Gallstone Disease and the Risk of Stroke: A Nationwide Population-based Study.

Gallstone Disease and Stroke: A Population-Based Longitudinal

Follow-Up Study

Cheng-Yu Wei,

,

,

Tieh-Chi Chung,

,‡ Chien-Hua Chen,

,

Che-Chen Lin,

,

Fung-Chang Sung,

,

Wen Ting

Chung,

,

Woon-Man Kung,

,

,

Chung Y. Hsu,

,†† and

Yung-Hsiang Yeh,

*Department of Neurology, Chang Bing Show Chwan Memorial Hospital, Changhua County, Taiwan;

†Department of Exercise and Health Promotion, College of Education, Chinese Culture University, Taipei, Taiwan;

‡Graduate Institute of Health Care, Meiho University, Pingtung County, Taiwan; xDigestive Disease Center, Chang Bing Show Chwan Memorial Hospital, Changhua County, Taiwan; kManagement Office for Health Data, China Medical University Hospital, Taichung, Taiwan;

{Department of Public Health, China Medical University, Taichung, Taiwan;

#Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; **Department of Neurosurgery, Lo-Hsu Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan;

††Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, Republic of China.

Address correspondence to Yung-Hsiang Yeh, MD, Digestive Disease Center,

Chang Bing Show Chwan Memorial Hospital, No 6, Lugong Rd,

Lugang Township,

Changhua County 505, Taiwan, Republic of China.

Abstract

Purpose: Gallstone disease (GD) and stroke share a number of risk factors including diabetes and hyperlipidemia. This nationwide population-based study was designed to estimate the risk of stroke following a diagnosis of GD.

Methods: Data were obtained from the Taiwan National Health Insurance Research Database. A total of 135,512 patients with a diagnosis of GD and 271,024 age- and gender-matched non-GD control patients were included to assess the risk of stroke using Cox proportional hazard regression.

Results: In this research, 12,234 (153.67/10,000 person-years) strokes occurred among the GD patients, and 20,680 (114.83/10,000 person-years) among the controls. The diagnosis of GD carried a higher risk for developing ischemic and hemorrhagic stroke with a hazard ratio (HR) of 1.28 and 1.33 (95% confidence interval [CI] 1.25– 1.31 and 1.25-1.41, both p<0.0001). The GD patients in three decades of life (age<45, 45-64, and 65) had higher risks respectively in all stroke, ischemic stroke and hemorrhage (all p<0.0001, except p<0.001 for hemorrhagic stroke in age 65 group). GD patients with or without conventional comorbidities showed higher stroke risk, except hemorrhagic stroke did not show significance in patient with atrial fibrillation or hyperlipidemia.

Conclusions: In this population-based longitudinal follow-up study, GD was associated with a significantly higher stroke risk, even in patients who did not have

any conventional comorbidity. Such GD patients should be followed closely to prevent strokes, not only be managed in GD.

Introduction

Gallstone disease (GD) (cholelithiasis) is a common disorder worldwide [1], with varying prevalence in different populations. In the United States, the prevalence of GD has been reported to be approximately 7.9% in men and 16.6% in women [2], and in Europe 1% to 5% in men and 2% to 6% in women of young age (20 to 30 years). The prevalence increases with age, and has been reported to be 9% to 25% in men and 22% to 30% in women of older age (50 to 60 years) [3]. In China, one large-scale study reported prevalence rates of 9.9% in men and 11.6% in women [4], and in Taiwan one epidemiological survey reported rates of 17% in men and 18.7% in women [5]. GD is a multifactorial disease with risk factors including gender, age, genetic factors, race, obesity, rapid weight loss, diet, alcohol use, diabetes, hyperlipidemia, drug use and pregnancy [6-8].

Stroke is a debilitating and life-threatening disorder, and is the second leading cause of death worldwide [9]. The risk factors include nonmodifiable, well-documented modifiable and less well-well-documented modifiable risk factors [10]. The generally nonmodifiable risk factors include age [11,12], gender [13,14], low birth weight [15], race [14], and genetic factors [16]. The well-documented modifiable risk factors include hypertension [17], diabetes [18], hyperlipidemia [19], atrial fibrillation [20], other cardiac conditions [21], asymptomatic carotid stenosis [22], sickle cell

disease [23], cigarette smoking [24], postmenopausal hormone therapy [25], oral contraceptives [26], diet [27], physical inactivity [28] and obesity [29]. The less well-documented modifiable risk factors include migraine [30], metabolic syndrome [31], alcohol consumption [32], drug abuse [33], sleep-disordered breathing [34], hyperhomocysteinemia [35], elevated lipoprotein(a) [36], hypercoagulability [37], inflammation and infection [38].

