Abstract
Helicobacter pylori(H. pylori) which are known as Gram-negative bacteria tend to selectively colonize in the gastric epithelium. The infiltration of neutrophilic and mononuclear cells in the antrum and corpus mucosa is one of the consequences of acute and chronic gastritis colonization with H. pylori. This chronic active gastritis is the primary condition related to H. pylori colonization, and other H. pylori-associated disorders result from this chronic inflammatory process. The present study aimed to assess the relationship between H. pylori infection and extra-gastroduodenal manifestations, such as iron deficiency anemia, chronic spontaneous urticarial, diabetes mellitus, and celiac diseases with low ferritin levels. There were 235 subjects aged 3-75 years in the patient's group. The selected eligible patients were subjected to examination by non-invasive methods using stool antigen test and 14C-urea breath test (14C-UBT). The H. pylori antigen rapid test cassette (feces) was used for the qualitative detection of H. pylori antigens in human feces specimens. In the present study, 183 (71.8%) patients demonstrated positive results for H. pylori which had been detected by stool antigen test, out of whom 106 (57.9%) and 77 (42.1%) cases were female and male, respectively. The recorded data pointed out that the rates of Iron deficiency anemia, diabetes mellitus, and celiac diseases were 92(50.3%), 62 (33.9%), and 25 (13.7%), respectively. The findings of the present study revealed that H. pylori is more prevalent in females. Moreover, the diagnostic potential of the 14C UBT method was higher and more accurate than the stool antigen assay.
Keywords: Celiac, Diabetes, Gastric manifestation, Gastritis
1. Introduction
Helicobacter pylori(H. pylori) which are known as Gram-negative bacteria tend to selectively colonize in the gastric epithelium. These bacteria which are urease, catalase, and oxidase-positive use three to five polar flagella for motility. Moreover, it is well documented that the H. pylori host cell signaling pathways are affected by the H. pylori virulence factors. It is approved that H. pylori have several distinctive features, such as its capability to survive for decades in a highly acidic gastric environment, leading to the inability of the host to remove the infection. The ability of H. pylori to resist the highly acidic gastric environment is explained due to the mechanisms of urea metabolization to ammonia by the activity of the urease enzyme. This chemical and enzymatic reaction produces a neutral environment which can preserve the optimum condition for H. pylori ( 1 ).
The infiltration of neutrophilic and mononuclear cells in the antrum and corpus of stomach mucosa is one of the consequences of acute and chronic gastritis colonization with H. pylori. The preliminary complication of H. pylori colonization is known as chronic active gastritis, a chronic inflammatory process, which is the main cause of other H. pylori-related disorders ( 2 ). It is well documented that several disorders from the outside of the gastrointestinal tract, such as hematologic, metabolic, neurologic cardiopulmonary, and dermatologic disorders, are the consequences of H. pylori infection. These are strong pieces of evidence for the so-called extra-gastroduodenal manifestation of H. pylori infection ( 3 ).
Several mechanisms have been identified that result in iron deficiency anemia (IDA) which is caused by Helicobacter pylori. One of the main reasons for IDA would be the active hemorrhage caused by gastritis, peptic ulcer disease, or gastric cancer which leads to an increment in iron loss ( 4 ). Some previously conducted studies pointed out that H. pylori actively consume iron ( 5 ). The role of H. pylori in the iron acquisition was reviewed in a study performed by Muhsen et al. ( 5 ). It is established that H. pylori express some proteins with a key role in iron transport and storage. Nonetheless, the exact underlying molecular mechanisms by which H. pylori consume iron have remained unclear ( 5 , 6 ).
In some previous case studies, it was suggested that H. pylori infection may occur concomitantly with diabetes mellitus. Moreover, according to the current knowledge, H. pylori leads to gastritis which may consequently affect gut-related hormones ( 7 ). The possible reasons for this could be explained as the following: Firstly, an impairment in the cellular and humoral immunity functions caused by diabetes may increase one’s susceptibility to H. pylori infection. Secondly, diabetes leads to a significant reduction in gastrointestinal tract (GI) movements. Furthermore, the secretion of gastric acid is strongly reduced as a result of diabetes. The reduction of GI movements and gastric acid production brings about a significant increase in the rate of H. pylori colonization and infection ( 8 ). Thirdly, the consequent changes in glucose metabolism caused by diabetes have a strong influence on the alteration of the gastric mucosa chemical productions. All these alterations lead to the colonization of more bacteria ( 9 - 11 ).
