Abstract: Background and Objective: Helicobaeter pylori is a common bacterial infections worldwide, and linked to induction of chronic atrophic gastritis in infected individuals, and subsequently proceeded to gastric carcinoma. The aim of study to determine the frequency rate of biomarkers positivity, family history of gastritis and drug usage between H. pylori positive and negative gastritis. Materials and Methods: Serum collected from 136 subjects of the 72 were H. pylori positive and 64 were H. pylori negative as control group. Pepsinogen A, pepsinogen C, CD44, gastrin and human interferon gamma in serum were detected using ELISA test. Results: Pepsinogen A frequency of positivity rate was higher in H. pylori negative cases (37.5%) than in those H. pylori positive cases (23.6%), but the difference was not significant. The frequency rate of pepsinogen C positivity was 68.6% in H. pylori positive group and 31.4% in H. pylori negative cases with significant difference. The frequency positivity rate of gastrin was 70.8% in H. pylori positive gastritis, while it was 50% in H. pylori negative cases and the difference was significant. The frequency positivity rate of CD44 was 80.6% in H. pylori positive gastritis, while it was 50% in H. pylori negative cases and the difference was significant. The frequency positivity rate of interferon gamma was 81.9% in H. pylori positive gastritis, while it was 50% H. pylori negative cases and the difference was significant. Conclusion: High frequency rate of low positive pepsinogen A, high positive rate of gastrin, CD44 and interferon gamma were predictive biomarkers for chronic gastritis.
INTRODUCTION
Helicobaeter pylori is a common bacterial infections worldwide1 and linked to induction of chronic atrophic gastritis in infected individuals and subsequently proceeded to gastric carcinoma2. The incidence of H. pylori infection was varied between studies performed in different countries and between the studied within the same country3,4. In a biopsy based sampling method H. pylori prevalence rate was 60.5-94% in African studies5-14. In a recent review, Khedmat et al.15 reported a high incidence of H. pylori infection in the Middle East Region and needs attention and the rate was more in subjects with gastritis than those without. In Saudi Arabia, the infection rate was 28.3% - 51% in general population16-18, 66.4-78% in subjects with gastritis19-21 and 23.6-27.4% in children22,23, with trends on increase rate with age. In Turkey, the rate of H. pylori infection is high and with a range of 58.4-100% in general population24-27, while it was 50.6-89.6% in symptomatic individuals and 20.8-78.5% in children28-31.
In Iran, H. pylori infection rate was 69-90% in general population32, with trends of increase with age34 and 50-86.6% in subjects with gastritis34,35. In Egypt, the infection rate was 91.7% in general population36, 30.2-82.9% in patients with gastritis37,38 and 10.2-72.4% in children39-42. In Palestine general population the infection rate was 48.3 and 49.7% in children43. In Libya, the infection rate was 76% and it was 50% in those with age of 1-9 years of age that increased to 84% in subjects 10-19 years and continued with increasing age and reached upto 94% in those over 70 years of age44,45. While in Libyan symptomatic patients, the infection rate was 82%46. In Oman, H. pylori infection rate was 69.5%, with 71% rate at age of 15-20 years and 87% in those with age of 41-50 years47. In Morocco the infection rate in symptomatic patients was 69.9%48, while it was 44% in Jordan49, 100% in Bahrain50, 75-82.2% in Yemen51,52, 66-96.6% in Kuwait53-56. In United Arab Emirates, the infection rate in general population was 64.3-78.4%57,58 and it was 82.4 -90.9% in symptomatic patients59,60. In Tunisia, H. pylori infection rate was from 30.4-51.4% in children61,62 and 21% in Lebanon children63.
Most of the reported studies that evaluated the association between H. pylori infection, chronic atrophic gastritis and gastric carcinoma used mean serum values in their evaluation64,4. This approach of analysis extracted the mean serum value of any biomarkers from the sum of all patients values. Thus, the mean value affected by the low values of the biomarkers in some individuals included in the study cohort and the outcome for that is the reduction in the mean value. In order to overcome such bias we used the frequency rate of positivity for comparison between H. pylori positive and negative gastritis. This study performed to determine the frequency rate of biomarkers positivity, family history of gastritis and drug usage between H. pylori positive and negative gastritis.
