|Year : 2018 | Volume
| Issue : 1 | Page : 41-46
Prevalence and risk factors for helicobacter pylori infection in gastroduodenal diseases in Kano, Nigeria
Ahmad Kumo Bello1, Ali Bala Umar2, Musa Muhammad Borodo3
1 Department of Medicine, Ahmadu Bello University, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria
2 Department of Pathology, Bayero University Kano, Aminu Kano Teaching Hospital, Kano, Nigeria
3 Department of Medicine, Bayero University Kano, Aminu Kano Teaching Hospital, Kano, Nigeria
|Date of Web Publication||2-Jul-2018|
Ahmad Kumo Bello
Department of Medicine, Ahmadu Bello University Teaching Hospital, P. M. B. 06, Shika - Zaria, Kaduna State
Source of Support: None, Conflict of Interest: None
Background: Helicobacter pylori (H. pylori) has been well noted as a causative agent of many diseases in the gastrointestinal (GI) tract notably, gastritis, peptic ulcer disease, and gastric adenocarcinoma. Determining the burden and the risk factors for acquiring this infection may be crucial to containing it and its sequelae in Kano, Nigeria. Methodology: The study was cross-sectional in design. Questionnaires were administered in dyspeptic patients to obtain the relevant clinical, and sociodemographic data. Upper GI endoscopy was performed in the patients, and gastric biopsy specimens were taken and sent to the histopathology laboratory for assessment and H. pylori identification. Results: Of the 306 participants, 136 (44.4%) were males, while 170 (55.6%) were females, with male: female ratio of 1:1.3. The ages of the participants ranged from 18 to 84 years with a mean of 41.2 ± 15.3 years. Of the 306 samples, 250 (81.7%) were positive for H. pylori. This gives H. pylori prevalence of 81.7%. Only 4 (1.3%) of the participants belonged to the higher social class, out of which 25% had positive H. pylori, while 230 (75.2%) participants belonged to the lower socioeconomic class with 87.8% H. pylori prevalence. The lower social class had a significant association (P < 0.0001) with increased H. pylori infection. A total of 290 subjects (94.8%) shared a room with three or more other siblings in childhood, out of which 233 (80.3%) had H. pylori. Only 80 subjects (26.1%) used pipe-borne water in childhood, while 226 (73.9%) sourced their water from either well, pond or stream during childhood. Conclusion: This study showed a high prevalence of H. pylori in Kano, and low socioeconomic status, unclean water source, overcrowding, and cigarette smoking were significant risk factors for H. pylori infection.
Keywords: Histology, prevalence of Helicobacter pylori in Kano, risk factors, water source
|How to cite this article:|
Bello AK, Umar AB, Borodo MM. Prevalence and risk factors for helicobacter pylori infection in gastroduodenal diseases in Kano, Nigeria. Afr J Med Health Sci 2018;17:41-6
|How to cite this URL:|
Bello AK, Umar AB, Borodo MM. Prevalence and risk factors for helicobacter pylori infection in gastroduodenal diseases in Kano, Nigeria. Afr J Med Health Sci [serial online] 2018 [cited 2019 Aug 23];17:41-6. Available from: http://www.ajmhs.org/text.asp?2018/17/1/41/235736
| Introduction|| |
Helicobacter is motile, Gram-negative, microaerophilic bacteria which is endemic in Africa and Asia; the two continents contributing two-thirds of the world's disease burden. Barry Marshall and Robin Warren who isolated and identified Helicobacter pylori (H. pylori) from the human stomach also drew attention to the association of H. pylori with gastritis; and much evidence showed that H. pylori causes peptic ulcers, and is also involved in the development of gastric mucosa-associated lymphoid tissue lymphoma., Infection with this bacterium has been established as the etiologic factor in the development of gastric cancer, thus, H. pylori was designated a Class 1 carcinogen by the WHO.,
In developing countries, 70%–90% of the population harbor H. pylori which is mostly acquired during childhood, while in the developed countries, the prevalence is lower ranging from 30% to 40%. Studies from Nigeria by Bashir and Ali  in Kano reported an H. pylori prevalence of 81%, Malu et al. in Jos, found a prevalence of 87%, while Aboderin et al. reported 73% in South-West. Studies from many African countries reported similar prevalence rates of 91.7% in Egypt, 97% in Gambia, and 75.4% in Ghana. Similarly, in Asia, prevalence rates of 92% have been reported in Bangladesh  and 62% prevalence was found in Chinese.