In light of the aforementioned issues, the current study aimed to evaluate the relationship between H. pylori infection and extra-gastroduodenal manifestations, such as iron deficiency anemia, chronic spontaneous urticarial, diabetes mellitus, and celiac diseases with low ferritin levels.
2. Materials and Methods
2.1. Patients
This clinical trial study was conducted on 235 patients referring to the gastroenterology clinic of Azadi Teaching Hospital and private Kirkuk clinic in Kirkuk city for upper and lower GI endoscopy and fiberoptic bronchoscopy. Data were collected from November 2019 to February 2021 with clinical symptoms of pain or discomfort in the upper abdomen, nausea, vomiting, loss of appetite, weight loss, black or tarry stool, or red or maroon blood mixed stool. The inclusion criterion was the age range of 3-75 years.
2.2. Samples
The patient's stool was collected in clean, dry, and waterproof containers. The stool assay was performed using H. pylori Antigen rapid test cassette.
2.3. Helicobacter pyloriRapid Test (Stool Antigen test)
The H. pylori antigen rapid test cassette (feces) was used for the qualitative detection of H. pylori antigens in human feces specimens (Linear, Spain catalog No. 5094503).
2.3.1. Principle
The H. pylori Antigen rapid test is a qualitative lateral flow immunoassay for the detection of H. pylori antigen in human feces specimens. In this test, the membrane is pre-coated with anti-H. pylori antibodies on the test line. During testing, the specimen reacts with the particle coated with H. pylori antibodies. The mixture migrates upward on the membrane by capillary action to react with anti-H pylori antibodies on the membrane and generate a red line. The presence of this red line in the test region indicates a positive result, while its absence is suggestive of a positive result. To serve as a procedural control, a red line will always appear in the control line region, indicating that a proper volume of specimen has been added and membrane wicking has occurred.
2.3.2. Procedure
1- A sufficient quantity of feces (1-2 ml or 1-2 g) was collected in a clean dry specimen collection container to obtain maximum antigens (if present).
2- Fecal specimen was processed as the following:
-For solid specimens
The cap of the specimen collection tube was unscrewed; thereafter, the specimen collection applicator was randomly stabbed into the fecal specimen in at least three different sites.
-For liquid specimens
The dropper or pipette was held vertically. Fecal specimens were aspirated and then transferred into the specimen collection tube containing the extraction buffer.
3- The pouch was brought to room temperature before opening and prepared to use immediately after the opening of the foil pouch.
4- The specimen collection tube was held upright and the cap was opened onto the specimen collection tube. The specimen collection tube was inverted and transferred two full drops of the extracted specimen to the specimen well of the test cassette, then started the timer.
5- The results were read 10 min after dispensing the specimen.
2.4. Urea Breath Test
Heliprobe system is intended for the diagnosis of H. pylori infection in the gastrointestinal tract (stomach, duodenum) using the non-invasive 14C Urea breath test from Kibion AB company, Sweden, catalog No. HPC-001.
2.4.1. Principle
Helicobacter pyloriproduce urease, an enzyme that catalyzes the hydrolysis of 14C-urea to 14CO2 and NH3. The 14CO2 was excreted in exhaled air, while NH3 and excess 14C-urea were excreted in the urine. Under healthy conditions (absence of Helicobacter pylori), 14C-urea was not hydrolyzed and no 14CO2 will be present in exhaled air. Therefore, 14CO2 was only present in exhaled air during H. pylori infection.
2.4.2. Procedure
The patient swallows a HeliCap capsule containing 14C urea (1μCi) and waits 10 min before exhaling into Heliprobe Breath Card, where the reactivity filters adsorb the CO2. The indicator changes color from orange to yellow to indicate when the reactivity filters were saturated and sampling completed.
2.5. Analysis
The analysis principle was based on measuring ß-radiation from 14CO2 sampled in Heliprobe BreathCard. Radiation was measured, and the result was presented as Heliprobe 0=not infected Heliprobe 1=borderline and Heliprobe 2=infected (Table 1).
Table 1.
