Prevalence and Association of Helicobacter pylori Infection in Gastric Disease at Dr. Cipto Mangunkusumo General National Hospital 2010–2021

Background: Several studies showed contrasting associations between Helicobacter pylori infection and organic gastric disorders. We aim to determine the association between H. pylori infection and gastroesophageal reflux disease (GERD), gastric polyp, and gastric cancer in an Indonesian national referral hospital. Method: Data was collected from patients referred to Cipto Mangunkusumo


INTRODUCTION
Helicobacter pylori is a gram-negative bacterium that colonizes the stomach. 1 H. pylori can reach the mucous protective layer on the upper part of the gastric mucosa and survive in extremely acidic conditions.The flagella helps to avoid the location of acid pH by chemotaxis.The large amounts of urea produced by H. pylori would subsequently become ammonia and carbon dioxide, which would neutralize its inhabited areas. 2 Most common H. pylori manifestations are mainly gastroduodenal disturbances, such as peptic ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. 3Record stated that gastric cancer has the third-highest disease burden in the world. 4This statement correlated with the fact that since 1994, Helicobacter pylori has been classified as a class I carcinogen by the International Agency for Research on Cancer (IARC), a subdivision of the World Health Organization (WHO).
Helicobacter pylori infection affects 60.3% of the world's population, and its prevalence is particularly high in developing countries. 3However, the relationship between H. pylori infection and the occurrence of organic gastric disease in specific developing countries has not been much discussed.This study focuses on H. pylori infection in Indonesia, one of the developing countries. 5The study aims to determine the prevalence and relationship of H. pylori infection in patients with organic diseases of the gastric (gastroesophageal reflux disease/GERD, gastric polyps, and gastric cancer) in Indonesia with a sample of patients undergoing endoscopy at RSUPN Dr. Cipto Mangunkusumo, Jakarta, Indonesia, from 2010 to 2021.

Research design and population
The study was conducted at Dr. Cipto Mangunkusumo, the General National Hospital in Indonesia.In this study, a total sampling method was carried out with a total of 338 patient records obtained from electronic medical records.Using a minimal sample equation from the previous study we had a minimal sample of 66. 6 In this study, the Helicobacter pylori-negative group consists of 274 patients, with 22 patients excluded due to incomplete medical records.The Helicobacter pylori-positive group consists of 64 patients, with two patients excluded due to incomplete medical records.
The inclusion criteria are patients who are ≥ 18 years of age, undergo an examination of H. pylori, and undergo an endoscopic examination.The inclusion diagnosis is that the patient has one of three gastric diseases (gastric cancer, gastric polyps, or GERD) and has a complete medical record.The exclusion is a patient who has already been diagnosed with H. pylori before or already finished H.pylori therapy outside Dr. Cipto Mangunkusumo General Hospital.The study was conducted with the approval of the Universitas Indonesia Ethics Committee with protocol number 20-07-0753 using secondary data in the form of medical records.Electronic medical record data is collected from patients performing endoscopy and colonoscopy examinations at the Digestive Endoscopic Center, Dr. Cipto Mangunkusumo General National Hospital in 2010-2021 who underwent H. pylori examination through both histopathological biopsy and urea breath test.
The diagnosis of gastric cancer and gastric polyps is established through endoscopy and histopathology examination with biopsy.The diagnosis of gastritis and GERD is established through anamnesis and physical examination.The diagnosis of esophagitis, hiatal hernia, and peptic ulcers is established through an endoscopy examination.The diagnosis of H. pylori is obtained through a urea breath test and histopathological examination with biopsy.

Statistical Analysis
Statistical analysis is done using IBM SPSS version 25.The method of analysis used is chi-square analysis to determine the significance value of p < 0.05 and 95% CI.

RESULT
Out of a total of 314 patients meeting the inclusion criteria, there were 131 male (41.7%) and 183 (58.3%) female patients.No significant differences were found between sex and the incidence of H. pylori infection (p = 0.152).There were 62 (19.74%) patients with a positive diagnosis of H. pylori infection and 252 (80.25%) patients with H. pylori negative.The demographics of patients are shown in Table 1.