Studies have shown that low socioeconomy was a major risk factor in H. pylori acquisition. Allaker et al. noted that transmission of H. pylori is largely by the oral–oral or fecal–oral routes. This may have been encouraged by poor environmental sanitation, crowding, and fecal contamination of water source used for irrigation of vegetables in farms or domestic use. Jemikajah and Okogunand Etukudo et al. in separate studies showed that sourcing water from well and borehole confers a higher risk of H. pylori infection than pipe-borne water., Studies also by Bateson in Glasgow and Ogihara et al. in Jiangsu , showed that there is increased prevalence of H. pylori in subjects who smoked cigarettes than in those who never smoked. Understanding the risk factors for acquiring H. pylori infection in Kano, Nigeria is therefore critical if we are to reduce the prevalence and thus the burden of the diseases caused by this infection.
The aim of our study, therefore, was to determine the prevalence and risk factors for H. pylori infection in gastroduodenal diseases in Kano, North-West, Nigeria.
| Methodology|| |
The study was carried out from August 2011 to April 2013 in Aminu Kano Teaching Hospital (AKTH), a tertiary hospital in Kano, the most populous state in Nigeria. AKTH is the only public hospital in the North-West with a functioning endoscopy and endoscopic retrograde cholangiopancreatography facility and thus receives referrals from many hospitals. The study was cross-sectional in design, and the ethical approval for the study was obtained from the research ethics Committee of AKTH before the commencement of the study. Dyspeptic patients referred for upper gastrointestinal endoscopy constituted the study population. Dyspeptic patients 18 years and above who consented to participate in the study were randomly recruited to meet the required sample size. Excluded from participating were patients on antibiotics, proton pump inhibitors, or bismuth salts in the preceding 4 weeks, and those with medical conditions such as congestive cardiac failure and cardiac arrhythmias. Written informed consent was sought and obtained from each patient before commencing the procedure.
With the aid of interviewer-administered questionnaire, relevant clinical, and sociodemographic data was obtained from the recruited patients. Social class of the participants was determined using the National statistics socioeconomic classification. which assigns people to social class based on standard occupation classification. The three-class version of the classification was adopted here for convenience as follows: Higher social class (Class 1): Higher managerial administrative and professional occupations (company Chief Executive Officer, Directors; Doctors, Lawyers Senior Army and Police officers, etc.,); middle social class (Class 2): Intermediate occupations (Musicians, Nurses, Journalists, actors, etc.,); and lower social class (Class 3): Routine and manual occupations (Artisans, Publicans, Farmers, laborers, etc.). Patients were then booked for oesophagogastroduodenoscopy and asked to fast overnight, at least 8–10 h before the endoscopy. The process of the endoscopy procedure was explained to the patients, then 10% xylocaine pharyngeal spray was administered to the patient's pharynx to paralyze the gag reflex. The patient was then placed on his left lateral position on the endoscopy couch, and a forward viewing fiber-optic Pentax FC-38 LW 2008 endoscope was used to examine the esophagus, stomach, and duodenum of the patients. During the procedure, four biopsy specimens, two each from the body of the stomach and antrum were taken and fixed in 10% formaldehyde and sent to the histopathology laboratory for histologic assessment and identification of H. pylori.
In the histopathology laboratory, the paraffin-embedded tissue blocks were sectioned at 4 μm thickness and stained with the routine H and E stain for morphology while modified Giemsa and Warthin-Starry stains were used for the identification of H. Pylori. Sections found to show spiral bacteria in the mucosal layer or on the surface of the gastric epithelial cells were considered positive for H. pylori as assessed independently by two consultant histopathologists who were blinded to the endoscopic findings. Gastritis was evaluated according to the updated Sydney system, i.e., inflammation (mononuclear cell infiltration), activity (neutrophil infiltration), atrophy and intestinal metaplasia.