Cut-off value
| Cut-off value | ||
|---|---|---|
| Heliprob 0 | Not infected | d ≤ 25 counts |
| Heliprob 1 | Borderline | 25 counts < d < 50 counts |
| Heliprob 2 | Infected | d ≥ 50 counts |
3. Results
3.1. Distribution of Helicobacter pyloriInfection According to Age and Gender of Patients
Out of 255 patients, 183 cases demonstrated a positive result for H. pylori which was detected by stool antigen test (as a gold standard) as illustrated in figures 1 and 2. The patients were assigned to six groups according to gender and age. The age ranged from 3-75 years with a peak age group of 26-35 years old. The statistical differences between age group and gender were not significant (P= 0.927) as depicted in table 2 and figure 3.
Figure 1.
Flow chart of the study with summarized results
Figure 2.
H. pylori status of the study patients by using the Stool antigen test as the gold standard
Table 2.
Classification by age and gender of patients with H. pylori infection
| Gender | Frequency of age | |||||
|---|---|---|---|---|---|---|
| 4-15 | 16-25 | 26-35 | 36-45 | 46-55 | 56-75 | |
| Male 77 (42.1%) | 3 (1.6%) | 12 (6.6%) | 23 (12.6%) | 23 (12.6%) | 9 (4.9%) | 7 (3.8%) |
| Female 106 (57.9%) | 7 (3.8%) | 25 (13.7%) | 33 (18%) | 20 (10.9%) | 11 (6%) | 10 (5.5%) |
| Total 183 (100%) | 10 (5.5%) | 37 (20.2%) | 56 (30.6%) | 43 (23.5%) | 20 (10.9%) | 17 (9.3%) |
Chi-Square = 4.407 P-Value = 0.927
Figure 3.
Prevalence of H. pylori according to gender
3.2. Gastric Manifestation for H. pylori and Relationship with Extra-Gastroduodenal Manifestation
Data were collected through interviews using a questionnaire that looked at H. pylori infection with the clinical indication for endoscopic examination. Moreover, invasive and noninvasive methods were used to detect the H. pylori infection. It was observed that the highest incidence was chronic gastritis 66 (36.1%). In addition, it was indicated that extra-gastroduodenal manifestation was associated with Helicobacter pyloriinfection. There was no significant difference between gastric manifestation and extra-gastroduodenal manifestation (P=0.990) (Table 3).
Table 3.
Association between H. pylori infection and the extra-gastroduodenal manifestation
| Clinical manifestation | Frequency % | Extra-gastroduodenal manifestation | ||||
|---|---|---|---|---|---|---|
| IDA | DM | SI | CD | CVD | ||
| Acute gastritis | 42 (22.9%) | 27 | 15 | 18 | 6 | 11 |
| Chronic gastritis | 66 (36.1%) | 33 | 18 | 20 | 9 | 14 |
| Gastric ulcer | 35 (19.1%) | 17 | 13 | 16 | 5 | 8 |
| Duodenal ulcer | 27 (14.8%) | 11 | 11 | 9 | 5 | 6 |
| Gastric cancer | 13 (7.1%) | 4 | 5 | 5 | - | 3 |
| Total Positive (%) | 183 (100%) | 92 (50.3%) | 62 (33.9%) | 68 (37.2%) | 25 (13.7%) | 42 (22.9%) |
Chi-Square = 3.608 P-Value = 0.990
IDA= Iron deficiency anemia, DM= Diabetes mellitus, SI= Skin infection, CD= Celiac disease, CVD= Cardiovascular diseases
3.3. Extra-Gastroduodenal Manifestation
With positive H. pylori, stool antigen test (HpSA) was 183 (77.9%). Several accompanying extra-gastroduodenal manifestations were observed and the highest percentage pertained to iron deficiency anemia (50.3%) as presented in figure 4.
Figure 4.
Percentage of extra-gastroduodenal manifestation, using HpSA as the gold standard
IDA= Iron deficiency anemia, DM= Diabetes mellitus, SI= Skin infection, CD= Celiac disease, IHD= Ischemic heart disease
3.4. Noninvasive Urea Breath Test and Comparison with A Stool Antigen Test
The urea breath test indicated that 144 (78.7%) cases tested positive for H. pylori infection using the stool antigen test. The male showed higher percentage 69 (89.6%) of urea breath test compared with female 75 (70.8%). The relation between gender and UBT was highly significant (P=0.002), as displayed in table 4.
Table 4.