GD and stroke have certain risk factors in common, including gender, age, genetic factors, race, obesity, diet, alcohol consumption, diabetes and dyslipidemia. However, to the best of our knowledge, no study to date has sought to evaluate the relationship between GD and stroke. This nationwide population-based study was designed to investigate whether there is an increased risk of stroke after a diagnosis of GD.

Materials and Methods Database

This study used the National Health Insurance Research database (NHIRD) released by the Taiwan National Health Research Institute (NHRI). The NHIRD contains all claim data in the National Health Insurance (NHI) program, which covers 98% of the population of Taiwan. The NHIRD is de-identified secondary data released by the NHRI for research purposes, and thus this study was exempt from full review by the Institutional Review Board [39-40].

The disease history was collected from inpatient file and the disease definition based on International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM).

Study sample

The study was population-based retrospective cohort study. The GD cohort was selected the individual with newly GD diagnosed (ICD-9-CM 574) in 2000-2003. The index date of GD cohort set on the date of GD diagnosed. The comparison cohort was enrolled the individual without GD diagnosed in NHIRD, and 2-fold frequency matched by age (per 5 years) and sex. The index date of comparison cohort was randomly assigned a date with the same index year of GD cohort. We excluded the individual with stroke diagnosed before index date, or aged less than 20 years. The study follow-up was terminated when the individual withdrawn the insurance, event

occurrence, or until December 31, 2010.

The interesting event of the study was developing stroke (ICD-9-CM 430-438). The study was also investigated the association between GD and risk of stroke subtypes. The stroke classified into two subtypes: ischemic stroke (ICD-9-CM 433-438) and hemorrhagic stroke (ICD-9-CM 430-432).

The comorbidities of conventional risk factors were included hypertension (ICD-9-CM codes 401-405), diabetes mellitus (ICD-(ICD-9-CM codes 250), coronary heart diseases (ICD-9-CM codes 410-414), atrial fibrillation (ICD-9-CM codes 427.3) and hyperlipidemia (ICD-9-CM codes 272) before the index date.

Statistical Analysis

The SAS statistical package (version 9.1.2; SAS institute, Cary, NC) was used to perform all statistical analyses. The Pearson χ2 test was performed to examine differences in the conventional risk factors of stroke including hypertension, diabetes, coronary arterial disease, hyperlipidemia and atrial fibrillation between the study and comparison groups. We then estimated stroke-free survival probability during the follow-up period using the Kaplan-Meier method, and differences between the two groups were examined using the log-rank test. Cox proportional hazard regression analysis was performed to estimate the association between GD and risk of developing stroke, expressed as adjusted hazard ratios (HR) and 95% confidence intervals (CI). The risk factors for stroke were included as covariates in the regression

models. We also stratified the two cohorts by age, sex and risk factors for stroke in subgroup analysis.

Results

The baseline characteristics of the GD and comparison groups were shown in Table 1. After matching for age and gender, the age and sex distribution was similar between the two groups. The rate of comparison group without any comorbidity was 87.2% more than 73.6% of the rate in GD group without any comorbidity (p<0.0001). Patients with GD were more likely to have hypertension, diabetes mellitus, coronary arterial diseases, atrial fibrillation and hyperlipidemia (p<0.0001).

During the follow-up period, of the 135,512 patients with GD, 12,234 (153.67/10,000 person-years) experienced a higher incidence of overall stroke, compared to 20,680 (114.83/10,000 person-years) of the 271,024 comparison cohort (Table 2). GD patients also had higher obvious incidences in both ischemic and hemorrhagic strokes. In multivariate-adjusted models, the HR of the GD group to the comparison group was 1.29 (95% CI, 1.26-1.32) for all stroke, 1.28 (95% CI, 1.25-1.31) for ischemic stroke, and 1.33 (95% CI, 1.25-1.41) for hemorrhagic stroke. The cumulative incidence curves of all stroke, ischemic stroke and hemorrhagic stroke in the GD group were significantly higher than in the comparison group (log rank test p < 0.0001; Figure 1).

Table 3 presented the adjusted HR for all stroke, ischemic stroke and hemorrhagic stroke in the further stratification analysis. After stratification by age, the

GD patients in three decades of life (age<45, 45-64, and 65) had higher risks respectively in all stroke, ischemic stroke and hemorrhage (all p <0.0001, except p <0.001 for hemorrhagic stroke in age 65 group). There were all significant risks in both gender among three types of stroke (all p <0.0001). In GD patient without any medical history, the HR was 1.28 (95% CI, 1.25-1.32) for all stroke, 1.28 (95% CI, 1.23-1.32) for ischemic stroke, and 1.33 (95% CI, 1.23-1.43) for hemorrhagic stroke. By stratification by medical history, the three types of stroke cohorts had a significantly higher HR in GD patients with or without hypertension, diabetes, coronary arterial disease, atrial fibrillation and hyperlipidemia, except hemorrhagic stroke did not show obvious HR in GD patient with atrial fibrillation or hyperlipidemia.