Data were analyzed using Statistical Package for Social Sciences, version 16.0 (SPSS Inc., 2009, Chicago Illinois, USA). Quantitative variables were summarized using range, means, and standard deviation while qualitative variables were summarized using ratios, proportions, and percentages. P < 0.05 was regarded as statistically significant. Determinants and predictors were explored using univariate and multivariate analyses with logistic regression.
| Results|| |
Of the 320 samples sent to the histology laboratory for analysis, 14 (4.4%) were lost during processing. The remaining 306 samples were analyzed as follows.
Out of the 306 samples examined by the pathologist, a total of 250 (81.7%) were positive for H. pylori, while 56 (18.3%) were negative. This gave H. pylori prevalence of 81.7% at histology.
[Table 1] shows 136 (44.4%) participants were males, while 170 (55.6%) were females, with a male: female ratio of 1:1.3. The ages of the subjects ranged from 18 to 84 years with a mean age of 41.2 ± 15.3 years. Univariate analysis on demographic factors in this study showed that there is an increased prevalence of H. pylori in male subjects which is statistically significant (P< 0.0041) when compared with that of females. Of the 306 participants, 230 (75.2%) participants belonged to the lower socioeconomic class with 87.8% of them being H. pylori positive. [Table 3] reveals that lower social class had a statistically significant association (P< 0.0001) with H. pylori infection. We noted that of the 290 participants who lived in a room with two or more other siblings in childhood, 233 (80.4%) had positive H. pylori on histology. This shows that living in crowded condition is association with increased risk of H. pylori infection (P = 0.0001). [Table 4] shows that sourcing water from well or stream increases the risk of H. pylori infection P < 0.0001. Only 7 (2.2%) subjects had a history of cigarette smoking out of which 5 (71.4%) were found to have H. pylori. Statistical analysis [Table 3] revealed a significant association between cigarette smoking and increased prevalence of H. pylori infection (P< 0.0001).
|Table 1: The prevalence of Helicobacter pylori according to gender of the study subjects|
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|Table 3: Univariate analysis of risk factors for Helicobacter pylori infection (histology)|
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|Table 4: Multivariate analysis using binary logistic regression to determine independent predictors of histologically defined Helicobacter pylori infection|
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| Discussion|| |
The prevalence of H. pylori in this study was 81.7% using histology, as seen in [Figure 1], which is the gold standard for the detection of H. pylori in our environment. This prevalence is consistent with H. pylori prevalence rates as reported in other Nigerian studies. An earlier study in 2009 from the same center by Bashir and Ali  reported 81% prevalence. In another study from Gombe H. pylori prevalence was found to be 77.1%, while Ndububa et al. in Ile-Ife reported prevalence rates of 73%. Nigerian prevalence rates are similar to those reported in studies in South Africa  and Kenya  which reported, respectively, rates of 66% and 94%. Woodward et al. in a study in Glasgow, UK reported a prevalence of 66% which they noted was more typical of prevalence in developing countries and thus concluded that the high degree of social deprivation in Glasgow at that time was the explanation for the high prevalence of H. pylori found in the study.
|Figure 1: Modified giemsa stain of gastric tissue from the study subject showing Helicobacter pylori in the glandular crypts and lumina (×400)|
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In our study, as shown in [Table 1], the prevalence of H. pylori infection is higher in males (82.4%) than females (81.6%). Univariate analysis [Table 3] on demographic factors in this study showed that there is an increased prevalence of H. pylori in male subjects which is statistically significant (P< 0.0041) when compared to that of females. Similarly Omosor et al. revealed that the prevalence of H. pylori infection was also higher in males (55%) than females (51.4%). Woodward et al. also reported a higher prevalence of H. pylori in men than in women. Ford and Axonobserved that male gender is a risk factor for H. pylori infection. In contrast, a study from Warri, Nigeria  reported a higher H. pylori prevalence in females than in males.