Distribution of infection among patients according to gender by using Urea breath test in positive cases by using HpSA as the gold standard
| gender | Urea breath test | ||
|---|---|---|---|
| Positive (%) | Negative (%) | Total (%) | |
| Male | 69 (89.6%) | 8 (10.4%) | 77 (100%) |
| Female | 75 (70.8%) | 31 (29.2%) | 106 (100%) |
| Total | 144 (78.7%) | 39 (21.3%) | 183 (100%) |
Chi-Square = 9.456 P-Value = 0.002
HpSA= H. pylori stool antigen test
UBT= Urea breath test
4. Discussion
4.1. Distribution of Helicobacter pyloriInfection according to Patients’ Age and Gender
The accurate diagnosis and management are vital for facing the H. pylori challenge due to its strong association with gastroduodenal diseases and high rate of infectivity, especially in developing countries. Although many diagnostic tests had developed for the detection of H. pylori, all have advantages and disadvantages. Helicobacter pyloristool antigen test (SAT) is used as a gold standard test for the detection of H. pylori infection. As reported by many international studies, it is an accurate and reliable test. The high rates of infections caused by H. pylori have been detected in high population densities, low socioeconomic communities, and the prevalence of the bacteria is different between countries ( 12 ). The results of the present study indicated that the frequency of identification of H. pylori was 71.8% by using SAT as the gold standard. The results were in agreement with those reported by Huwiage, Nami ( 13 ) and Thapa, Thapa ( 14 ); nonetheless, they were inconsistent with the findings of the studies by Mawlood, Kawther ( 15 ) and Bordin, Voynovan ( 16 ).
The present study pointed out that the peak incidence of H. pylori infection (30.6%) occurred among the age group 26-35 for both genders. Concerning gender, the current study illustrated the highest incidence in females (57.9%). The differences in age and gender distribution were not statistically significant. The same findings were reported by Huwiage, Nami ( 13 ) and Alhashimi ( 17 ). In their studies, Mawlood, Kawther ( 15 ) and Majeed and Khoshnaw ( 18 ) reported that the rate of infection was higher among females; moreover, the people over 45 were more infected with this bacterium. Nevertheless, some reports indicated that gender and age were significantly associated with H. pylori infection ( 19 ). The reason for the gender difference was not known and needs further study ( 20 ); however, the present study did not demonstrate such variability.
4.2. Gastric Manifestations and Extra-Gastroduodenal Manifestation
Helicobacter pyloriinfection results from a complex interplay between bacterial, environmental, and host genetic factors. The spectrum of gastro-duodenal affection mostly passes through asymptomatic infection. Furthermore, the infection evolves into acute and chronic gastritis, and peptic ulcers; moreover, a minority of patients is prone to the most serious sequel gastric cancer. H. pylori are classified as a class I carcinogen by the World Health Organization (WHO); therefore, the identification and eradication of the infection are recommended for subgroups of patients as per the current practice guidelines ( 21 ). Helicobacter pyloriinfection has remained the most common cause of chronic gastritis ( 20 ). In agreement with the studies by Makaju, Dhakal ( 22 ), as well as Hagag, Amin ( 23 ), the current study illustrated that 36.1% of patients with chronic gastritis infected with Helicobacter pylori. This result was higher than those of other studies by Bahadir, Sag ( 24 ) and Alsultan (22.5%) Alsultan ( 25 ). This discrepancy can be ascribed to the different numbers of patients in these studies.
The list of extra-gastric associations is long and diverse. H. pylori have been linked to many metabolic, cardiac, neurological, allergic, ocular, hematological, dermatological, and hepatobiliary diseases. It seems that these associations have been overestimated since the evidence linking H. pylori infection to these diseases depends on epidemiological studies ( 26 ).