MATERIALS AND METHODS
Study population: The subjects included in this study were recruited gastroenterology clinic in Balad General Hospital and serum samples were collected from 206 individuals with gastritis. Subjects with history of H. pylori eradication, who receive anti-hyperlipidaemia drug, those with chronic or acute inflammatory conditions, liver disease, renal dysfunction, diabetes and malignancy were excluded from the study. The study population divided according to H. pylori positivity into patients with H. pylori positive group and H. pylori negative as control group. Informed consent taken from each subject before enrolment in the study. The study protocol was approved by the Ethical Committee of College of Science, Tikrit University and Salhuldean Health Authority.Samples: Serum collected from 136 subjects, of the 72 were H. pylori positive and 64 were H. pylori negative as control group. H. pylori kit purchased from Spectrum Company, Germany. Human pepsinogen A ELISA kit, human pepsinogen C ELISA kit, human CD44 ELISA kit, human gastrin ELISA kit and human interferon gamma ELISA kit were purchased from Elabscience, China.
Statistical analysis: The serum level of each biomarker was stratifies into positive or negative using a cut-off value calculated from the mean of control plus 2 standard deviation. Data collected analysed using SPSS package version 20 to determine the difference significance, odd ratio and area under ROC curve p<0.05 considered significant.
RESULTS
Frequency of family history of gastritis and drug use: Of the total 62 patients (30.1%) were with family history of gastritis and without significant difference between H. pylori positive and negative cases. In 53.4% (110/206) of the total patients included in the study were not using drug. However, none drug use was more predominant in H. pylori positive (30.6%, 63/110) than in H. pylori negative cases (22.8%, 47/110). Librax oral tablet was the predominantly used drug 15.5%), followed by omeprazole (9.7%), with higher rate in negative cases, Table 1.
Frequency of biomarkers in patients compared to controls: Pepsinogen A frequency of positivity rate was higher in H. pylori negative cases (37.5%, 24/64 cases) than in those H. pylori positive cases (23.6%, 17/64 cases), however, the difference was not significant (X2 = 3.1, p>0.05), Table 4. In addition, from the total 30.1% pepsinogen A positive cases in our cohort, 12.5% of the cases were H. pylori positive and 17.6% were H. pylori negative, Table 2.
The frequency rate of pepsinogen C positivity was 75% (102/136), 70 cases (68.6%) in H. pylori positive group and 32 cases (31.4%) in H. pylori negative cases with significant difference (X2 = 40.26, p = 0.000). In addition, in H. pylori positive cases, 97.2% (70/72 cases) were with positive pepsinogen C, while only 50% (32/64 cases) were positive for pepsinogen C in H. pylori negative cases, Table 2.
The frequency positivity rate of gastrin was 70.8% (51/72 cases) in H. pylori positive gastritis, while it was 50% (32/64 cases) in H. pylori negative cases and the difference was significant (p = 0.014), Table 2. The frequency positivity rate of CD44 was 80.6% (58/72 cases) in H. pylori positive gastritis, while it was 50% (32/64 cases) in H. pylori negative cases and the difference was significant (p = 0.000), Table 3. The frequency positivity rate of interferon gamma was 81.9% (59/72 cases) in H. pylori positive gastritis, while it was 50% (32/64 cases) in H. pylori negative cases and the difference was significant (p = 0.000), Table 3.
OR and area under ROC curve indicated that there is a significant association between age and H. pylori infection in patients with gastritis. The predictive value was higher for AUC ROC than that of OR. Gender was with significant association as confirmed by OR but not AUC ROC. However, both OR and AUC ROC confirmed the significant association between BMI and H. pylori gastritis. Family history of gastritis was with significant association with H. pylori infection as demonstrated by OR but not AUC ROC. While drug history was significant as demonstrated in AUC ROC but not OR, Table 4. The predictive value of demographic characteristics in patients.
Age with a significant inverse correlation with gastrin serum levels in patients with gastritis, while with weak none significant correlations with pepsinogen A, pepsinogen C, CD44 and interferon gamma. BMI, LDL, HDL, triglyceride, cholesterol were without any significant correlations with pepsinogen A, pepsinogen C, gastrin, CD44 and gamma interferon serum levels, Table 5.
Pepsinogen A (r = 0.68, p = 0.000) and pepsinogen C (r = 0.32, p = 0.006) serum levels were significantly correlated to interferon gamma serum levels. In contrast, gastrin serum levels were inversely significantly correlated to interferon gamma (r = -0.69, p = 0.000) and CD44 (r = -0.28, p = 0.017). While interferon gamma serum levels were significantly correlated with CD 44 (r = 0.27, p = 0.024). Gastrin serum levels were significantly inversely correlated to pepsinogen A (r = -0.53, p = 0.000) and pepsinogen C (r = -0.049, p = 0.000) serum levels, Table 6.
