Abstract
Background and aims
Neutrophil to lymphocyte ratio (NLR), a novel inflammatory marker, has been shown to increase in various systemic inflammatory conditions. In this way, we want to evaluate the relationship between the presence of H. pylori, duodenal ulcer related H. pylori and NLR in dyspeptic patients.
Material and methods
The patients were divided into three groups after evaluating of the EGD and histopathology results. The groups were determined as follow; Group A: H. pylori positive and DU negative, Group B: H. pylori positive and DU positive, Group C: H. pylori negative and DU negative. Then, groups were compared with each other for demographic features, laboratory tests and NLR.
Results
There were significant differences between groups for NLR when groups compared with each other. Significantly high NLR was seen in group A (H. pylori positive, DU negative) and group B (H. pylori positive, DU positive) when compared with group C (H. pylori negative, DU negative) (respectively p < 0.042, p < 0.001). Significantly higher NLR was determined in the group B when compared with group A and group C (respectively p < 0.021, p < 0.001). The cut-off value for NLR was 2,17 with a specificity of 61% and sensitivity of 66% for group B comparing with Group C (AUC:0,66).
Conclusions
Significantly higher NLR was determined in patients with H. pylori and DU. As a result, NLR may be used as a non-invasive test for documenting the presence of H. pylori and H. pylori related DU.
1. Introduction
Helicobacter pylori (H. pylori) causes various gastric disease from dyspeptic complaints to chronic gastritis, peptic ulcer especially duodenal ulcer (DU), gastric adenocarcinoma and mucosa associated lymphoid tissue (MALT) lymphoma [1,2]. Several extra gastric diseases including coronary atherosclerosis, autoimmune thrombocytopenia, diabetes have been attributed to chronic systemic inflammation related H. pylori infection [[3], [4], [5]].
Recently, NLR has been evaluated as a new inflammatory marker increasing in different conditions such as malignancies, rheumatological and cerebrovascular diseases [[6], [7], [8]]. Neutrophil to lymphocyte ratio has been shown to be superior to C-reactive protein (CRP), leukocyte and lymphocyte count in determining bacteremia in infectious diseases [9]. In another study, NLR has been found more reliable in predicting worse outcomes of acute pancreatitis that is an inflammatory process of pancreas [10].
Invasive and non-invasive tests are used to diagnose H. pylori infection. Invasive tests are required expert personal, upper gastrointestinal endoscopy and gastric biopsy that is an uncomfortable, time consuming, and expansive procedure. Invasive tests are not widely accessible in developing countries which are have high H. pylori prevalence, up to 85%, due to low socioeconomic status [11]. Non-invasive tests consist of urea breath test, H. pylori stool antigen that are also not widely used and accessible in most health centers especially in developing countries. A simpler, cheaper, and more accessible diagnostic test such as NLR may help to manage H. pylori infection in dyspeptic subjects especially in developing regions.
It can conclude from previously performed studies that H. pylori infection causes both local gastric, and systemic inflammation and neutrophil to lymphocyte ratio increases in systemic inflammatory conditions. In this way, we want to evaluate a possible association between the presence of H. pylori, DU related H. pylori and NLR.
2. Material and methods
Patients with dyspeptic complaints such as epigastric pain, regurgitation, heartburn, bloating, nausea, early satiety who admitted to outpatient clinic were included in the study. Patients on proton pump inhibitor treatment within one month, patients who have infectious disease within one month, patients with history of H. pylori eradication, patients with malignancy, hematological, chronic kidney and liver disease and patients on immunosuppressive therapy were excluded from the study. The demographic characteristics of patients were determined. Blood samples were obtained from antecubital vein after 8 h of night meal before upper gastrointestinal endoscopy. Complete blood count was determined by automatic complete blood analysis device (Urit 3300, China). Biopsies were obtained from the stomach (prepyloric, antrum, angulus, or corpus) for the diagnosis of H. pylori during esophagogastroduodenoscopy (EGD) (Fujinon Eve Eg-450). Biopsy samples were transported in 10% formalin solution for histopathologic evaluation. Sydney scoring system was used to detecting the presence of H. pylori infection [12]. The patients were divided into three groups after evaluating of the EGD and histopathology results. The groups were determined as follow; Group A: H. pylori positive and DU negative, Group B: H. pylori positive and DU positive, Group C: H. pylori negative and DU negative. Then, groups were compared with each other for demographic features, laboratory tests and NLR.
Written informed consent form was obtained from all participants. The study was performed after approving by local ethical community of Ankara Education and Research Hospital. The ethical number given for this prospective study is 4625.
3. Statistical analysis
Data analysis was performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, United States). Variables were shown as mean ± standard deviation (SD) or median ± interquartile range (IQR), where applicable. Differences between groups were determined by using One-Way ANOVA and Tukey multiple comparison test. P < 0.05 was accepted to have significant difference between groups.
4. Results
A total of 404 patients consisting 208 (51.5%) female and 196 (48.5%) males were included in the study. There were no statistically significant differences between groups for demographic features and biochemical tests (p > 0.005) (Table 1).