Our study, as seen in [Table 2], revealed that 87.83% of the subjects in lower socioeconomic class and 76.4% of those in the middle class have H. pylori when compared to only 25% of those in higher social class. Univariate analysis [Table 3] showed that lower social class is significantly association (P< 0.0001) with increased H. pylori infection. Multivariate logistic regression analysis [Table 4] in our study showed that belonging to a lower social class increases the risk of infection with H. pylori (P< 0.0043). A study by Malaty and Grahamin the USA also reported the prevalence of H. pylori infection was 82% in the lower social class, 52% in the middle class, and 11% in the higher social class. Similarly, in Denmark, Steffen et al. found an increase in the risk of chronic H. pylori infection with decreasing socioeconomic status. Individuals from low socioeconomic class are more likely to be associated with low level of education, including poor health education and more tendency to living in an environment that predisposes to fecal contamination of food and water.
|Table 2: Relationship between Helicobacter pylori positivity and risk factors for infection|
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[Table 2] shows that more than 80% of subjects who shared a room with three or more other siblings during childhood were found to have H. pylori on histology. Univariate analysis [Table 3] showed that crowding is a major risk factor for H. pylori infection and is statistically significant in our study subjects (P< 0.0001). Multivariate binary logistic regression [Table 4] showed that multiple occupants per room (crowding) is strongly associated with H. pylori infection (P< 0.043). Similarly, several studies in Nigeria by Etukudo et al. and Olufemi et al. showed that the higher the number of persons in the household, the higher the rate of H. pylori infection. Khalifa et al. also identified household crowding, sharing of bed, and increasing household contact as risk factors for H. pylori infection. A study by Torres et al. found density of living conditions as a major determinant in the acquisition of H. pylori infection,
We found in our study, as seen in [Table 2], a higher prevalence of H. pylori infection among subjects that sourced their drinking water from wells, stream, and ponds when compared to those who use tap water (P< 0.0001). Multivariate logistic regression [Table 4] shows that patients who sourced their drinking water from wells and ponds had higher prevalence of H. pylori than those who used pipe-borne water (P< 0.042). The reason for this could be attributed to the more likelihood of fecal contamination of well and surface water when compared to tap water which is usually treated before distribution. A similar study in Nigeria showed that sourcing water from well and borehole confers a higher risk of H. pylori infection than pipe-borne water. Another study from Kazakhstan  found high prevalence of H. pylori infection among subjects who use the river and well water for drinking compared to those who use tap water. In another study Hegarty et al. found anti-H. Pylori antibody in surface and shallow groundwater samples tested in the USA and concluded that the route of transmission for H. pylori is also waterborne.
As seen in [Table 3], there is a strong association between cigarette smoking (P< 0.0001) and increased prevalence of H. pylori infection. Multivariate logistic regression shows that cigarette smoking is significantly associated with increased risk of H. pylori infection (P< 0.038). This is consistent with the finding by Bateson which showed that there is a strong association between H. pylori infection and current cigarette smoking in his study subjects. Other studies that reported similar findings are those of Ogihara et al., and Halter et al., Similarly, a study in the UK also revealed a strong correlation between H. pylori infection and cigarette smoking (P< 0.01). In contrast to our study, Shi et al. found no association between H. pylori prevalence and smoking. The likely reason for this difference may be due to the high prevalence of cigarette smoking in Jiangsu  their study area where close to 70% of the population smoke.
| Conclusion|| |
This study showed that the prevalence of H. pylori infection is very high among patients with dyspepsia in Kano, Nigeria, and low socioeconomy, crowding, cigarette smoking, and using well or stream water are strongly associated with increasing risk of H. pylori infection.