DISCUSSION
H. pylori infection was detected in 55.8% of patients with gastritis and 30.1% were with family history of gastritis. This rate of incidence was within the range that was reported for African countries5-14, Turkey24-31, Iran32-35, Egypt36-42, Palestine43,44, Libya45,46, Oman47, Morocco48, Jordon49, Bahrain50, Yemen51,52, Kuwait53-56, United Arab Emirates57-60, Tunisia61,62 and Lebanon63. The pattern of infection illustrated a high rate incidence and prevalence trends in individuals with gastritis as compared to general population. However, the incidence rate in general population was high as the above mentioned studies indicated. This finding suggest, that H. pylori infection in general population and in subjects with underlying disease such as gastritis is a health problem with impact on quality of life.
Pepsinogen A frequency of positivity rate was higher in H. pylori negative cases (37.5%) than in those H. pylori positive cases (23.6%), however, the difference was not significant. In addition, the frequency rate of pepsinogen C positivity was 97.2% in H. pylori positive group and 50% in H. pylori negative cases with significant difference. Mansour-Ghanaei et al.65 reported a frequency rate of positivity for pepsinogen A of 25% in precancerous and 17.5% in chronic gastritis patients. In addition, pepsinogen C positivity rate was 45% in precancerous and 50% in chronic gastritis patients. Furthermore, urinary pepsinogen was positive in 35.4% of general population and in 60.5% of those with peptic ulcer66.
The frequency positivity rate of gastrin was significantly higher in H. pylori positive (70.8%) gastritis compared to H. pylori negative cases. Kim et al.67 reported a frequency of 20% for hypergastrinaemia in patients with gastritis compared to 5.1% in controls. Mansour-Ghanaei et al.65 reported serum gastrin positivity rate of 57.5% in precancerous and 54.5% in chronic gastritis. The local and serum/or plasma concentrations of gastrin alteration may affect the risk of developing an epithelial gastric tumour by altering key cellular processes including proliferation, apoptosis, migration and angiogenesis68. Increased serum gastrin levels in animal models may act as a cofactor with Helicobacter infection during gastric adenocarcinoma development69. However, it is still unclear whether gastrin is a central player or a secondary phenomenon in the development of gastric adenocarcinoma70.
Gastrin is normally produced at high levels by endocrine (G) cells located in the gastric antrum and is often upregulated in the setting of acid suppression and Helicobacter pylori infection71. In some cases, the increase in serum gastrin may relate to increased cytokine release in the vicinity of antral G cells. Alternatively, the increase in serum gastrin may be secondary to Helicobacter pylori colonization of the gastric body and fundus, resulting in decreased acid secretion and reduced inhibitory feedback on gastrin release71. The interpretation of hypergastrinemia in a chronic gastritis setting, however, is difficult owing to the complex interplay between gastritis severity, the extent or severity of corpus atrophy and concomitant use of proton pump inhibitors67. Although, the role of gastrin in precancerous lesion induction is well documented in preclinical studies70, however, clinical studies for such issue were controversial67. The pro-carcinogenic role of serum and tissue gastrin was supported in a few clinical studies72-76.
The present study indicated that the frequency positivity rate of CD44 significantly higher in H. pylori positive gastritis (80.6%) than in H. pylori negative cases (50%). In literature, we don’t found an article that reported the estimation of CD44 in serum or plasma to compare with. However, in animal model, Garay et al.77, suggest that immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. In addition, the expression of CD44 is increased in advanced gastric lesions and CD44 mice develop less severe and less extensive H. pylori induced metaplasia. CD44 is a homing cell adhesion molecule, a cell surface glycoprotein for hyaluronic acid. This marker is expressed on the surface of red blood cells and platelets and they have been known as lymphocytic homing receptors. CD44 plays an important role in adhesion to the extracellular matrix and matrix functions, such as degeneration, proliferation and cell survival78-81. Previous studies in animal models and human indicated that CD44 play a role in the pathogenesis of atrophic gastritis78,81-98.