Iron deficiency anemia is highly prevalent in underdeveloped countries, and a few studies have claimed that H. pylori eradication can be used to cure the IDA for which no cause has been identified ( 27 ). One of the major causes of IDA during H. pylori infection is blood loss due to ulcer bleeding in infected patients. However, H. pylori-associated IDA may also occur in patients with intact mucosa, thereby leading to further investigations to better define the pathophysiological mechanisms underlying such association. One of the pathways through which H. pylori infection may lead to iron deficiency is affecting iron absorption by enterocytes and its release from macrophages via hepcidin level upregulation and concomitant therapy with non-steroidal anti-inflammatory drugs, including aspirin ( 28 ). In this study, IDA was noted in 92 (50.3%) patients with H. pylori infection, as compared to results of the studies by Rahat and Kamani ( 29 ) (37.5%) and Alboraie, Elhossary ( 21 ). It was also suggested that H. pylori gastritis can be a common etiological reason for IDA among patients with iron deficiency. A previously conducted study stated that a large proportion of patients with atrophic body gastritis also encounter IDA, out of whom 61% cases were diagnosed with H. pylori infection ( 30 ). This variation may be attributed to the different prevalence of H. pylori in developed and developing countries.
A positive association was detected between H. pylori infection and diabetes mellitus in the present study with 33.9%, pointing to a non-significant difference. This result is in agreement with those reported by Chen et al. who demonstrated no significant differences in patients with H. pylori infection and diabetes mellitus. Among the hypothesis on how H. pylori infection increases the risk of chronic gastritis, it is believed that increased cytokine production leads to the phosphorylation of serine residues from the insulin receptor substrate, whose linkage with insulin receptors turns deficient ( 31 ). In contrast, Tawfeeq, Amin ( 32 ) demonstrated that the prevalence of H. pylori infection is higher in patients with high HbA1c levels, while the rate of H. pylori infection is lower in patients with low levels of HbA1c. A meta-analysis of case-control studies found a significant association between H. pylori and diabetes mellitus, and the authors acknowledged a significant heterogenicity ( 33 ). Moreover, according to Al-Awadhi, Bahaj ( 34 ), the prevalence of H. pylori was 49% in diabetic patients. Therefore, the association between H. pylori infection and diabetes mellitus remains inconclusive.
In the current study, 33.9% of patients with dermatological diseases were infected with H. pylori, and no significant differences were detected between H. pylori infection and dermatological diseases. The aforementioned findings are in accordance with those reported by Majeed and Khoshnaw ( 18 ), Alfahaad ( 35 ), and Dennis, Mavura ( 36 ) who explained that Chronic Urticaria (CU) occurs mostly in adults.
The current study demonstrated that the prevalence of H. pylori in celiac disease was 13.7%. Agin, Batun ( 37 ), ( 38 ) determined the prevalence rates of H. pylori to be 30.7% and 27.5%, respectively. In their meta-analysis of 26 studies, Amlashi, Norouzi ( 39 ) revealed a significant and negative association between H. pylori colonization and cardiovascular diseases (CVDs). The present study demonstrated that 22.9% of patients who tested positive for H. pylori infection had CDVs. These findings disagreed with Aldhalmi, Aldabbagh ( 40 ) who reported Aldhalmi, Aldabbagh ( 40 ) that H. pylori positivity was 67% in patients with CVDs, pointing to a significant association between the prevalence of H. pylori and CVDs. Epidemiological research indicated that H. pylori infection may be a new risk factor for CVDs, and a higher prevalence of hypertension in patients with H. pylori infection may be ascribed to the factors specific to H. pylori that also play a role in CVDs ( 41 ). These discrepancies in the ratio can be attributed to differences in the number of patients.
4.3. Urea Breath Test
The present study used a 14C urea breath test and H. pylori stool antigen. This study aimed to assess the most accurate method for the diagnosis of H. pylori, compared to the gold standard SAT. In addition, these methods were used to evaluate the success of H. pylori eradication after the use of an appropriate regime by gastroenterologists. These results pointed out that the 14C urea breath test outperformed the H. pylori stool antigen for diagnosis. The 14C urea breath test was more sensitive and accurate than H. pylori stool antigen testing. The accuracy of the 14C urea breath test was 78.7% and it was highly associated with gender, being more positive with the male gender (89.6%). However, the detected prevalence rate in this study was much higher than that reported by Altamimi, Alsharkhat ( 42 ) from Jordan using the UBT method (14.6%). This discrepancy may be due to the differences in the studied population or the age of participants.
Regarding gender differences, a study for adult patients in occupied Palestine by Eisdorfer, Shalev ( 43 ) proved quantitative differences between men and women. They also found that environmental or host-related factors might affect the quantitative value of UBT. This study reported that the 14C urea breath test outperformed SAT for the diagnosis of H. pylori. In agreement with the current research, Eisdorfer, Shalev ( 43 ) compared H. pylori diagnosis methods and concluded that the sensitivity, positive predictive, negative predictive values, and accuracy of UBT were higher than those of SAT.
