42 Acta Med Indones - Indones J Intern Med • Vol 54 • Number 1 • January 2022 ORIGINAL ARTICLE Urease Levels and Gastritis Stage in Dyspeptic Patients Muhammad Miftahussurur1,2,3*, Chyntia Dewi Maharani Putri1, Titong Sugihartono1, Ari Fahrial Syam4, Herry Purbayu1, Diah Priyantini5, Hartono Kahar6, Yudith Annisa Ayu Rezkitha2,7, Iswan Abbas Nusi1, Poernomo Boedi Setiawan1, Ummi Maimunah1, Langgeng Agung Waskito2, Ulfa Kholili1, Budi Widodo1, Amie Vidyani1, Husin Thamrin1, Gontar A. Siregar8, Reny I’tishom9, Tomohisa Uchida10, Yoshio Yamaoka1,3 1 Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya 60286, Indonesia 2 Helicobacter pylori and Microbiota Study Group Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia 3 Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan 4 Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta 10430, Indonesia 5 Faculty of Nursing, Universitas Airlangga, Surabaya 60115, Indonesia 6 Department of Clinical Pathology, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya 60131, Indonesia 7 Faculty of Medicine, Muhammadiyah University of Surabaya, Surabaya 60113, Indonesia 8 Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, North Sumatra University, Medan, 20115, Indonesia 9 Department of Medical Biology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia 10 Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu 879-5593, Japan Corresponding Author: Muhammad Miftahussurur, MD., Ph.D. Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine Universitas Airlangga - Dr. Soetomo Hospital. Jalan Mayjend Prof. Dr. Moestopo No. 6-8 Surabaya, Surabaya 60286, Indonesia. E-mail: muhammad-m@fk.unair.ac.id. ABSTRACT Background: Dyspepsia is a frequent main symptom of inpatients and outpatients scenario in Indonesia. However, the number of endoscopy facilities are still low, thus the use of non-invasive method to detect gastritis is necessary. We measured the relationship between urease levels and the stage of gastritis in dyspeptic adult patients. Methods: A cross-sectional study included outpatient dyspepsia patient from November 2018 to February 2019. We examined 14C-Urea Breath Test (UBT) and determined the stage of gastritis based on the Updated Sydney System classification. Results: The urease level of acute and chronic gastritis positive patients were higher than negative patients (p = 0.001, r = 0.353; p <0.0001, r = 0.433, respectively). The AUC value of 14C-UBT to detect acute, chronic, and atrophic gastritis are 0.889, 0.632 and 0.544, respectively. The best cut-off points of 14C-UBT to predict acute gastritis was ≥26.50δ‰ with sensitivity and specificity being 88.89% and 63.95%, respectively. Whereas the best cut-off points for chronic gastritis was ≥34.50δ‰ with 82.89% sensitivity, 63.16% specificity. As for atrophic gastritis, it showed very low AUC value, hence it is not a sufficient test modality to predict atrophic gastritis cases. Conclusion: 14C-UBT is sufficient for predicting acute or chronic gastritis but not for atrophic gastritis. Keywords: Dyspepsia, gastritis severity, urea breath test, cancer. Vol 54 • Number 1 • January 2022 Urease Levels and Gastric Stage in Dyspeptic Patients 43 INTRODUCTION Dyspepsia is the most common gastrointestinal symptom in clinical practice.1Approximately 44.7% patients with dyspepsia had gastritis or duodenitis diagnosed by endoscopic examination in Indonesia.2 Dyspepsia might be caused by two factors, infection and non-infection. Infection is mostly caused by Helicobacter pylori, whereas non-infection might be caused by stress, diet habits, hormonal factors and other functional factors.3 Detection of H. pylori infection could be performed by many ways, such as histological examination, stool antigen test, anti H. pylori antibody and urea breath test (UBT).4 Gastritis, especially atrophic gastritis is the common contributing factor for gastric cancer.5 Inflammation of the gastric mucosa may cause loss of glands that will eventually be replaced by intestinal-type epithelial cells, which is considered as a low-grade dysplasia.6 This dysplastic tissue then become intestinal type gastric cancer as the end