The frequency positivity rate of interferon gamma was significantly higher in H. pylori positive gastritis (81.6%) than in H. pylori negative cases (50%). Cell cultures stimulated with H. pylori products show a prominent production of IFN-γ99,100. Other studies reported an increased number of gastric T cells expressing IFN-γ101,102. These in vitro findings suggest a predominance of Th1 response in H. pylori infection, which may be involved in the pathogenesis of gastritis and ulcer in H. pylori-positive patients103-105. Previous studies reported enhancement of IFN-γ expression in gastric mucosa in patients infected with H. pylori103,106 and IFN-γ secreting cells increased in gastritis compared to patients with no gastritis107. Thus epithelial cells destruction and inflammation as a sequence in pathogenesis of H. pylori could be induced by Th1 immune response103. However, non-immunological mechanisms should also be considered since PBMC and whole-blood cultures from H. pylori-negative individuals caused increased IFN-γ secretion by in vitro stimulation with H. pylori or its products100,108. Experiments on gastric epithelial cell lines indicate that IFN-γ production could increase class II MHC expression on the epithelium leading to increased H. pylori attachment and possible induction of epithelial cell apoptosis109-111 but other apoptotic pathways should also be taken into account110,111.
CD44 is associated with disease progression through mechanisms associated that include induction of interferon gamma responses77. OR and area under ROC curve indicated that there is a significant association between age and H. pylori infection in patients with gastritis. The predictive value was higher for AUC ROC than that of OR. H. pylori in developing countries are more common at younger ages than in developed countries112. However, different geographical regions are with different infection rate in relation to age. In Europe, the infection rate was 1.2% for age of 2-4 years in Netherland, while the minimum rate in adults was 11.9% in Switzerland. In contrast, in Asia, the infection rate was 50-60% for age of 0-4 years in Bangladesh, while it was >90% in adults in Bangladesh. In the Middle East, the rate of infection was 40-50% in those with age of 1-9 years and 80-90% in adults112. Gastric cancer increased with age113, however, in multivariate analysis, age is only a surrogate marker and is not an independent risk factor for gastric cancer114. Agreus et al.113 reported that gastric cancer risk in 70 years old individual with normal and healthy stomach is low as the cancer risk in a 30 years old subject with healthy stomach. In addition, Ebule et al.115 not found a significant association between H. pylori infection and age. However, Jin et al.116 reported that age significantly associated with H. pylori infection.
Both OR and AUC ROC confirmed the significant association between BMI and H. pylori gastritis. However, the association between obesity and H. pylori infection is controversial in the literature. Although, previous data already have suggested that weight gain may occur after antibiotic therapy targeting H. pylori eradication, however, Xu et al.117 results showed that BMI was significantly and positively associated with H. pylori infection and a high BMI was associated with an increased risk of the infection. Lender et al.118 in a recent review that included 50 articles from 10 European countries found an inverse association between the H. pylori prevalence in various countries and the prevalence of overweight or obesity in these countries. In addition, the successful eradication of H. pylori was followed by increase in weight of patients119. Other study in children shows that subjects who were cleared from the infection or never infected with H. pylori or grew significantly faster (gained weight) than those with persistent H. pylori infection120.
Weight gain following H. pylori eradication could be attributed to improvement of postprandial symptoms such as early satiety that may affect some people118. However, the ef ciency of H. pylori eradication with regard to symptoms is 4 very small121 and other large well controlled studies were not able to demonstrate any effect122. More importantly, a positive trial 6 conducted in a geographical region that had a high peptic ulcer prevalence and long waiting times for endoscopic procedures suggests that the beneficial effect might be due to undiagnosed peptic ulcer disease. There is also some evidence that H. pylori may protect against symptoms of gastro-oesophageal re ux while obesity is a risk factor for the manifestation of GERD123. Thus, it might be speculated that the manifestation of GERD symptoms affects behaviour and thus may have an impact on weight gain118. Among other factors, the hormone ghrelin is relevant for the regulation of appetite and food intake124.
The plasma ghrelin increased after H. pylori infection treatment in asymptomatic subjects125. This could lead to increased appetite and consequently weight gain and contribute to the increasing obesity seen in Western populations where H. pylori prevalence is low. Previous studies reported the increase in leptin and ghrelin plasma levels following eradication of H. pylori infection, a direct evidence that H. pylori colonisation is involved in ghrelin and leptin regulation, with consequent effects on body weight126.
Other study suggest reduction in circulating ghrelin in subjects with H. pylori infection independent of BMI and sex127. In contrast, in a study that included 7000 subjects, H. pylori seropositivity and CagA antibody status were not associated with serum leptin level or BMI128. It might be argued that the inverse relation between H. pylori and obesity that was found in Lender et al.118 study is mediated by the development status of the various countries which is re ected by the gross domestic products (GDP). The data of Lender et al.118 review support the assumption that the association is not simply mediated by the income or the development status of the populations included in this analysis and suggest that the decrease in H. pylori prevalence observed in many countries in recent decades could be a contributing factor to the obesity endemic of the Western world. However, Lender et al.118 study cannot rule out that other factors that are correlated with the risk of a H. pylori infection are causal for the observed association.
