COMMENTARIES

Vascular Risks and Complications in Diabetes Mellitus: The role of Helicobacter Pylori infection

Sherifa A. Hamed1, Nabila F. Amine2, Ghada M. Galal3, Shaaban R. Helal4, Lubna M. Tag El-Din4, Ola A. Shawky1, Eman A. Ahmed5, and Mohamed S. Abdel Rahman6, 1Department of Neurology, Assiut University Hospital, Assiut, Egypt, 2Department of Internal Medicine, Assiut University Hospital, Assiut, Egypt, 3Department of Tropical Medicine and Gastroenterology, Sohag University, South Valley, Egypt, 4Department of Clinical Pathology, Assiut University Hospital, Assiut, Egypt, 5Department of Radiology, Assiut University Hospital, Assiut, Egypt, and 6Department of Ophthalmology, Assiut University Hospital, Assiut, Egypt

Please address correspondence to:
Sherifa Ahmed Hamed, MBBch., MSc., M.D.
Consultant Neurologist
Associate Professor, Department of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt
P.O.Box 71516
Tele: (+20) 88 2371820
Fax: (+20) 88 2333327/8
Email: hamed_sherifa@yahoo.com

Introduction

It has been found that traditional risk factors for atherosclerosis including age, gender, ethnicity, hypertension, smoking, diabetes mellitus (DM), hyperlipidemia, and hyperhomocysteinemia do not sufficiently explain all clinical and epidemiological features of atherosclerosis as well as the incidence of its related vascular complications. There is increasing evidence that some atherogenic vascular risk factors (e.g. homeostatic factors and lipids) are liable to be altered by inflammation and infection by certain microbial agents including helicobacter pylori (H. pylori) [1,2]. H. pylori is a gram negative micro-aerophilic bacterium occurs naturally and inhabits the mucous layer of the gastric epithelial cells. It is the most prevalent infection worldwide affecting ~50% of the world’s population and considered the causative agent of many gastrointestinal (GIT) and extra-digestive conditions [3]. It has been suggested that production of excessive amounts of pro-inflammatory factors and cross mimicry between H. pylori and host antigens may contribute to the development of gastric mucosal damage and extra-digestive manifestations associated with H. pylori infection [4]. In coronary heart disease, although the association between antibody titers against H. pylori has been evidenced by many studies [1], however, the influence of H. pylori infection on major plasma biochemical risk factors for atherosclerosis and cerebrovascular diseases are still controversial [5]. DM is considered a risk for developing many infections due to impaired immune status. The seroprevalence risk of H. pylori infection among diabetics is still controversial [6].

This study was conducted on 80 patients with DM with mean age of 47.65 ± 1.2 years; 37.5% were insulin dependent (IDDM) and 62.5% were non-insulin dependent (NIDDM); and 92.5% were rural residents while 7.5% were urban. The mean duration of DM was 7.9 ± 4.1 years. Forty-five per cent have acute ischemic cerebrovascular stroke (CVS). Sixty age, sex and socioeconomic-matched subjects were included as controls for comparison. This study aimed to evaluate: 1) the prevalence of H. pylori infection in patients with DM; 2) the association between vascular complications of DM and H. pylori infection; and 3) the influence of H. pylori infection on inflammatory biomarkers and their relation to atherosclerosis and CVS. We investigated patients comparing them with controls by measuring carotid artery IMT (CA-IMT) using duplex ultrasound. Neuroimaging studies were done to confirm the presence of CVS, as well as examinations for the presence of peripheral vascular disease, retinopathy, nephropathy, and neuropathy.