Efforts should be made by Governments at all levels, together with well-meaning individuals in the community in making education accessible and affordable. Provision of clean potable water to the rural communities will significantly reduce the burden of this infection.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Morris AJ, Ali MR, Nicholson GI, Perez-Perez GI, Blaser MJ. Long-term follow-up of voluntary ingestion of Helicobacter pylori
. Ann Intern Med 1991;114:662-3.
Forman D, Sitas F, Newell DG, Stacey AR, Boreham J, Peto R, et al.
Geographic association of Helicobacter pylori
antibody prevalence and gastric cancer mortality in rural China. Int J Cancer 1990;46:608-11.
Alvarado-Esquivel C. Seroepidemiology of Helicobacter pylori
infection in Tepehuanos aged 15 years and older in Durango, Mexico. J Pathog 2013;2013:243246.
International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to human schistosomes, liver flukes and Helicobacter pylori
. Int Agency Res Cancer 1994;61:3-12.
Saad RJ, Chey WD. Persistent Helicobacter pylori
infection after a course of antimicrobial therapy-what's next? Clin Gastroenterol Hepatol 2008;6:1086-90.
Bashir MT, Ali BU. Peptic ulcer disease and Helicobacter pylori
infection at Kano, Nigeria. Internet J Gastroenterol 2009;8:1-3.
Malu AO, Ani AE, Bello SS. The prevalence of Helicobacter pylori
in dyspeptic patients from the Jos Plateau, Nigeria. Niger Med J 2000;41:1-3.
Aboderin OA, Abdu AR, Odetoyin B', Okeke IN, Lawal OO, Ndububa DA, et al.
Antibiotic resistance of Helicobacter pylori
from patients in Ile-Ife, South-west, Nigeria. Afr Health Sci 2007;7:143-7.
El Dine SS, Mubarak M, Salama R, El Raziky M, El Sherbily E, Zakzria S, et al
. Low seroprevalence of anti-CagA antibodies inspite of high seroprevalence of anti-H pylori
antibodies in rural Egyptian community. Res J Med Med Sci 2008;3:118-23.
Secka O, Antonio M, Tapgun M, Berg DE, Bottomley C, Thomas V, et al.
PCR-based genotyping of Helicobacter pylori
of Gambian children and adults directly from biopsy specimens and bacterial cultures. Gut Pathog 2011;3:5.
Baako BN, Darko R. Incidence of Helicobacter pylori
infection in Ghanaian patients with dyspeptic symptoms referred for upper gastrointestinal endoscopy. West Afr J Med 1996;15:223-7.
Ahmad MM, Rahman M, Rumi AK, Islam S, Huq F, Chowdhury MF, et al.
Prevalence of Helicobacter pylori
in asymptomatic population – A pilot serological study in Bangladesh. J Epidemiol 1997;7:251-4.
Shi R, Xu S, Zhang H, Ding Y, Sun G, Huang X, et al.
Prevalence and risk factors for Helicobacter pylori
infection in Chinese populations. Helicobacter 2008;13:157-65.
Tsai CJ, Perry S, Sanchez L, Parsonnet J. Helicobacter pylori
infection in different generations of Hispanics in the San Francisco Bay area. Am J Epidemiol 2005;162:351-7.
Allaker RP, Young KA, Hardie JM, Domizio P, Meadows NJ. Prevalence of Helicobacter pylori
at oral and gastrointestinal sites in children: Evidence for possible oral-to-oral transmission. J Med Microbiol 2002;51:312-7.
Jemikajah DJ, Okogun GR. Health point prevalence of Helicobacter pylori
in central hospital, Warri, Nigeria. Afr J Cell Pathol 2014;3:57-60.
Etukudo OM, Ikpeme EE, Ekanem EE. Seroepidemiology of Helicobacter pylori
infection among children seen in a tertiary hospital in Uyo, Southern Nigeria. Pan Afr Med J 2012;12:39.
Bateson MC. Cigarette smoking and Helicobacter pylori
infection. Postgrad Med J 1993;69:41-4.
Ogihara A, Kikuchi S, Hasegawa A, Kurosawa M, Miki K, Kaneko E, et al.