result of progressive changes in the gastric mucosa.7 Mechanism of gastritis induced by urease enzyme activity remains unclear. Urea and urease may increase mucosal damage due to increased ammonia level in the gastric mucosa.8 A study in mice given ammonia showed an increase in the number of inflammatory cells induced by chronic gastritis, suggesting a significant relationship between ammonia levels and gastritis.9 Another study in patients with dyspepsia confirmed that ammonia levels were significantly associated with the severity of gastritis.10 In addition, peptic ulcer patients had significantly higher urease level than patients without peptic ulcers.11 It is suspected that there are urease-producing bacteria, including pathogens other than H. pylori which cause chronic gastritis in areas with low prevalence of H. pylori such as Indonesia. UBT is a non-invasive method to detect H. pylori which relied on the fact that H. pylori secretes urease enzyme which converts urea into ammonia and carbon dioxide.12,13 The UBT is a reliable method to detect H. pylori and performed based on the ability of H. pylori to break down urea, which is absorbed from the stomach and eliminated in exhalation.14 If the isotope is detected in the breath, the test is positive, suggesting H. pylori presence in the stomach.15 The amount of urease activity, detected by value from UBT may reflect the H. pylori bacterial load in the stomach.16 Indeed, UBT is mainly used for detecting H. pylori, but since there are other bacteria that has urease activity, such as Proteus mirabilis, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae and Staphylococcus aureus).17 However, the end point of urease activity is producing ammonia, a toxic substance for the stomach. Therefore, UBT may have potential usage and become a non-invasive alternative diagnostic modality to detect urease- related gastritis. Indonesia is a multi-ethnic country with over 267 million people living in more than seventeen thousand islands with regional disparities in health service quality.18 Dyspepsia and gastritis are included in the top 10 diseases and is common in inpatients and outpatients clinics of Indonesia. However, the number of endoscopy experts in Indonesia is lacking and the number of endoscopy centers is still low.19 Recently, 14C-UBT, a non-invasive method with simple, less expensive, accurate and easy handling is massively used in clinical practice. This study aimed to determine relationship between urease levels with the severity of gastritis in dyspeptic patients. METHODS We conducted a cross sectional study from November 2018 to February 2019 in Dr. Soetomo Teaching Hospital, Surabaya, Indonesia. Ninety five dyspeptic patients aged 18 to 70 years old were included in this study. We excluded patients receiving antibiotics and bismuth drugs 4 weeks prior to examination, proton pump inhibitor 2 weeks prior to examination, patients with history of gastric surgery, bleeding gastrointestinal tract within 4 weeks, impaired kidney diseases, liver cirrhosis, diabetes mellitus, gut malignancy, history of smoking and alcohol consumption, history of NSAID consumption and patients with endoscopy contraindication. We collected demographics data and dietary habits by questionnaire. One day before endoscopy, all patients were examined by 14C-UBT (Heliprobe, Stockholm, Muhammad Miftahhussurur Acta Med Indones-Indones J Intern Med 44 Sweden) using 14C-urea (250 uCi, Amersham) reconstituted with 25 ml of sterile distilled water. Subjects were fasted for at least six hours prior to the test. They removed false teeth (if present), and cleansed their mouth with antiseptic solution such as thymol, salol, menthol, saccharin, fuchsin, water and ethanol. A baseline breath sample was collected and identified as time 0. Then, they swallowed 5 uCi of 14C-urea dissolved in 20 ml of water. Breath samples were collected at 5, 10, 15, 20 and 30 minutes. Patients were instructed to blow through tubing attached to a safety trap into a scintillation vial containing 2.5 ml of 400 mM Hyamine (Sigma) in methanol with 15 mg/l thymolphthalein (blue alkaline color). They had