The comparison cohort without comorbidity as reference group, the risk of all stroke, ischemic stroke, and hemorrhagic stroke had an increased trend following individual with GD only, with comorbidity only and both with GD and comorbidity (Table 4). Our results suggested that there had interaction to the risk of all stroke and ischemic stroke between GD and diabetes mellitus, and had interaction to the risk of all stroke between GD and hyperlipidemia (p<0.05).

Discussion

The findings of this study showed that GD patients had higher comorbidities of hypertension, diabetes, coronary arterial disease, atrial fibrillation and hyperlipidemia, all of which had been proved as conventional risk factors for stroke [17-20, 41]. After adjusting for potential confounding factors, the population-based cohort study demonstrated a significant association between the GD and increased risks in overall stroke, ischemic and hemorrhagic stroke. Although the cumulative incidence of ischemic stroke was more than hemorrhagic stroke about 26%, the two type strokes were still higher than comparison group. To the best of our knowledge, there had not been any studies about the direct relationship of GD and stroke.

In subgroup analysis by age (<45, 45-64, and 65 years old), GD showed obvious association with overall stroke, ischemic and hemorrhagic stroke in all age groups. At the same time, the highest HR of each stroke type all occurred in young stroke patients. It meant that the younger GD patients should pay more attention to the prevention of stroke, including ischemic or hemorrhagic type.

One cross-sectional study reported that subjects with GD had greater carotid atherosclerosis [42], and carotid atherosclerosis was a known marker of cardiovascular risk for both myocardial infarction and stroke [43-44]. Another study reported that carotid plaque was more common in GD subjects than in those with

non-alcoholic fatty liver disease. Fatty liver of unspecified etiology was more common in younger individuals, but GD was more in older individuals. The study also found the fatty liver subjects had an increased prevalence of intima-media thickening and a decreased prevalence of plaques. Fatty liver might be a protective factor for plaques in these younger individuals [45]. We therefore hypothesized that GD subjects might have cerebral arteriosclerosis which then leaded to stroke.

Inflammation is also a less well-documented modifiable risk factor for stroke. Inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase A2 are predictors of ischemic stroke [38]. The inflammation process of GD may promote atherosclerosis or vasculopathy in the cerebral vasculature, thereby increasing the risk of stroke. Related liver diseases including non-alcoholic fatty liver disease and pyogenic liver abscesses have been found to increase the risk of subsequent stroke via a similar mechanism [46-47]. Inflammation may be one of pathogeneses for GD inducing vascular risk.

Although the prevalence of female GD people was more than men, both female and male GD patients all had a higher risk in overall stroke, ischemic and hemorrhagic stroke. Female GD patients have special stroke risks such as pregnancy or oral contraceptives [48-49]. The other hands, more male GD patients have the habit of smoking or alcohol [7]. These influent factors might offset each other. At the same

time, these special risk factors did not be included in this population-based analysis. Regardless of GD patients with or without conventional comorbidities, our data showed increased stroke risk significantly. This suggested that GD might be a new-found risk factor for stroke including ischemic and hemorrhagic stroke. Our results also revealed that GD and diabetes or GD and hyperlipidemia interacted to increase the stroke risk. GD and stroke share the same risks in diabetes and hyperlipidemia [6,18-19]. So we inferred that diabetes or hyperlipidemia with GD might have the synergistic effects for stroke. Checking for GD in the patients with diabetes or hyperlipidemia may be a new strategy for stroke prevention.

There are some potential limitations of this study. First, the patients’ medical histories were only traced back to 1996, the year the LHID was established. The study group may therefore have included patients whose GD and stroke occurred before 1996. Second, some clinically relevant patient and lifestyle data such as smoking status, physical inactivity, alcohol consumption, dietary habits, obesity, postmenopausal hormone therapy, oral contraceptive or other pharmaceutical use were not available in the LHID, all of which may contribute to the risk of stroke. Third, there was no information about the type or severity of GD and ischemic stroke. Therefore, a more detailed analysis of GD and ischemic stroke was not possible in this study.

This is the first longitudinal follow-up and evidence-based study to find an increased risk of stroke among individuals with GD. Further studies are needed to elucidate our findings and to investigate the underlying mechanism. A strength of this study is the statistical power leveraged through a population-based dataset to make significant estimates about the association between GD and subsequent stroke in a Taiwanese population. Further studies with different populations are warranted to confirm our findings. In conclusion, GD was found to be a risk factor for all stroke, ischemic and hemorrhagic stroke. Our findings highlight the need for a systematic approach to prevent subsequent stroke in patients with GD.

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