Zhang et al.129 study in Chinese population shows an increased prevalence of H. pylori infection in patients with higher BMI levels. The effect of obesity on H. pylori infection Obese individuals show an increased susceptibility to infections with different pathogens130. Arsalan et al found that the H. pylori infection rate in the obese group was 57.2% versus 27.0% in the control group and there was a significant association between the obesity and serum antibody positive for H. pylori131. Yang et al. found that obesity was positively associated with increased risk of gastric H. pylori infection in Chinese individuals132. In contrast a study in Greece indicated that the incidence of H. pylori infection was not increased among overweight/obese young individuals133. In addition, previous studies also not found an association between H. pylori infection and obesity128,134-137. Obesity is usually associated with impaired immune function and immune deterioration is also related to the grade of obesity138. The maturation of monocytes into macrophages was found to be lower and the capacity of polymorphonuclear to be bactericidal was found to be reduced in obese individuals139,140. Severely obese individuals also have a significant decrease in NK cell activity compared with control individuals after adjustment for age and gender141. Kopacova et al. studied 2,436 people (between 4 and 100 years of age) and found that there were positive associations between H. pylori infection and the levels of BMI both in overweight/obese and obese subjects over 15 years of age142. In Zhang et al.129 study, the H. pylori-positive group had significantly higher BMI levels than did the H. pylori -negative group. In multiple linear regression models with BMI levels as the dependent variable, the association between H. pylori positivity and BMI levels was statistically significant after adjustment for H. pylori status, gender, age, smoking status, drinking status, hypertension, coronary heart disease, diabetes and dyslipidemia. Furthermore, they found a positive association between H. pylori infection and overweight/obesity according to different BMI criteria. However, the association between H. pylori infection and obesity was consistently significant only according to the Asian criteria (BMI>27.5), but not significant according to the more restrictive Chinese criteria (BMI>28). H. pylori infection may stimulate overfeeding through leptin reduction143-145 and induction of inflammatory cytokines which may lead to insulin resistance and subsequently overweight or obesity146-148.
Family history of gastritis was with significant association with H. pylori infection as demonstrated by OR but not AUC ROC. This finding may suggest that H. pylori may be with genetic predisposition, however, this need a confirmation in a large scale study. In general population 5-10% is never infected with H. pylori even in the presence of high exposure rate149. A contribution of genetic factors to H. pylori susceptibility is supported by differences in H. pylori susceptibility between African Americans and US residents of European ancestry after adjusting for socioeconomic status, age and living conditions150. Significantly higher concordance for H. pylori infection in monozygotic compared with dizygotic twins, or for household members who are siblings rather than unrelated persons, +also argues for a genetic influence, with a heritability estimate in twins of 57%151. Previous studies indicated that genetic variations modulate the susceptibility for cancer of stomach among Hp infected subjects152,153 + and may be atrophic gastritis.
Mayerle et al.154 in a genome-wide association study for determinants of H. pylori seroprevalence identified an association between TLR1 and H. pylori seroprevalence, a finding that requires replication in other independent populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H. pylori infection.
Pepsinogen A and pepsinogen C serum levels were significantly correlated to interferon gamma serum levels. In contrast, gastrin serum levels were inversely significantly correlated to interferon gamma and CD44. This correlation was dependent on the site of gastritis and severity of the disease65,67, for example, at the early stage of gastritis, pepsinogen A supposed to reduced slightly, but the reduction is increased with time course of disease natural history and severity.
Gastrin serum levels were significantly inversely correlated to pepsinogen A. Serum gastrin levels increased in H. pylori infected gastritis, while pepsinogen decreased in such patients113,155 and this contribute to inverse correlation between serum gastrin and serum pepsinogen levels. Interferon gamma serum levels were significantly correlated with CD 44. This could expected since CD44 is associated with disease progression through mechanisms associated that include induction of interferon gamma responses77.