 

The Increased Prevalence of H. Pylori Infection in Diabetes Mellitus and Its Relation to Demographic Variables

This study demonstrated a significant percentage of H. pylori infection in diabetic patients [85% versus 76.7% for controls (P < 0.05)] [7]. Hence, this infection should be carefully investigated in this subgroup of the population. Delayed gastric clearance could contribute to bacterial colonization or overgrowth in GIT as a result of autonomic neuropathy which is common in DM (gastroparesis diabeticorum) [6]. Males demonstrated a high percentage of H. pylori infection compared to females (P < 0.01) which can be explained by the frequent utilization of antimicrobial agents for urogenital infection in females [8]. H. pylori infection was high in rural (66.7%) compared to urban residents (22.2%) (p < 0.001). Low socioeconomic status as poverty, bad living conditions in crowded places, low income, and lower grades of education are strong factors predisposing to infection in general [9].

 

The Association between Vascular Risks and Complications in DM and H. Pylori Infection

This study demonstrated increased risk for atherosclerosis and vascular complications among diabetic patients with H. pylori infection [10], which is evidenced by: 1) increased frequencies of coronary heart, cerebrovascular, peripheral vascular diseases, diabetic retinopathy, nephropathy and peripheral neuropathy among infected patients compared to non-infected, 2) increased CA-IMT and more carotid atherosclerotic plaques in infected patients compared to their controls and non-infected persons, and 3) increased levels of inflammatory markers in infected patients compared to non-infected.

 

The Influence of H. Pylori Infection on Inflammatory Biomarkers and Their Relation to Atherosclerosis and Ischemic CVS in DM

In this study, significantly higher levels of ESR, triglycerides, HbA1c%, IL-6, and TNF-α in H. pylori seropositive were identified in infected patients with CVS than those without CVS (p < 0.05). Positive serology of H. pylori increased the odds for atherothrombotic risk of cerebral ischemia among diabetics in both univariate (p < 0.05) and multivariate analysis (p < 0.001). This association remained significant even after adjustment for age, sex, residency, and other risk factors (p = 0.015). In multivariate analysis the following biochemical parameters increased the odds for atherothrombotic etiology of cerebral ischemia among diabetics: blood glucose (p = 0.06), triglycerides (p = 0.044), ESR (p = 0.015), IL-6 (p = 0.0014), and TNF-α (p = 0.001).

The pathophysiological mechanism underlying the association between H. pylori infection and the development of micro- and macro-vascular complications in DM, particularly coronary heart disease, thrombo-occlusive cerebral disease, and increased CA-IMT, seems likely to be a chronic inflammatory response to bacterial infection. This effect could be mediated by raising cytokine levels (IL-6 and TNF-α). Previous studies demonstrated that chronic infection as a vascular risk factor could explain the association of leukocyte count and fibrinogen with ischemic CVS [11] and myocardial infarction [12].

 

The Possible Mechanism(s) of Induction of Atherosclerosis by H. Pylori Infection

The exact mechanism(s) by which H. pylori infection can induce atherosclerosis is still unknown; however, several possibilities are suggested: 1) the actual presence of H. pylori in the vessel wall might contribute for the increased CA-IMT, initiation and progression atherosclerosis, and destabilization of the atherosclerotic plaques [13]. Direct invasion of the arterial wall by bacteria can result in maturation and activation of moncytes, accelerate the proliferation of smooth muscle cells or endothelial cells within blood vessels, and trigger thrombosis and cerebral ischemia. Activated monocytes produce proinflammatory cytokines which increase platelet aggregation, promote procoagulant activity, and convert fibrinogen to fibrin [14]. 2) Inflammation of atherosclerotic plaques by H. pylori triggers production of excess IL-6 and TNF-α. These cytokines may induce a direct endothelialitis [15]. 3) Infection of plaques by H. pylori can trigger membrane lipid peroxidation, oxidation of low density lipoprotein (LDL), antioxidant loss, elevated production of various superoxides, activated macrophages, activated T-lymphocytes and lipoprotein (a), which aggravate atherosclerosis [16] and, (4) chronic H pylori infection causes atrophic gastritis and decreased absorption of both vitamin B12 and folic acid resulting in hyperhomocysteinemia. Homocysteine has a role in vascular endothelial damage, atherogenesis, thrombogenesis, and coronary heart disease. Homocysteine affects platelet function and coagulation factors and increases the oxidation of LDL [17].

References

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