In our nationwide cohort study, PUD did not increase the risk of either ischemic or hemorrhagic stroke at any age or in either sex. This finding was inconsistent with the findings of previous cohort study .
Known risk factors for stroke are age, obesity, DM, high blood pressure, dyslipidemia, smoking, atrial fibrillation, and metabolic syndrome (MetS), and MetS was also shown to be associated with upper gastrointestinal diseases . Several cohort studies have been performed on the association between stroke and gastrointestinal diseases, including gastroesophageal reflux disease and ulcerative colitis [15, 16].
Recently, several studies have been performed to investigate the association between PUD and the risk of stroke. A cohort study conducted in Sweden reported that gastric ulcers were significantly associated with the incidence of stroke risk factors (relative risk = 2.21, 95% CI = 1.03–4.71)) . In a study conducted in Taiwan, the authors concluded that PUD is a risk factor for ischemic stroke independent of conventional risk factors of stroke (HR 1.31, 95% CI = 1.20–1.41) . In another cohort study, ischemic stroke patients with PUD had an increased risk of stroke recurrence (HR 1.85, 95% CI = 1.11–3.09) . Xu et al. reported that ischemic stroke patients with PUD have a higher risk of less favorable neurological outcomes (OR = 2.89, 95% CI, 1.79–2.48) .
HP infection has been considered the main cause of PUD due to gastrointestinal inflammation and immune reactions. Previous studies have been performed on the association between HP infection-related chronic infection and atherogenesis. HP-related chronic inflammation, endothelial dysfunction, and hyperhomocysteinemia can result in an increased risk of cardiovascular disease (CVD) [18, 19]. HP staining with seropositive cytotoxin-associated gene A (CagA) resulted in systemic inflammation, and higher infectivity of Cag-positive HP strains was associated with an increased risk of atherosclerotic stroke . In a longitudinal study that enrolled new-onset stroke patients with seropositive HP infection, CagA-positive patients had a higher risk of stroke than CagA-negative patients, with an HR of 3.5 .
Psychological stress has been known to increase the risk of PUD through gastric mucosal damage by increasing the secretion of pepsin and gastric acid, and neurological dysfunction, which influences the hypothalamic-pituitary-adrenal axis and subsequently increases cortisol levels [22, 23]. Stress is also related to increased catecholamine release and sympathetic activation, which may affect blood pressure reactivity, the cerebral endothelium, or coagulation . The amygdala is more active in individuals with posttraumatic stress disorder, anxiety and depression and increased activity of the amygdala increases bone marrow activity and inflammation in the arteries, which may result in an increased stroke risk .
In this study, PUD was not associated with an increased risk of stroke in either males or females, irrespective of age and this result was in contrast to previous studies. Yu et al. reported that the odds ratio for HP infection and stroke was 0.96 (95% CI, 0.78–1.14) in prospective observational studies and concluded that HP infection did not increase the risk of stroke . The role of chronic inflammation caused by HP infection in atherosclerosis has been studied for the past decade, but the clinical significance is not strong enough to affect stroke incidence by HP infection. In addition, psychological stress can be a common risk factor for both PUD and stroke, so an increased risk of stroke may be due to sharing common risk factors rather than to PUD itself.
Rates of obesity and MetS have increased as a result of insufficient physical activity and excessive intake. Several studies have shown that obesity and MetS are associated with an increased risk of upper gastrointestinal disease including PUD [14, 27]. The gastric mucosa of patients with diabetes has increased vulnerability due to decreasing gastric acid secretion and motility, and PUD occurs with a high prevalence in patients with type 2 DM . The plausible risk factors for PUD, including MetS, obesity, and DM, tend to have an increased risk of stroke compared with PUD itself.
This study has revealed some limitations. First, the diagnosis of stroke and PUD was made according to the ICD codes from the administrative billing data, and the number of visits for stroke or PUD was counted, which may not reflect the actual number of stroke or PUD events experienced by the patients. The use of ICD codes in the large claim code can lead to the possibility of misdiagnosis. Second, patient information, including alcohol intake, smoking, dietary factors, and body mass index all of which may contribute to stroke and PUD, was unavailable in the administrative dataset. Thus, the association between PUD and stroke may be partially explained by the absence of these confounding factors In the Korean National Health and Nutrition Examination Survey, the smoking rate in Korea was 30.8% in adult men and 6.3% in adult women . Despite this difference between men and women in the rate of smoking, we found no association between PUD and stroke among either men or women. Moreover, the control group selected by the randomization process is likely to have a similar smoking rate to women with PUD because of the low rate of smoking. We think that the confounding effect of smoking is unlikely to affect our conclusion of an association between PUD and stroke. Third, potential confounders that our study did not control were HP infection and stress. Although PUD is currently considered an infectious disease associated with HP, only 5–10% of HP infections are known to cause PUD, and it was estimated that 2.2% of PUD cases were related to psychosocial stress, although it is difficult to measure the incidence and intensity of stress in individuals . Since the control group was generated using a random selection process, the likelihood of a significant difference in HP infection rate and stresses between the PUD and control groups was low.
This study had several strengths. First, we used a population-based dataset of one million subjects with a 12-year follow-up period to assess stroke risk in patients with PUD. Second, our study was the first to evaluate the association between PUD and stroke using nationwide population-based data from South Korea. Third, the control group was matched with the PUD group for risk factors of stroke, such as hypertension, diabetes, dyslipidemia, and ischemic heart disease, as well as basic characteristics, including age, sex, income, and region of residence. This detailed matching may provide valid evidence of the effect of PUD on stroke.