at any other location in the stomach. Intestinal metaplasia usually begins in the incisure and spreads to the antrum and the corpus. ^37,38

Intestinal Metaplasia

Intestinal metaplasia is classified as either complete or incomplete. Whether intestinal metaplasia is reversible is a matter of controversy which is the reason a point of no return is under investigation. ^39,40 Complete intestinal metaplasia is considered a short-term reactive process that usually regresses while incomplete intestinal metaplasia is related to chronic prolonged damage, so it is more likely to progress to dysplasia. ⁴¹

Patients with intestinal metaplasia may have up to 10 times more risk of GC than the general population. ⁴² There is controversy about the usefulness of classifying intestinal metaplasia in clinical practice. Incomplete intestinal metaplasia significantly increases the risk of GC beyond that of complete intestinal metaplasia. ^2,42,37,39

Prevention and treatment of gastric atrophy and intestinal metaplasia decrease the prevalence of GC. H. pylori eradication is the fundamental management step while detection of GC in its early stages is the other strategy for these patients. ⁴⁰

Correa proposed an algorithm for managing and monitoring preneoplastic lesions. For patients with intestinal metaplasia, the presence of H. pylori and the extent of intestinal metaplasia should be measured. If the infection is present, it should be treated. If intestinal metaplasia is extensive and incomplete, digestive endoscopy should be repeated every year and then every three years if the lesion persists. Otherwise monitoring is not required. ⁴³ Patients with intestinal metaplasia who have at least one of these risk factors - incomplete intestinal metaplasia, family history, history of smoking, and salt consumption - may have a higher risk of developing GC and would probably benefit from more intense and frequent endoscopic monitoring. ^33,37

Digestive endoscopy’s diagnostic performance has been poor in the West, so the diagnosis of gastric atrophy and intestinal metaplasia requires systematic biopsies of the corpus and the antrum. ⁴⁴ The protocol for staging with the OLGA system includes 5 biopsies: two from the antrum, two from the corpus, and one from the incisure. A greater number of biopsies may increase sensitivity. ^37,38,39

In a case-control study, the OLGA protocol identified 61.8% more cases of atrophy than did protocols with fewer biopsies. This could allow correction of the under diagnosis of gastric atrophy. ⁴⁵

It would be justified to practice quality digestive endoscopy to search for premalignant lesions in the high-risk population from the age of 40. Their extent and the risk of GC according to the OLGA system would determine the frequency of endoscopic follow-up. ^7,33,39

Intestinal metaplasia is a premalignant condition that can result from a process of adaption to an environmental stimulus such as H. pylori infection, smoking and/or high levels of salt consumption. ⁴⁰ English studies that evaluated benefits of follow-ups for patients with intestinal metaplasia have found the incidence of GC to be 11%. Endoscopic follow-up was associated with earlier detection of GC and improved survival. ⁴⁰

Cancer detection figures range from 33% to 85% in European studies of endoscopic follow-up of patients with intestinal metaplasia, dysplasia. ⁴⁰

In the low-risk populations of the United States, the risk of progression is low and clinical follow-up is not indicated unless there are other risk factors for GC such as family history or Asian or Latin American country of origin. ⁴²

A European consensus suggests that endoscopic follow-up should be performed with mapping and biopsies within one year of detection of low-grade dysplasia in a patient with intestinal metaplasia. The ideal frequency of endoscopic monitoring is not known. Follow-ups may be suspended when two consecutive endoscopies are negative for dysplasia. Unlike patients with low grade dysplasia, patients with high grade dysplasia should undergo surgical or endoscopic resection due to the high probability of coexisting invasive adenocarcinoma. Twenty-five percent of patients with high grade dysplasia can progress to adenocarcinoma within one year. If H. pylori infection is identified, it must be eradicated even though controversy remains as to whether empirical eradication should be performed when intestinal metaplasia is diagnosed. ⁴²

The presence of incomplete intestinal metaplasia is a recognized predictor of increased risk for development of high grade dysplasia or GC in areas with high prevalence such as Japan. Several studies have concluded that incomplete intestinal metaplasia identifies patients at high risk of developing GC, and they require intensive follow-up (Figure 4). ⁴⁶

Figure 4 Summary of secondary prevention strategies. 

Dysplasia

Gastric dysplasia is a precancerous lesion and is the penultimate stage in the cascade of gastric oncogenesis, as formulated by Correa. Therefore, identification, management and monitoring of this lesion is important for early detection and prevention of GC. Dysplasia is usually classified as low or high grade. ⁴⁷

Patients with dysplasia are generally men and who are 10 years younger than their relatives with GC (61.35 years for dysplasia and 70 years for GC). ⁴⁷

Dysplasia can be found anywhere in the stomach, but most often it is found in the antrum. Dysplasia is most often discovered incidentally during screening endoscopies. ⁴⁷

The real risk of progression of dysplasia to carcinoma is unclear because it is difficult to establish the natural history of dysplasia. However, several studies have shown that high-grade dysplasia has a high risk of progressing to either carcinoma or synchronous carcinoma. Figures ranging from 60% to 85% have been reported in an interval of 4 to 48 months. It is also known that 25% of patients with high-grade dysplasia have progressed to carcinoma within one year of diagnosis. ^39,47

High-grade lesions require endoscopic resection due to their potential for progression to carcinoma and coexistence with carcinoma. When lesions are not well defined endoscopically, it is recommended that they be followed up one year after diagnosis. Lesions with high grade dysplasia should be managed with endoscopic resection. ⁴⁷

Sometimes endoscopic resection is indicated not only for diagnosis but for treatment of dysplasia.