DISCUSSION
Helicobacter pylori is one of the most common bacteria in the world.A study reported that H. pylori infection is associated with the host's genetic susceptibility, environmental factors where the host lives, and the genetic diversity affecting the strain of H. pylori itself. 7A study showed that several habits such as eating food with fingers, washing hands before eating, or drinking alcohol, may affect the increase of H. pylori prevalence. 8Other socio-cultural risk factors including salary, source of water, history of medicine, and smoking were also associated with the increased prevalence in Indonesia. 9ERD is one of the most common gastrointestinal diseases. 10Based on the Montreal classification, GERD is defined as a condition in which reflux from the gastric content leads to unwanted symptoms or complications. 11The pathophysiology of GERD begins with the failure of the lower esophageal sphincter, which can be caused by various factors such as hernia hiatus, obesity, pregnancy, drugs, and smoking. 2 Globally, an increase in GERD incidence is expected to occur. 12The best treatment for H. pylori infection in GERD patients is still debatable, and there is still insufficient agreement on the association between H. pylori infection and GERD.H. pylori has been identified as a protective factor in GERD by multiple studies. 13It is thought that there may be a link between H. pylori and GERD because the frequency of GERD has been rising in developing nations while the prevalence of H. pylori infection has been dropping.
In this study, we have found there is a positive association between H. pylori infection with esophagitis and GERD.According to other studies with the same outcome, H. pylori infection is related to the severity of GERD and is less common in people with severe GERD than it is in people with mild GERD. 14A study by Fatin et al in Turkey showed that there is a positive association between H. pylori infection with GERD, with H. pylori infection found in 82.4% of patients with GERD based on the study. 14Jie et al in their study concluded that the prevalence of H. pylori-positive was higher among patients with GERD and peptic ulcers. 15ther research, however, demonstrates no connection between GERD and H. pylori.A cross-sectional study conducted in Iran for 7 years with more than 1900 participants showed there was no association between H. pylori infection and erosive GERD. 16elicobacter pylori can induce esophagitis in GERD through one of the following three potential mechanisms: (1) H. pylori infection becomes a predisposition to GERD by increasing the secretion of gastric acid; (2) H. pylori infection may result in esophageal damage by infecting the columnar-type epithelium of the gaster that lines the distal or as part of Barrett's esophagus; or (3) H. pylori infection may lead to indirect damage to the esophagus.One study showed no statistically significant differences between esophagitis and reflux in patients with and without H. pylori infection. 17 randomized controlled trial (RCT) by Yan Xue showed that no association was found between H. pylori and GERD or erosive esophagitis. 13A metaanalysis showed that the long-term use of PPI is associated with an increased risk of gastric atrophy.The exact mechanism is still unknown.One of the theories is the concurrent use of PPI can change the distribution of organisms in the corpus, resulting in active chronic corpus gastritis with atrophy. 18Since many GERD patients use PPI medicines for a sufficiently long period, this is considered to be an association between H. pylori and GERD.
H. pylori is also considered to be the leading cause of gastritis and peptic ulcers, which can develop into gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma.Gastritis caused by H. pylori occurs as a result of a decrease in the production of somatostatin, which regulates gastrin, resulting in hypergastrinemia. 19If not addressed immediately, this will result in inflammation of the gastric mucosa and atrophy, which can increase the risk of gastric ulcers and non-cardia adenocarcinomas.
A study in Iran showed that H. pylori is isolated in 60-80% of cases of peptic ulcers. 20The frequency of duodenal ulcers is higher than that of gastric ulcers, with the majority of patients being male.The virulence factors of H. pylori, which are gene A (cagA) and cytotoxin A (vacA), are considered to be the factors that induce the process of apoptosis in cells and result in the death of the host cell on the epithelium of the gaster.It also leads to the dysregulation of the pathway of mitogen-activated protein kinases (MAPKs).
Keikha et al's meta-analysis showed a significant correlation between the occurrence of peptic ulcers and vacA and cagA-positive strains of H. pylori (RR = 1.63; 95% CI: 1.39-1.91;p = 0.00). 21The ability of cagA/vacA-positive bacteria to withstand gastric acid conditions and evade the immune system is a distinctive trait that links them to peptic ulcers. 22All strains of H. pylori include the vacA gene, but only 50% of them also contain the vacA toxin, which is the functional protein.For the bacteria to thrive in the mucous layer, the vacA protein creates a channel on the bacterial membrane that draws various ions and metabolites into the cytoplasm.
CagA is a protein that has high immunity; some studies stated that the cagA-positive strain has been associated with more severe inflammation, increased degrees of atrophy, and a greater likelihood of developing into adenocarcinoma compared with the cagA-negative strain.CagA will bind to the membrane cell when it enters the host cell, then pass through the tyrosine phosphorylation process that will change the cell morphology and affect a variety of other intracellular processes that then result in inflammation. 4he researchers discovered a link between H. pylori infection and hiatal hernia, which is a contributing factor to Gastroesophageal Reflux Disease (GERD) and is connected with the development of esophagitis. 23nother study found that the incidence of hiatal hernias without infection with H. pylori was higher compared to hiatal hernias with H. pylori (91 versus 31; p < 0.0001). 17elicobacter pylori is an etiological agent for gastric adenocarcinoma, which then, more than 50% of the time, becomes gastric cancer.Other factors are thought to influence the carcinogenesis in the H. pylori infection process, such as smoking.A study in East Asia showed that smoking at the time of research increased the risk of non-cardiac gastric cancer, but only in subjects who harbored antibodies to the H. pylori virus, specifically CagA-positive H. pylori.This implies that smoking status is an additional risk factor for gastric cancer incidence in regions with high H. pylori prevalence, such as East Asia, and that quitting smoking may be a useful tactic to lower the risk of gastric cancer. 24nfection with H. pylori results in damage to the gastric mucous membrane, causing atrophic gastritis that then turns into intestinal metaplasia, dysplasia, and gastric cancer.However, in this study, significant correlations were found only in esophagitis and GERD.There are some limitations to this study, especially in the number of samples.Data from 2010-2014 is difficult to find through electronic medical records, and not all patients undergoing endoscopy are examined for Helicobacter pylori.This study did not include GERD patients who did not go through endoscopy examination, thus selection bias may occur as a limitation.
The strength of this study lies in the way it diagnoses gastric cancer and gastric polyps through endoscopy and H. pylori infection through tissue histopathological examination.The study used immunohistochemistry to diagnose H. pylori on a gastric biopsy because it has high sensitivity and specificity, especially in patients who have just started therapy. 25

CONCLUSION
This study found a significant correlation between Helicobacter pylori infection and the occurrence of esophagitis and GERD.No significant correlation was found between H. pylori infection and the occurrence of gastric cancer or gastric polyps.This may occur due to a lack of data on patients with H. pylori infection.Research with more samples is recommended for further research.
Prevalence and Association of Helicobacter pylori Infection in Gastric Disease atDr.Cipto Mangunkusumo General National Hospital 2010-2021