to blow until the solution became colorless indicating the collection of 1 mmol of CO2. Once the breath samples had been collected, scintillation fluid (10 ml-5.5 g PPO/0.2g POPOP of 2:1 v/v Toluene/Triton-X) was added to the vial; counting proceeded for 5 minutes per vial, and the results were expressed as cpm/mmol CO2. Counting efficiency of the Beckman LS 100C was 93%. Endoscopy and biopsy were performed on the next day. Experienced endoscopists collected single biopsy samples from corpus and antrum of the gaster for histological examination. Patients with evidence of activity or inflammation in the antrum or corpus upon histological examination were considered positive for gastritis. The severity of gastritis is determined by histological examination based on the updated Sydney system classification.20 Informed consent was obtained from all participants, and the protocol was approved by the Ethics Committee of Dr. Soetomo Teaching Hospital (Surabaya, Indonesia). Statistical Analysis Statistical Analysis is done using the SPSS statistical software package version 23 (SPSS, Inc., Chicago, IL, USA). Correlation analysis used Spearman’s Signed Rank Test because the distribution data was abnormal. Correlation coefficient considered with r and significant analysis with P value was <0.05. In addition, to determine the cut-off point of UBT examination we used Receiver Operating Characteristic (ROC) analysis for showing area under curve (AUC) then we calculated the sensitivity and specificity from the determined cut-off point. RESULTS Demographical Characteristics of Patients The total study population was 95 consecutive dyspeptic patients (52 female and 43 male; age range 20-65 years). Female patients had a higher proportion of chronic and atrophic gastritis (4/52, 7.7%; and 15/52, 28.8%, respectively, Table 1), however statistically insignificant (p = 0.130). Age group of >60 years old had a more acute gastritis than other age groups (6/21, 28.6%, p = 0.018). Christian (5/20, 25.0%) and Buddhist (1/3, 33.3%) patients had higher association with acute gastritis (p = 0.038). However, there was no association between marital status, job, income, education and ethnics with prevalence of gastritis (all p >0.05). The amount of resident 1–4 people had higher proportion in acute and chronic gastritis (7/71, 9.9%, p = 0.049 and 15/71, 21.1%, p = Table 1. Demographical Characteristic of Respondents Demographical Characteristic n Acute Gastritis Chronic Gastritis Atrophic Gastritis Sex Male Female 43 52 5 (11.6) 4 (7.7) 6 (14.0) 13 (25.0) 9 (20.9) 15 (28.8) Age 20-29 years old 30-39 years old 40-49 years old 50-59 years old >60 years old 4 9 31 30 21 0 (0.0) 0 (0.0) 2 (6.5) 1 (3.3) 6 (28.6)* 1 (25) 0 (0.0) 5 (16.1) 5 (16.1) 8 (38.1) 2 (50.0)* 0 (0.0) 4 (12.9) 10 (33.3) 8 (38.1) Marital Status Married Single 87 8 9 (10.3) 0 (0.0) 18 (20.7) 1 (12.5) 21 (24.1) 3 (37.5) Vol 54 • Number 1 • January 2022 Urease Levels and Gastric Stage in Dyspeptic Patients 45 0.031, respectively, Table 2), but only tended in atrophic gastritis (19/71, 26.8%, p = 0.094). The frequency of eating with hand had association with acute, chronic and atrophic gastritis (p = 0.026, p = 0.045 and p = 0.036, respectively). Smokers had higher prevalence of acute gastritis than non-smokers (5/22, 22.7% vs. 4/73, 5.5%, p = 0.015). Source of water, alcohol drinker, hand washing after toilet use and before eating did not influence prevalence of gastritis (all p >0.05). Among 95 subjects, 19 (26.3%) frequently consumed analgesics and had association with acute gastritis (p = 0.005, Table 3). In addition, anxiolytic users had a higher acute gastritis rather than non-users (5/26, 19.2% vs. 4/69, 5.8%, p = 0.045). The most six common symptoms in acute, chronic and atrophic gastritis were epigastric pain (9/92, 9.8%; 14/92, 20.3%; 23/92, 24.2%, respectively), easy to feel full when consuming food or drink (8/64, 12.5%; 16/64, 25.0%; 17/64, 26.6%, respectively), nausea (6/64, 9.4%; 12/64, 18.8%; 15/64, 23.4%, respectively), feeling bloated (6/69, 8.7%; 14/69, 20.3%; 16/69, 23.2%, respectively), heart burn (4/46, 8.7%; 8/46, 17.4%; 13/46, 28.3%, respectively) and vomiting (7/72, 9.7%; 14/72, 19.4%; 16/72, 22.2%, respectively), but there was no significant association between all symptoms with gastritis (all p >0.05). There were three most comon diseases from endoscopy including erosive gastritis (20/95, 21.1%), gastroesophageal reflux disease (18/95, 18.9%) and superficial gastritis (13/95, 13.7%). The prevalence of H. pylori-positive subjects in this study was very low (4/48, 8.3%). When we used the cut-off point of UBT from manual Job Civil Servant Housewife Employee Doctor Teacher Student Retired Farmer 5 35 42 1 2 2 2 6 0 (0.0) 2 (5.7) 5 (11.