Authors' Contribution
Study concept and design: K. O. M. A.
Acquisition of data: K. O. M. A.
Analysis and interpretation of data: S. S. A. H.
Drafting of the manuscript: S. S. A. H.
Critical revision of the manuscript for important intellectual content: Y. I. S.
Statistical analysis: S. S. A. H.
Administrative, technical, and material support: Y. I. S.
Ethics
Ethical approval for the study was obtained from the Northern Technical University, Kirkuk Technical Institute, Kirkuk, Iraq Ethics and Law Committee and the Local Research Ethics Committees.
Conflict of Interest
The authors declare that they have no conflict of interest.
References
- 1.Weeks DL, Eskandari S, Scott DR, Sachs G. A H+-gated urea channel: the link between Helicobacter pylori urease and gastric colonization. Science. 2000;287(5452):482–5. doi: 10.1126/science.287.5452.482. [DOI] [PubMed] [Google Scholar]
- 2.Bibi F, Alvi SA, Sawan SA, Yasir M, Sawan A, Jiman-Fatani AA, et al. Detection and genotyping of Helicobacter pylori among gastric ulcer and cancer patients from Saudi Arabia. PaK J Med Sci. 2017;33(2):320. doi: 10.12669/pjms.332.12024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hooi JK, Lai WY, Ng WK, Suen MM, Underwood FE, Tanyingoh D, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology. 2017;153(2):420–9. doi: 10.1053/j.gastro.2017.04.022. [DOI] [PubMed] [Google Scholar]
- 4.Papagiannakis P, Michalopoulos C, Papalexi F, Dalampoura D, Diamantidis MD. The role of Helicobacter pylori infection in hematological disorders. Eur J Intern Med. 2013;24(8):685–90. doi: 10.1016/j.ejim.2013.02.011. [DOI] [PubMed] [Google Scholar]
- 5.Muhsen K, Cohen D. Helicobacter pylori infection and iron stores: a systematic review and meta‐analysis. Helicobacter. 2008;13(5):323–40. doi: 10.1111/j.1523-5378.2008.00617.x. [DOI] [PubMed] [Google Scholar]
- 6.Boyanova L. Role of Helicobacter pylori virulence factors for iron acquisition from gastric epithelial cells of the host and impact on bacterial colonization. Future Microbiol. 2011;6(8):843–6. doi: 10.2217/fmb.11.75. [DOI] [PubMed] [Google Scholar]
- 7.Newman JD, Schwartzbard AZ, Weintraub HS, Goldberg IJ, Berger JS. Primary prevention of cardiovascular disease in diabetes mellitus. J Am Coll Cardiol. 2017;70(7):883–93. doi: 10.1016/j.jacc.2017.07.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Jeon CY, Haan MN, Cheng C, Clayton ER, Mayeda ER, Miller JW, et al. Helicobacter pylori infection is associated with an increased rate of diabetes. Diabetes Care. 2012;35(3):520–5. doi: 10.2337/dc11-1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Qi L, Hu FB, Hu G. Genes, environment, and interactions in prevention of type 2 diabetes: a focus on physical activity and lifestyle changes. Curr Mol Med. 2008;8(6):519–32. doi: 10.2174/156652408785747915. [DOI] [PubMed] [Google Scholar]
- 10.Bener A, Micallef R, Afifi M, Derbala M, Al-Mulla HM, Usmani MA. Association between type 2 diabetes mellitus and Helicobacter pylori infection. Turk J Gastroenterol. 2007;18(4):225–9. [PubMed] [Google Scholar]
- 11.Alshareef SA, Rayis DA, Adam I, Gasim GI. Helicobacter pylori infection, gestational diabetes mellitus and insulin resistance among pregnant Sudanese women. BMC Res Notes. 2018;11(1):1–5. doi: 10.1186/s13104-018-3642-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zamani M, Ebrahimtabar F, Zamani V, Miller W, Alizadeh‐Navaei R, Shokri‐Shirvani J, et al. Systematic review with meta‐analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment Pharmacol Ther. 2018;47(7):868–76. doi: 10.1111/apt.14561. [DOI] [PubMed] [Google Scholar]
- 13.Huwiage G, Nami A, Akadh A. stool antigen (hpsa) test in detection of helicobacter pylori infection among adult dyspeptic patients in tripoli, Libya. Int J Med Med Res. 2019;5(2):5–14. [Google Scholar]
