Infection with Helicobacter Pylori, Coronary Heart Disease, Cardiovascular Risk Factors, and Systemic Inflammation: DISCUSSION


This study of a national sample of American men aged 40-74 years confirmed that seropositivity for H. pylori is associated with MI prevalence in men with diabetes but not in men without diabetes. Seropositivity for H. pylori was not significantly associated with prevalent diabetes mellitus or certain variables of the metabolic syndrome. For example, fasting serum insulin and glucose concentrations showed no significant associations with seropositivity for H. pylori in nondiabetic men. Serum or blood markers of inflammation were not associated with seropositivity for H. pylori, with the exception of serum ferritin.


The microbiology, transmission, and immunology of H. pylori have been described. Since its initial isolation in 1982, serologic tests for IgG (and IgA) antibodies against H. pylori have been developed. Such tests have made possible the population-based study of the epidemiology of infection and its sequelae. Studies to date have indicated an equivocal association of seropositivity for H. pylori with CHD. Mechanisms for putative associations of seropositivity for H. pylori with CHD have not been elucidated. Although atherogenic mechanisms in humans are unproven, mechanisms for vascular damage postulated based on experimental results include promoting atherogenesis, along with other bacteria, such as Chlamydia pneumonia or viruses, by facilitation of a synergistic inflammatory response that could cause oxidative arterial injury and augmentation of smooth muscle proliferation. Infection-induced molecular mimicry is another postulated mechanism. Increased plaque vulnerability may result from an enhanced immune response. Prothrombotic effects may also occur. Early trials of antibiotic therapy for secondary prevention of coronary events have not supported such therapy, but larger trials are needed. Seropositivity for H. pylori may be more important as a contributor to infectious burden, i.e. infections with multiple pathogens. Although one cross-sectional study reported independent associations of infectious burden with death and extent of atherosclerosis, a prospective study failed to find an association.
There is a need for research on the biological plausibility of the association of H. pylori infection and MI in men with diabetes. A clue in this study may be in the serum ferritin. Serum ferritin levels are higher with H. pylori infection and though ferritin is an acute phase reactant, ferritin levels probably represent total-body iron stores. High ferritin/total-body iron has been linked to increased formation of highly reactive forms of oxygen free radicals that can modify lipoproteins in an atherogenic way and perhaps diminish nitric oxide effects.

Mechanisms for an association of seropositivity for H. pylori with insulin resistance are unclear. Clinical diabetes might promote infection by lowering immunocompetence or altering gastric motility with autonomic neuropathy. Alternatively, infection by H. pylori since childhood might induce beta-cell damage by molecular mimicry or systemic inflammation. Cross-sectional studies have linked insulin resistance and diabetes to low-grade inflammation and alterations in the innate immune system. Follow-up studies have linked baseline inflammation (elevated CRP and interleukin-6) to the subsequent onset of type-2 diabetes. Statins, which reduce CRP as well as LDL cholesterol, reduce the risk of new diabetes. An association of diabetes with serum ferritin may reflect altered iron absorption with chronic gastritis. Serum ferritin is also an acute phase reactant as well as an iron transport protein, perhaps explaining its association with H. pylori status in this study. Serum ferritin has been reported to be higher in CHD cases than controls in some studies but not in NHANESII. canadian antibiotics

The metabolic syndrome, also termed insulin resistance syndrome, is usually defined as associated insulin resistance or hyperinsulinemia, glucose intolerance, dyslipoproteinemia (low HDL, elevated triglycerides), and hypertension. It may also include central obesity, hyperuricemia, hypercoagulability, and is a risk factor for atherosclerotic vascular disease and related disorders. Insulin resistance may be defined as “a state in which greater-than-nor-mal amounts of insulin are required to elicit a quantitatively normal response.” In large epidemiologic studies, fasting serum insulin concentration is used as the best measure of insulin resistance, since it is not feasible to measure it more directly using the eug-lycemic hyperinsulinemic clamp technique. Insulin resistance and/or hyperinsulinemia is postulated to cause the metabolic components of the narrowly defined metabolic syndrome, but its role in arteriosclerotic vascular disease is in question. Inflammation has been described as a possible component of the metabolic syndrome, with mechanisms for the association not established but perhaps include the aforementioned. Infectious burden, including H. pylori, might be hypothesized to be linked to the syndrome through resulting inflammation.