Table 1.
Comparing demographic, laboratory characteristics, and NLR between groups.
| Group A HP(+)DU(−) n, (%) 135, (33.4%) | Group B HP(+)DU(+) n, (%) 136, (33.7%) | Group C HP(−)DU(−) n, (%) 133, (32.9%) | p | |
|---|---|---|---|---|
| Gender | ||||
| Female (n, %) | 68, (50.4%) | 64, (47.1%) | 76, (57.1%) | >0.242 |
| Male(n, %) | 67, (49.6%) | 72, (52.9%) | 57, (42.9%) | |
| Age (year) | 46.49 ± 14.59 | 45.74 ± 14.09 | 48.42 ± 14.01 | >0.282 |
| Leukocyte (μL) | 7218 ± 1875 | 7784 ± 2072 | 6941 ± 1550 | <0.001 |
| Platelet (μL) | 253460 ± 63986 | 259740 ± 59855 | 251550 ± 64023 | >0.529 |
| Hb (gr/dL) | 13.38 ± 1.73 | 13.11 ± 1.86 | 13.39 ± 1.68 | >0.325 |
| Neutrophil (μL) | 4545 ± 1535 | 5033 ± 1668 | 3962 ± 1098 | <0.001 |
| Lymphocyte (μL) | 2108 ± 617 | 2063 ± 651 | 2121 ± 620 | >0.727 |
| NLR | 2.34 ± 1.19 | 2.73 ± 1.47 | 1,99 ± 0.77 | <0.001 |
| AST (IU/L) | 22.25 ± 6.95 | 23.52 ± 7.84 | 22.96 ± 5.54 | >0.312 |
| ALT (IU/L) | 20.71 ± 9.07 | 22.95 ± 11.42 | 20.81 ± 8.78 | >0.108 |
| Creatinine (mg/dL) | 0.87 ± 0.16 | 0.86 ± 0.20 | 0.92 ± 0.47 | >0.210 |
| Glucose (mg/dL) | 102.69 ± 20.99 | 100.56 ± 17.75 | 101.37 ± 19.57 | >0.666 |
| Height (meter) | 1.647 ± 0.083 | 1.659 ± 0.076 | 1.639 ± 0.073 | >0.111 |
| Weight (kilogram) | 68.81 ± 10.31 | 68.40 ± 8.30 | 69.40 ± 9.51 | >0.681 |
| BMI (kg/m2) | 25.39 ± 3.81 | 24.97 ± 3.71 | 25.40 ± 3.73 | >0.145 |
HP: Helicobacter pylori, DU: Duodenal ulcer, Hb: Hemoglobin, NLR: Neutrophil to lymphocyte ratio, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, BMI: Body mass index.
A significant difference was determined between groups for leukocyte and neutrophil count (respectively p < 0.001; p < 0.001) (Table 1). There was no significant difference between groups for lymphocyte count (p > 0.727) (Table 1).
There were significant differences between groups for NLR when groups compared with each other. Significantly high NLR was seen in group A (H. pylori positive, DU negative) and group B (H. pylori positive, DU positive) when compared with group C (H. pylori negative, DU negative) (respectively p < 0.042, p < 0.001) (Table 2). Significantly higher NLR was determined in the group B when compared with group A and group C (respectively p < 0.021, p < 0.001) (Table 2). The cut-off value for NLR was 2,17 with a specificity of 61% and sensitivity of 66% for group B comparing with Group C (AUC:0,66).
Table 2.
The differences between groups when compared with each other for NLR, leukocyte, and neutrophil count.
| NLR |
Leukocyte |
Neutrophils |
||
|---|---|---|---|---|
| p | p | p | ||
| Group A | Group B | <0.021 | <0.032 | <0.017 |
| Group C | <0.042 | >0.437 | <0.003 | |
| Group B | Group A | <0.021 | <0.032 | <0.017 |
| Group C | <0.001 | <0.001 | <0.001 | |
| Group C | Group A | <0.042 | >0.437 | <0.003 |
| Group B | <0.001 | <0.001 | <0.001 |
Group A: H. pylori positive, DU negative; Group B: H. pylori positive, DU positive; Group C: H. pylori negative, DU negative; NLR: Neutrophil to lymphocyte ratio.
5. Discussion
NLR has been evaluated in several medical conditions which the inflammatory responses play a role in their pathogenesis. A poor prognosis in gastric and pancreatic cancer has been shown to be associated with higher NLR [13,14]. The presence of atherosclerosis, severity of coronary atherosclerosis, mortality and poor outcomes of coronary artery disease have been shown to be related with NLR [15,16]. A relationship has been shown between NLR and ischemic complications of type 2 diabetes mellitus such as ischemic cardiovascular diseases that is known a chronic inflammatory vascular microangiopathy [17]. In a different study, NLR has been found to be related with poor prognosis and serious disease in patients with community acquired pneumonia [18]. The underlying pathogenesis of high NLR in infectious diseases has been speculated to be that NLR increases in infectious processes due to resistance of neutrophils to apoptosis and early apoptosis of lymphocytes [19,20].