- 14.Thapa S, Thapa J, Karki B, Khadka D, Thapa AB. Noninvasive diagnosis of Helicobacter pylori among patients with dyspepsia. Nepal J Med Sci. 2020;5(1):28–34. [Google Scholar]
- 15.Mawlood AH, Kawther RS, Balaky STJ. Evaluation of invasive and non-invasive methods for the diagnosis of H. pylori in dyspepsia patients. Diyala J Med. 2019;16(2):55–63. [Google Scholar]
- 16.Bordin DS, Voynovan IN, Andreev DN, Maev IV. Current Helicobacter pylori Diagnostics. Diagnostics. 2021;11(8):1458. doi: 10.3390/diagnostics11081458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Alhashimi R. Heli-cobacter Pylori Infection, Epidemiology, Endoscopic Findings and Associated So-cio-Demographic Factors in Uninvestigat-ed Dyspepsia in the People of Misan, Iraq. J Gastrointest Disord Liver Func. 2017;3(2):109–13. [Google Scholar]
- 18.Majeed PD, Khoshnaw KJS. Seroprevalence of Helicobacter pylori infection among patients with gastroduodenal disorders in Erbil city. Diyala J Med. 2020;18(1):91–101. [Google Scholar]
- 19.Rajan A, Ganguli P, Pathak N, Ranjan A, Thapa R, Tripathi S. Correlation of serology with morphological changes in gastric biopsy of H. pylori infection. Int J Res Med Sci. 2017;5(5):1851–7. [Google Scholar]
- 20.KC SR, Lakhey A, Koirala K, Amatya G. Prevalence of Helicobacter pylori among patients with dyspepsia and correlation between endoscopic and histological diagnosis. J Pathol Nepal. 2016;6(11):942–6. [Google Scholar]
- 21.Alboraie M, Elhossary W, Aly OA, Abbas B, Abdelsalam L, Ghaith D, et al. Egyptian recommendations for management of Helicobacter pylori infection: 2018 report. Arab J Gastroenterol. 2019;20(3):175–9. doi: 10.1016/j.ajg.2019.09.001. [DOI] [PubMed] [Google Scholar]
- 22.Makaju R, Dhakal B, Dhakal R. Prevalence and Clinical Manifestations of Helicobacter Pylori with Reference to Histopathological Diagnosis. Kathmandu Univ Med J. 2020;18(1):64–7. [PubMed] [Google Scholar]
- 23.Hagag AA, Amin SM, Emara MH, Abo-Resha SE. Gastric mucosal oxidative stress markers in children with Helicobacter pylori infection. Infect Disord Drug Target. 2018;18(1):60–7. doi: 10.2174/1871526517666170502154350. [DOI] [PubMed] [Google Scholar]
- 24.Bahadir A, Sag E, Çakır M, Erduran E. Low isolated ferritin levels without anemia: is gastrointestinal tract endoscopy sufficient to explain the cause? Ir J Med Sci. 2021:1–6. doi: 10.1007/s11845-021-02589-0. [DOI] [PubMed] [Google Scholar]
- 25.Alsultan N. Determination the relationship between Iron Deficiency and some physiological and immunological parameters in individual infection with Helicobacter pylori in Kirkuk city: Tikrit University, College of Education for Pure Sciences. 2018 [Google Scholar]
- 26.Gravina AG, Priadko K, Ciamarra P, Granata L, Facchiano A, Miranda A, et al. Extra-gastric manifestations of Helicobacter pylori infection. J Clin Med. 2020;9(12):3887. doi: 10.3390/jcm9123887. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Gravina AG, Zagari RM, De Musis C, Romano L, Loguercio C, Romano M. Helicobacter pylori and extragastric diseases: a review. World J Gastroenterol. 2018;24(29):3204. doi: 10.3748/wjg.v24.i29.3204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Mendoza E, Duque X, Hernández Franco JI, Reyes Maldonado E, Morán S, Martínez G, et al. Association between Active H. pylori Infection and Iron Deficiency Assessed by Serum Hepcidin Levels in School-Age Children. Nutrients. 2019;11(9):2141. doi: 10.3390/nu11092141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Rahat A, Kamani L. Frequency of iron deficiency anemia (IDA) among patients with Helicobacter pylori infection. PaK J Med Sci. 2021;37(3):776. doi: 10.12669/pjms.37.3.3944. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Mwafy SN, Afana WM. Hematological parameters, serum iron and vitamin B12 levels in hospitalized Palestinian adult patients infected with Helicobacter pylori: a case–control study. Hematol Transfus Cell Ther. 2018;40:160–5. doi: 10.1016/j.htct.2017.11.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Chen J, Xing Y, Zhao L, Ma H. The association between Helicobacter pylori infection and glycated hemoglobin A in diabetes: a meta-analysis. J Diabetes Res. 2019;2019 doi: 10.1155/2019/3705264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Tawfeeq RD, Amin ZA, Nuraddin SM, Jalal A, Baiz SKH. Relationship between type II diabetes mellitus and Helicobacter pylori infection in Erbil city. Zanco J Med Sci. 2019;23(1):43–50. [Google Scholar]
- 33.Mansori K, Moradi Y, Naderpour S, Rashti R, Moghaddam AB, Saed L, et al. Helicobacter pylori infection as a risk factor for diabetes: a meta-analysis of case-control studies. BMC Gastroenterol. 2020;20(1):1–14. doi: 10.1186/s12876-020-01223-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Al-Awadhi E, Bahaj S, Al-Oferi B. Helicobacter pylori infection among patients with type II diabetes mellitus. J Diab Metab Disorder Control. 2020;7(2):53–6. [Google Scholar]
- 35.Alfahaad HA. Chronic urticaria and dyspepsia: Association and treatment, an experimental study. J Pak Assoc Dermatol. 2019;28(4):443–8. [Google Scholar]
- 36.Dennis MF, Mavura DR, Kini L, Philemon R, Masenga EJ. Association between Chronic Urticaria and Helicobacter pylori Infection among Patients Attending a Tertiary Hospital in Tanzania. Dermatol Res Pract. 2020;2020 doi: 10.1155/2020/5932038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Agin M, Batun I, Ozdemir S, Doran F, Tumgor G. Prevalence of Helicobacter pylori in Turkish children with celiac disease and its effect on clinical, histopathological, and laboratory parameters. Arch Med Sci. 2019;15(6):1475. doi: 10.5114/aoms.2019.83699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Bahadori A, De Witte C, Agin M, De Bruyckere S, Smet A, Tümgör G, et al. Presence of gastric Helicobacter species in children suffering from gastric disorders in Southern Turkey. Helicobacter. 2018;23(5):12511. doi: 10.1111/hel.12511. [DOI] [PubMed] [Google Scholar]
- 39.Amlashi FI, Norouzi Z, Sohrabi A, Shirzad-Aski H, Norouzi A, Ashkbari A, et al. A systematic review and meta-analysis for association of Helicobacter pylori colonization and celiac disease. PloS One. 2021;16(3):e0241156. doi: 10.1371/journal.pone.0241156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Aldhalmi AK, Aldabbagh L, Hamad AJ, Almuhana SJ, Hassoun HK, Alareedh MD, et al. Helicobacter Pylori and Recent Ischemic Stroke: Is there a Relationship? . Int J Pharm Res. 2020;12(4) [Google Scholar]
- 41.Wang B, Yu M, Zhang R, Chen S, Xi Y, Duan G. A meta‐analysis of the association between Helicobacter pylori infection and risk of atherosclerotic cardiovascular disease. Helicobacter. 2020;25(6):12761. doi: 10.1111/hel.12761. [DOI] [PubMed] [Google Scholar]
- 42.Altamimi E, Alsharkhat N, AlJawarneh A, Abu Hamad MdR, Assi AA, Alawneh S, et al. Declining prevalence of Helicobacter pylori infection in Jordanian children, report from developing country. Heliyon. 2020;6(7):04416. doi: 10.1016/j.heliyon.2020.e04416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Eisdorfer I, Shalev V, Goren S, Chodick G, Muhsen K. Sex differences in urea breath test results for the diagnosis of Helicobacter pylori infection: a large cross-sectional study. Biol Sex Differ. 2018;9(1):1. doi: 10.1186/s13293-017-0161-7. [DOI] [PMC free article] [PubMed] [Google Scholar]