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (2.1) 0 (0.0) 7 (20.0) 8 (19.0) 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0) 2 (33.3) 1 (20.0) 9 (25.7) 11 (26.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (50.0) Income Under Minimum Regional Income** Upper Minimum Regional Income** 69 26 6 (8.7) 3 (11.5) 15 (21.7) 4 (15.4) 16 (23.2) 8 (30.8) Religion Buddhism Hindu Moeslim Catholic Christian 3 2 65 5 20 1 (33.3)* 0 (0.0) 3 (4.6) 0 (0.0) 5 (25.0) 1 (33.3) 0 (0.0) 10 (15.4) 1 (20.0) 7 (35.0) 1 (33.3) 0 (0.0) 13 (20.0) 2 (40.0) 8 (40.0) Education Not educated Elementary school Junior high school Senior high school Diploma Bachelor Master 1 9 13 43 2 25 2 0 (0.0) 1 (11.1) 2 (15.4) 2 (4.7) 0 (0.0) 4 (16.0) 0 (0.0) 0 (0.0) 2 (22.2) 5 (38.5) 7 (16.3) 0 (0.0) 5 (20.0) 0 (0.0) 0 (0.0) 2 (22.2) 7 (53.8) 8 (18.6) 1 (50.0) 6 (24.0) 0 (0.0) Ethnic Ambon Bataknese Javanese Madura Sunda Tioghoa Alas Balinese Padang Pak Pak 2 22 49 4 1 11 1 3 1 1 0 (0.0) 5 (22.7) 2 (4.1) 0 (0.0) 0 (0.0) 2 (18.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (27.3) 9 (18.4) 0 (0.0) 0 (0.0) 4 (36.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (50.0) 7 (31.8) 10 (20.4) 1 (25.0) 0 (0.0) 5 (45.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) * p <0.05 with chi-square analysis ** USD 272 currency on March 2020 Muhammad Miftahhussurur Acta Med Indones-Indones J Intern Med 46 Table 3. Medical Status of Subjects Medical Status n Acute Gastritis Chronic Gastritis Atrophic Gastritis Symptom Bloated Yes No Epigastric pain Yes No Heart Burn Yes No Nausea Yes No Vomiting Yes No Easy to fill Yes No 69 26 92 3 46 49 64 31 23 72 64 31 6 (8.7) 3 (11.5) 9 (9.8) 0 (0.0) 4 (8.7) 5 (10.2) 6 (9.4) 3 (9.7) 2 (8.7) 7 (9.7) 8 (12.5) 1 (3.2) 14 (20.3) 5 (19.2) 18 (19.6) 1 (33.3) 8 (17.4) 11 (22.4) 12 (18.8) 7 (22.6) 5 (21.7) 14 (19.4) 16 (25.0) 3 (9.7) 16 (23.2) 8 (30.8) 23 (24.2) 1 (33.3) 13 (28.3) 11 (22.4) 15 (23.4) 9 (29.0) 8 (34.8) 16 (22.2) 17 (26.6) 7 (22.6) Proton Pump Inhibitor Yes No 4 91 1 (25.0) 8 (8.8) 2 (50.0) 17 (18.7) 1 (25.0) 23 (25.3) Antibiotics Yes No 11 84 2 (18.2) 7 (8.3) 4 (36.4) 15 (17.9) 2 (18.2) 22 (26.2) Table 2. Health Behavior of Subjects Health Behavior n Acute Gastritis Chronic Gastritis Atrophic Gastritis Resident in One House 1 – 4 people 5 and more people 71 24 7 (9.9)* 2 (8.3) 15 (21.1)* 4 (16.7) 19 (26.8) 5 (20.8) Source of Water Well New Mineral Water Refill Mineral Water Boiled Water 8 14 48 25 0 (0.0) 1 (7.1) 4 (8.3) 4 (16.0) 0 (0.0) 1 (7.1) 11 (22.9) 7 (28.0) 1 (12.5) 3 (21.4) 14 (29.2) 6 (24.0) Hand Wash After Toilet Never Rarely Sometimes Often Always 1 6 9 25 54 0 (0.0) 0 (0.0) 1 (11.1) 2 (8.0) 6 (11.1) 0 (0.0) 1 (16.7) 3 (33.3) 2 (8.0) 13 (24.1) 0 (0.0) 2 (33.3) 3 (33.3) 6 (24.0) 13 (24.1) Hand Wash Before Eat Never Rarely Sometimes Often Always 1 3 13 35 43 0 (0.0) 0 (0.0) 2 (15.4) 3 (8.6) 4 (9.3) 0 (0.0) 0 (0.0) 3 (23.1) 5 (14.3) 11 (25.6) 0 (0.0) 1 (33.3) 3 (23.1) 10 (28.6) 10 (23.3) Eating with Hand Never Rarely Sometimes Often Always 7 24 31 20 13 1 (14.3) 3 (12.5) 0 (0.0) 1 (5.0) 4 (30.8)* 1 (14.3) 8 (33.3) 2 (6.5) 3 (15.0) 5 (38.5)* 2 (28.5) 7 (29.2) 6 (19.4) 4 (20.0) 5 (38.5)* Smoking Yes No 22 73 5 (22.7)* 4 (5.5) 5 (22.7) 14 (19.2) 4 (18.2) 20 (27.4) Alcohol Yes No 21 74 4 (19.0) 5 (6.8) 5 (23.8) 14 (18.9) 5 (23.8) 19 (25.7) * p <0.05 with chi-square analysis Vol 54 • Number 1 • January 2022 Urease Levels and Gastric Stage in Dyspeptic Patients 47 instruction (50.00), there was no correlation between diseases and positivity of H. pylori. Urease Levels and