Comparisons with Previous Reports

In agreement with these results from NHANES III, one study reported a strong association of infection with H. pylori with prior MI in diabetic patients, while several studies reported equivocal associations in various large samples unselected for diabetes. The pooled odds ratio for seropositivity for H. pylori in 10 prospective studies was 1.15 (95% CI, 0.96 to 1.37). Seropositivity for H. pylori may be more important as a contributor to infectious burden, i.e., infections with multiple pathogens. Although one cross-sectional study reported independent associations of infectious burden with cardiovascular death and extent of atherosclerosis, a prospective study failed to find an association.

NHANES III was the first study to provide population-based data on distributions of seropositivity for H. pylori in a national survey of the U.S. Prevalence of seropositivity for H. pylori was higher in Mexican Americans than in non-Hispanic whites or blacks. Prevalence of seropositivity for H. pylori increased with age and was higher in men than women. A meta-analysis of data on associations of seropositivity for H. pylori and cardiovascular risk factors of the insulin resistance syndrome showed no significant associations except for slightly higher BMI and slightly lower HDL cholesterol in seropositive persons. In the total NHANES III sample, seropositivity for H. pylori was not associated with risk factors of the insulin resistance syndrome, consistent with these negative findings.
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Studies of H. pylori infection and diabetes or glucose intolerance have yielded conflicting results. For example, one Italian study of 385 diabetics and 506 controls found no excess prevalence of infection in diabetics at any age or social class. Other studies have reported a higher prevalence in diabetics, postulating that impaired host defenses in diabetes may enhance susceptibility to infection. A study of 59 hospital patients with antral gastritis suggested that both diabetes and obesity were associated with infection. A population-based study of hypertensives and controls found combined positive serology for H. pylori and C. pneumonia to be related to higher BMI but not to fasting insulin after controlling for age and BMI.

The lack of association of CRP or white blood cell count with seropositivity for H. pylori is consistent with studies indicating that cell-mediated immune response is responsible for the inflammatory response and for protective immunity.

Limitations of the present study include possible bias arising from survey nonresponse and from missing values for some variables. Several special studies of earlier NHANES and NHANES III data have indicated little bias due to nonresponse. Adequate reliability has been demonstrated for serum IgG and IgA ELISA. Day-to-day variability in serum IgG would tend to bias reported associations towards the null. Blood collection conditions in NHANES III were standardized with regard to body position and vein constriction. Although freshly collected plasma samples were not available for IgG determination in NHANES III, serum samples were promptly harvested and frozen in NHANES III and are suitable samples for IgG assay. Type of drug therapy in diabetics was not considered in this analysis. Some of the drugs used to treat persons with diabetes, for example thiazolidinediones, may suppress inflammatory markers. However, these were not in widespread use in 1988-1994 during NHANES III. kamagra uk

Unfortunately, no completely unbiased measure of insulin resistance is available for use in large population surveys. As in the present study, fasting serum insulin concentration has been used in many studies. However, traditional insulin assays, such as the one used in NHANES III, measure proinsulin and several split products as well as specific insulin, leading to falsely high values, especially in prediabetes. This could lead to biased estimates of the association of seroprevalence and serum insulin. However, this seems unlikely given the consistent lack of association will all variables of the insulin resistance syndrome. Insulin.glucose ratios were not used in this paper.

The lack of a single, generally accepted measurement protocol for insulin resistance or metabolic syndrome in epidemiologic studies remains a problem for interstudy comparisons, perhaps explaining in part inconsistencies among studies. Confounding by variables not controlled for cannot be excluded. However, given the uncertainty about the existence or nature of the association, it is unclear for which other variables should be controlled as confounders. Despite the large overall sample size in NHANES III, statistical power was limited for some subgroups, but such analyses were not reported here. The number of tests was restricted to those of weighted regression models. The representativeness of the sample and the use of sample weights provides wide generalizability of the results to U.S. men of the same ages but not necessarily to females or persons of other age groups. kamagra soft tablets

Future research should include longitudinal studies of H. pylori infection and subsequent CHD in Mexican Americans and African Americans with and without diabetes. H. pylori infection and multiple risk factors should be assessed prospectively as risk factors for development of noninvasively meas ured atherosclerosis (e.g., carotid intima-medial thickness) in noninsulin dependent diabetes.

Category: Disease

Tags: coronary disease, diabetes mellitus, glucose tolerance, health surveys, Helicobacter pylori, insulin, obesity, serum

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