There are few studies about the relationship between H. pylori, H. pylori related diseases and NLR. In this study, we found significant differences for NLR in patients infected with H. pylori (group A and group B) when compared with patients negative for H. pylori (group C).
This significant difference was more prominent in H. pylori infected patients complicated with DU (group B) when compared with patients without DU (group A and group C).
The exact mechanism resulting in high NLR in subjects with H. pylori infection is still not clear. Although H. pylori causes local gastric inflammation, it also induces systemic inflammation by trigger inflammatory pathways and immune responses [21,22]. Supporting the association between H. pylori and systemic inflammation, higher CRP levels has been shown in H. pylori positive patients [23,24]. Another evidence for this association is that H. pylori eradication has been resulted in lowering CRP concentrations, a reliable indicator elevating during systemic inflammation [25]. Different studies have contributed to elucidate the high NLR in H. pylori infected patients. H. pylori activates macrophage and T cells by producing heat sock proteins (HSP), urease and lipopolysaccharides that have antigenic properties [26]. Activated macrophage and T cells stimulate to produce some inflammatory cytokines including IL-1, IL-6, TNF-alfa, and IL-8 that is a potent chemotactic factor for neutrophil activation [[27], [28], [29]]. Cytotoxin associated gene A (CagA)-positive H. pylori strains have been shown to stimulate higher levels of IL-8 than CagA-negative H. pylori strains, resulting in more complicated gastroduodenal diseases such as atrophic gastritis, DU disease, and gastric cancer [30,31]. In our study NLR was significantly higher in H. pylori positive patients complicated with DU (group B) when compared with group A and group C that are negative for DU. The limitation of this study is that we could not demonstrate CagA on histopathology or serology due to absence of technical equipment. It can speculate that, in our study, patients in group B (H. pylori positive and DU positive) had more CagA-positive H. pylori strains than group A and group C. Thus, it may be resulted in significantly higher NLR in group B compared to other groups (group A and group C). Because of higher IL-8 levels that stimulate more neutrophils to cross peripheral blood system in group B. Endorsing our explanation, a recent study in which CagA-positive H. pylori strains have been demonstrated by tissue PCR of gastric biopsies showed higher CagA-positive strains in patients with complicated gastric diseases, especially DU [32]. A different study involving total of 155 patients has showed higher total leukocyte count, neutrophil count and NLR among H. pylori-infected patients and H. pylori infected-patients with DU compared with H. pylori-negative control patients, like our study. In that study there was no significant differences between CagA-positive and CagA-negative H. pylori strains regarding the leukocyte count and neutrophil count in H. pylori infected patients [33]. In another study, there was no association between inflammatory cytokines such as TNF-α and IL-6, and different H. pylori virulence factors such as CagA genes [34]. These results may be explained by the differences between studies regarding the number of study population, used tests such as serology or histopathology for determining H. pylori infection and CagA status. Further studies involving large population and histology proven diagnostic tests for H. pylori infection and CagA status are needed to determine association between systemic inflammatory responses and CagA genes of H. pylori.
Some studies have showed that the expression of IL-17A increases in H. pylori-infected subjects [35]. Interleukin-17A stimulates granulocyte colony stimulating factor (G-CSF) to increase peripheral blood neutrophil count [36]. This cytokine pathway may also play a role in higher NLR among patients infected with H. pylori. Although the present study showed high neutrophil and leukocyte count in H. pylori positive patients, there were no significant differences between groups for lymphocyte count. H. pylori may cause to increase neutrophil count, not lymphocyte count, by inducing several proinflammatory and inflammatory cytokines such as IL-17, IL-ß, and TNF-α [37]. A different result has been shown in a recent study involving 199 patients, the significant difference has not been found in terms of NLR between H. pylori negative-patients and H. pylori-positive patients. Therefore, lymphocyte count has been shown to be higher in H. pylori-negative subjects compared with H. pylori-positive subjects. This conflict result in that study has been attributed to involving patients with only antral gastritis, patients without more serious gastric disease such as DU [38]. The severity of gastroduodenal diseases (severe gastritis, DU) related to H. pylori that can alternate host immune system via some cytokines including IL-17, TGF-ß should be considered in explaining the association between H. pylori and inflammatory responses, such as elevated neutrophil count, lymphocyte count, and NLR [39].
In conclusion, in the present study, the NLR was significantly high in dyspeptic patients who are positive for H. pylori. Significantly higher NLR was determined in H. pylori-infected patients complicated with DU. As a result, NLR may be used as a non-invasive test for documenting the presence of H. pylori and H. pylori related DU in dyspeptic patients.
Declaration of competing interest
The content of this manuscript has not been published or submitted for publication elsewhere.
All authors have made a significant intellectual contribution to this manuscript.
This original article involved no financial support, and none of the authors had any conflicts of interest.
Acknowledgements
The authors are grateful to authorities of the endoscopy unit of Ankara Education and Research Hospital.
Data availability
No data was used for the research described in the article.
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Data Availability Statement
No data was used for the research described in the article.