Stage of Gastritis Based on the gastritis stage, we observed a significant trend of increasing UBT level with both degree of acute and chronic antral gastritis (r= 0.366 and r= 0.404, respectively; both P < 0.001) (Figure 1). However, we could not find correlation between degree of both atrophic gastritis and intestinal metaplasia in antrum. As for in the corpus, we only could find a significant Analgesic Yes No 19 76 5 (26.3)* 4 (5.3)* 5 (26.3) 14 (18.4) 4 (21.1) 20 (26.3) Anti-anxiety Yes No 26 69 5 (19.2)* 4 (5.8)* 6 (23.1) 13 (18.8) 7 (26.9) 17 (24.6) * p <0.05 with chi-square analysis correlation between corporal atrophy and UBT level (r= 0.270, P=0.036). The others histological parameter (acute gastritis, chronic gastritis and intestinal metaplasia) did not show a significant association (all P > 0.05). We validated the accuracy of 14C-UBT to predict acute gastritis. Acute gastritis is expressed as a neutrophil infiltration ≥1 on the gastric mucosa. The AUC of the urea levels compared with acute gastritis with AUC score was 0.889 (95% CI = 0.729 – 0.950) (Figure Figure 1. Association between urease levels with the degree of gastritis in each stage. Muhammad Miftahhussurur Acta Med Indones-Indones J Intern Med 48 2). The best cut-off point was ≥26.50 δ‰ with sensitivity of 88.89%, specificity of 63.95%, positive predictive value (PPV) of 71.15%, negative predictive value (NPV) of 85.20%, positive likelihood ratio of 2.47, negative likelihood ratio of 0.17 and accuracy of 76.42%. I n a d d i t i o n , w e a l s o d e t e r m i n e t h e performance of 14C-UBT for detecting chronic gastritis. UBT level yielded an AUC score of 0.632 (95% CI = 0.592 – 0.883) (Figure 3). The best cut-off point was ≥34.50 δ‰ with sensitivity, specificity, PPV, NPV, positive likelihood ratio and negative likelihood ratio being 82.89%, 63.16%, 78.69%, 69.23%, 3.69, and 0.44, respectively with overall 73.03% accuracy. The validation examination for atrophic gastritis showed a very low AUC score of 0.544 (95% CI = 0.396 – 692). Therefore, it is not sufficient for determining the best cut-off. As for the accuracy of the 14C UBT for intestinal metaplasia was not measured because there were only 2 positive cases. DISCUSSION We confirmed the accuracy of 14C-UBT to predict severity of gastritis but not for atrophic gastritis. The cut-off point 14C-UBT to measure acute and chronic gastritis were higher than atrophic gastritis. This result is in agreement with a previous study which showed that the UBT value was correlated to gastric cancer and was significantly lower than that for gastritis, duodenal ulcer, or gastric ulcer in H. pylori- positive patients.21,22 They also found a low UBT value were associated with the risk of gastric cancer, similar with this study where the cut- off points in atrophic was lower than acute or chronic gastritis.16 Urease level has better sensitivity in acute and chronic gastritis than atrophic gastritis due to the difference in H. pylori colonization bacterial load. Extensive gastric mucosal atrophy may decrease colonization by H. pylori and produce a low UBT value.4,23 In addition, UBT value is mainly influenced by H. pylori colonization which lead to increasing neutrophil infiltration, therefore it contribute to the higher association between acute gastritis rather than the atrophic gastritis.24,25 However, Indonesia has a low prevalence of H. pylori infection.26 In this study, we also confirmed that Figure 2. The urea levels compared with acute gastritis with AUC score. Figure 3. Urease activity level compared to chronic gastritis resulted AUC score. Vol 54 • Number 1 • January 2022 Urease Levels and Gastric Stage in Dyspeptic Patients 49 the prevalence of H. pylori infection was very low, suggesting in Indonesian cases generally the bacteria do not have a major influence on clinical outcomes27, especially in ethnic groups with low prevalence of H. pylori. Therefore, due to dyspepsia and gastritis being one of the top 10 diseases in Indonesia, non-H. pylori urease-producing bacteria might a major role causing gastritis. Non-H. pylori bacteria such as non-H. pylori Helicobacter