Gastric homeostasis is disrupted by H. pylori infection and subsequently lead to induction of cytokines with increased risk for developing gastric cancer152,156,157. However, IFN-γ demonstrated counteract effect against the cytokines with risk for development of gastric cancer157. Thus CD44 serum levels were significantly correlated to IFN-γ, which is one of the CD44 mechanisms that by which it oppose development of gastric tumor157. Disruption of host cell inflammatory cytokine production participates in gastric oncogenesis158. Age with a significant inverse correlation with gastrin serum levels in patients with gastritis, while with weak none significant correlations with pepsinogen A, pepsinogen C, CD44 and interferon gamma. Feldman et al.159 reported a decline in acid secretion in the elderly was primarily related to a higher prevalence of chronic atrophic gastritis and pepsin output was reduced approximately 40% in the elderly. Our study finding was consistent with this as there was no significant correlation between age and pepsinogens serum levels.
In 53.4% of the total patients included in the study were not using drug. However, no significant difference in drug use was recorded between H. pylori positive H. pylori negative cases. This indicated a partial treatment of gastritis in this study cohort. Librax oral tablet was the predominantly used drug followed by omeprazole with higher rate in negative cases. So such drug use may interfere with H. pylori and contribute to eradicate or reduce bacterial load and this assumption strengthened by the demonstrated significant association by AUC ROC. but not OR.
The BMI, LDL, HDL, triglyceride, cholesterol were without any significant correlations with pepsinogen A, pepsinogen C, gastrin, CD44and gamma interferon serum levels. This could be due to the metabolic changes that induced by H. pylori infection160. Gender was with significant association with H. pylori infection as confirmed by OR but not AUC ROC. Valliani et al.161 study demonstrated that H. pylori infection can be related to ABO blood group, middle age persons and male gender. In addition, Ghimire et al.162 not found a gender association with H. pylori infection and this is in accordance with others151,163. However, Chong et al.164 showed the male group had significantly higher prevalence. In addition, irrespective of location and ethnicity, men are twice as likely as women to develop gastric cancer with age-standardized incidence rates with regional variation165,166. The pattern of the M/F incidence of gastric cancer is a global phenomenon, equally seen in populations with high and low risk for gastric cancer. This remains one of the unresolved epidemiological questions as this sexual dimorphism has not been explained by putative risk factors such as smoking, alcohol and obesity167. However, epidemiological evidence points to the protective role of female hormones168 and we are just starting to study this using in vivo models169,170.
The present study indicated that H. pylori infection was more in female (58.3%) than in male. However, other studies suggest that men experience higher rates of infection and its associated mortality than women. Female are with greater inflammatory response than male, which provide advantages for host against infection171. The aetiology and progression of chronic inflammatory responses and diseases e.g., gastric cancer, prostatic cancer) are influenced by menstrual cycle, pregnancy and menopausal status as immunological and epidemiological studies indicated172,173 and suggest the role of sex hormones in their pathogenesis. Gastric cancer risk reduced by hormone therapies in both men and women168. In addition, the rate of gastrointestinal cancer reduced by postmenopausal hormone replacement174-176. Estrogen use in prostatic cancer patients reduced the risk of gastric cancer173 and anti-estrogen therapy (Tamoxifen) is linked to endometrial and gastrointestinal cancers177-181. Estrogen acts through decrease the apoptosis of immune cells, inhibit nitric oxide production, reactive oxygen species formation in the presence of inflammatory stimuli, direct effect on secretion of cytokines by T cells, B cells and macrophages171. Thus estrogen restores the Th2/Th1 ratio which are in favour of Th2 and increasing anti-inflammatory action171. Helicobacter pylori are a human carcinogen, but the mechanisms evoked in carcinogenesis during the chronic inflammatory disease remain incompletely characterized. Sheh et al.182 reported that H. pylori infection induced mutation in the gastric mucosa of male and female mice; however, females had more severe gastric lesions than males at 6 months post-infection. In addition, in all mice, infection significantly increased expression of IFNγ, IL-17, TNFα, iNOS and H. pylori-specific IgG1 levels. H. pylori infection induced host response is Th1 type which causes gastritis182, while BALB/c mouse, which with Th2 strong anti-inflammatory response to H. pylori infection show less severe gastritis183. In Sheh et al. study, the immune response of females to H. pylori infection was biased toward a greater Th1/Th2 ratio compared with males. Higher Th1/Th2 ratios re ect a stronger in ammatory response to H. pylori infection. This findings may explain why gastritis was more in female than in male.
CONCLUSION
In conclusion, this study indicated that high frequency rate of low positive pepsinogen A, high positive rate of gastrin, CD44 and interferon gamma were a predictive biomarkers for chronic gastritis.