Relationship between Helicobacter pylori
infection and smoking and drinking habits. J Gastroenterol Hepatol 2000;15:271-6.
Chandola T, Jenkinson C. The new UK National Statistics Socio-Economic Classification (NS-SEC); investigating social class differences in self-reported health status. J Public Health Med 2000;22:182-90.
Angtuaco TL, Sharma VK, Corder FA, Raufman JP, Howden CW. Seroprevalence of Helicobacter pylori
gastric infection and symptoms of upper gastrointestinal tract disease in two groups of health-care workers. Dig Dis Sci 2002;47:292-7.
Mustapha S, Pindiga U, Yusuph H, Goni B, Jibrin YH. Helicobacter pylori
infection among dyspeptic patients at a tertiary hospital in Northern Nigeria. Int J Infect Dis 2011;9:1528-36.
Ndububa DA, Agbakwuru AE, Adebayo RA, Olasode BJ, Olaomi OO, Adeosun OA, et al.
Upper gastrointestinal findings and incidence of Helicobacter pylori
infection among Nigerian patients with Dyspepsia. West Afr J Med 2001;20:140-5.
Kidd M, Louw JA, Marks IN. Helicobacter pylori
in Africa: Observations on an 'enigma within an enigma'. J Gastroenterol Hepatol 1999;14:851-8.
Kimang'a AN, Revathi G, Kariuki S, Sayed S, Devani S. Helicobacter pylori
: Prevalence and antibiotic susceptibility among Kenyans. S Afr Med J 2010;100:53-7.
Woodward M, Morrison C, McColl K. An investigation into factors associated with Helicobacter pylori
infection. J Clin Epidemiol 2000;53:175-81.
Omosor KI, Omasan OH, Ibe IN, Adejumo BI, Abdulkadir UI, Dimkpa U, et al
. Seroprevalence of Helicobacter pylori
infection and risk factors among asymptomatic subjects in Delta state, Nigeria. Adv Microbiol 2017:7;641-52.
Ford AC, Axon AT. Epidemiology of Helicobacter pylori
infection and public health implications. Helicobacter 2010;15 Suppl 1:1-6.
Malaty HM, Graham DY. Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori
infection. Gut 1994;35:742-5.
Steffen JR, Leif PA, Charlotte VR, Olaf B, Torben J. Socioeconomic factors in Helicobacter pylori
infection among Danish adults. Am J Pub Haelth 1996;86:1539-44.
Olufemi FO, Remi Q, Shittu BO, Akinduti PA. Helicobacter pylori
stool antigen in asymptomatic children in Lagos State, Nigeria. Int J Trop Dis Health 2015:7;156-62.
Khalifa MM, Sharaf RR, Aziz RK. Helicobacter pylori
: A poor man's gut pathogen? Gut Pathog 2010;2:2.
Torres J, Leal-Herrera Y, Perez-Perez G, Gomez A, Camorlinga-Ponce M, Cedillo-Rivera R, et al
. A community-based seroepidemiologic study of Helicobacter pylori infection in Mexico. J Infect Dis 1998;178:1089-94.
Nurgalieva ZZ, Malaty HM, Graham DY, Almuchambetova R, Machmudova A, Kapsultanova D, et al. Helicobacter pylori
infection in Kazakhstan: Effect of water source and household Hygiene. Am J Trop Med Hyg 2002;67:201-6.
Hegarty JP, Dowd MT, Baker KH. Occurrence of Helicobacter pylori
in surface water in the United States. J Appl Microbiol 1999;87:697-701.
Halter F, Brignoli R. Helicobacter pylori
and smoking: Two additive risk factors for organic dyspepsia. Yale J Biol Med 1998;72:91-9.
Liu S, Zhang M, Yang L, Li Y, Wang L, Huang Z, et al
. Prevalence and patterns of tobacco smoking among Chinese adult men and women: Findings of the 2010 national smoking survey. J Epidemiol Community Health 2017;71:154-61.
[Table 1], [Table 2], [Table 3], [Table 4]
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