spp., Mycobacterium spp., Staphylococcus spp, Proteus mirabilis, Citrobacter freundii, Klebsiella pneumoniae, and Enterobacter cloacae. could produce urease enzyme.17,25 Sufficient sensitivity but low specificity of 14C-UBT for determining acute gastritis, suggests that 14C-UBT has sufficient ability to screen for acute gastritis, but low specificity indicates UBT test was not a good diagnostic method.28,29 Thus, other modalities, either invasive or non-invasive to determine gastritis is necessary. There were options for non-invasive diagnostic method that had potential determining the gastritis status, such as serum pepsinogen level. Serum pepsinogen had been well recognized as a non- invasive screening option for early stages of gastric cancer. Combination of serum pepsinogen and anti-H. pylori antibody, Miki and co-workers had established a stratification method for gastric cancer risk.30 That method had been applied and showed promising results in several populations, including in Indonesia.31,32 Therefore, serum pepsinogen might be still become the best non- invasive methods to measure severity of gastritis, especially in Indonesia.33 Urease exposure can cause an inflammatory reaction by producing reactive oxygen species and inducing the expression of inducible NO- synthesizing enzyme.34 Urease can also give a toxic effect indirectly by producing ammonia, a product of urea hydrolysis.16 The presence of ammonia in the stomach can cause hypoxia in gastric tissue by increasing intracellular and intra mitochondrial pH. Ammonia also interferes with the activity of tricarboxylic acid which can reduce ATP synthesis so that it interferes with cell migration and cell proliferation which can inhibit repair of the gastric epithelium. This activity causes the activation of the danger associated molecular pattern (DAMP) that recognized by the pattern recognition receptor and activate monocytes and neutrophils and the recruitment of inflammatory cells, such as IL-1, IL-8 and TNF-αv.35 In addition to inducing the release of proinflammatory cytokines, ammonia can also enter the G cell nucleus easily and bind the gene-regulating gastrin unit so that it can activate expression and enhance gastrin formation.36 That mechanism might be a responsible way explaining observed gastritis in the high ammonia individuals. Based on demographic characteristics, age group of >60 years old had higher acute gastritis prevalence than other age groups because ageing reductes of mucous cells in the gastric mucosa of elderly, which is associated with a decreasing prostaglandin concentration.26 The research finding also stated smokers had higher prevalence of acute gastritis than non-smokers, and it is in agreement with other studies.15 Smokers have higher cases in gastritis because the gaster produce higher amounts of acid than in non-smokers. Female patients were found to have higher prevalence of chronic and atrophic gastritis, but it is statistically insignificant. Some authors support a small contribution of sex differences where there is predominance in H. pylori related outcomes in males, including gastric cancer. There were several limitations in this current study, first it had a very low sample number and was only collected in one center. In addition, there was no healthy individuals that were included in the population. Therefore, interpretation warrants caution since it may not represent the whole Indonesian population. Our study did not have any information regarding H. pylori status which might be considered as a main factor affecting the value of 14C-UBT, since urease is currently believed to mainly come from bacterial infection; therefore, the association between UBT and gastritis might be affected by H. pylori. This condition is needed a careful consideration. CONCLUSION Our study showed UBT has a sufficient potential for predicting acute and chronic antral Muhammad Miftahhussurur Acta Med Indones-Indones J Intern Med 50 gastritis with a good value of sensitivity. As for other gastritis parameters, UBT showed not a good choice for predicting those stages. 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