Long-term risk of acute coronary syndrome in patients with
cholangitis:
A 13-year nationwide cohort study☆
Ming-Shian Tsai
a,1, Yu-Fen Li
b,1, Cheng-Li Lin
c, Yao-Chun Hsu
d, Po-Huang Lee
a,
Fung-Chang Sung
c,e, Chia-Hung Kao
e,f,⁎
1. Introduction
Cholangitis is the infammation or infection of any segment of the biliary tract. The underlying pathophysiology of cholangitis typically includes: frst, the obstruction or refux of bile fow within the biliary system; second, increased bacterial growth in the bile duct; and third, elevated intraductal pressure in the bile duct, which allows the translocation of bacteria or endotoxins into the vascular and lymphatic system
(cholangiovenous or lymphatic refux) [1]. The primary etiology of
cholangitis is cholelithiasis. Other signifcant etiologies include the stenosis of the biliary tract,which can result from congenital anomalies, benign or malignant tumors, medical complications, autoimmune diseases, or external compression.
A signifcant proportion of cholangitis patients have latent or recurring cholangitis even after a successful initial treatment. The long-term recurrence rate of common bile stones after an endoscopic removal ranged from 11.0% to 17.4% [2,3]. Cholangitis occurred in approximately 10% of patients who underwent biliary reconstructions [4,5]. These studies have suggested that patients experiencing cholangitis may exhibit chronic biliary infammation, which theoretically results in adverse long-term effects on the cardiovascular system [6].
To our knowledge, no previous studies have examined the risks of cardiovascular events in cholangitis patients. In the present study, we investigate whether cholangitis is associated with an increased risk of acute coronary syndrome (ACS) based on a cohort study and data
from the Taiwan National Health Insurance Research Database. 2. Methods 2.1. Data sources
The Taiwan National Health Insurance Programwas established
in March 1995 by the Bureau of National Health Insurance, Department of Health, and covered over 99% of the Taiwanese population
linked to patient fles with personal information were scrambled to ensure patient confdentiality. We used 2 data fles including the registries of benefciaries and inpatient claims. The accuracy and high validity of the diagnoses in the National Health Insurance Research Database (NHIRD) have been previously demonstrated [9,10]. The International Classifcation of Diseases, ninth edition clinical modifcation (ICD-9-CM) was used to identify the diagnoses. In addition, Taiwan launched a national health insurance (NHI) in 1995, operated by a single-buyer, the government. All insurance claims should be scrutinized by medical reimbursement specialists and peer review. Therefore the diagnosed codes in NHIRD should be accurate and reliable. With the NHI's and China Medical University's approval, this study was approved by the Institutional Review Board of China Medical University in central Taiwan (CMU-REC-101-012).
2.2. Study patients
We conducted a retrospective cohort study of patients who were frst hospitalized for cholangitis (ICD-9 code 576.1) in 1998–2010, and the index date was the date of the diagnosis. The diagnoses of acute coronary syndrome (ACS) (ICD-9 code 410–411.1) were based on the ICD-9 code determined by clinical physicians according to the clinical symptoms and signs, the electrocardiogram (EKG), imaging and blood tests.
Patients younger than 20 years of age and those with previous incidence of acute coronary syndrome (ACS) (ICD-9 code 410–411.1),
hypertension (ICD-9 code 401–405), diabetes (ICD-9 code 250), hyperlipidemia (ICD-9 code 272), chronic obstructive pulmonary disease
(COPD) (ICD-9 codes 490–496), chronic kidney disease (CKD) (ICD-9 code 585), and heart failure (ICD-9 code 428)were excluded. A comparison cohort was randomly selected among patients that were not
diagnosed with cholangitis during 1998–2010 and frequency matched on age (every 5 years), sex, and index year at a 1:4 ratio. The same exclusion criteria were also applied to the non-cholangitis cohort. 2.3. Outcome defnition
All patient datawere examined for incidence of ACS until the date of death, date of loss (withdrawal frominsurance), or December 31, 2010. 2.4. Statistical analysis
The differences in demographic characteristics between the cholangitis cohort and non-cholangitis cohort were tested using a chisquare
test for categorical variables and a t-test for continuous variables. We calculated the incidence density rate of ACS developed in both cholangitis and non-cholangitis cohorts. In order to estimate the sex-, and age-specifc risk of ACS between the two study cohorts, we used the univariable and multivariable Cox proportional hazard model to estimate strata-specifc adjusted hazard ratio (HR) and 95% confdence interval (CI) of developing ACS in patients with cholangitis compared with the non-cholangitis cohort. The multivariable model was used for controlling age and sex. We estimated the cohort-specifc cumulative incidences by 1 – (Kaplan–Meier survival) for unadjusted curves and 1 – (direct adjusted survival function) for considering age and sex in the Cox model under the assumption of no other competing risks; while the difference in cumulative incidence curves between the two cohorts was tested by log-rank test and likelihood-ratio test, respectively. The analyses were performed using the SAS statistical package (version 9.3; SAS Institute Inc., Cary, NC, USA). The statistical signifcance was accepted at a two-tailed P value lower than .05. 3. Results
The eligible patients comprised 37 676 persons in the cholangitis cohort and 150 704 persons in the non-cholangitis cohort (Table 1). The distributions of age and gender were similar in both cohorts by the design of frequency matching. In the present study, 53.4% were males and 46.5% were over 65 years.
Table 2 lists the overall sex- and age-specifc incidence density rate of ACS in both cohorts. The sex-specifc analysis showed that male patients had a higher risk of ACS in both the cholangitis cohort (18.7 vs. 12.5 per 10 000 person-years) and the non-cholangitis cohort
(16.2 vs. 11.5 per 10 000 person-years). However, the ACS risk associated with cholangitis was similar in both males (HR = 1.19, 95% CI =
1.00–1.42) and females (HR = 1.16, 95% CI = 0.94–1.44). As expected, the age-specifc incidence ACS increased with age in both cohorts, especially that the highest incidence of ACS was found in the cholangitis patients over 75 years of age (27.2 per 10 000 personyears). Nevertheless, patients suffering from cholangitis were at the
highest risk for ACS in those ≤49 years of age (crude HR = 2.02, 95% CI = 1.14–3.57) with an adjusted HR of 2.11 (95% CI = 1.20–3.74). The corresponding adjusted HRs for those 50–64 years of age were also signifcant but smaller (adjusted HR= 1.54, 95% CI = 1.18–2.01).
Our fndings suggested that cholangitis was associated with an excessive risk of ACS in younger patients who usually exhibited a lower ACS risk. Table 3 summarizes the mutually adjusted main effects of age, sex, and cholangitis on ACS by Cox proportional hazard models. Male gender was at a higher risk for ACS (adjusted HR = 1.40, 95% CI = 1.26–1.56). The risk of ACS increased with age (adjusted HR = 4.44 for aged 50–64 years (95% CI = 3.34–5.91), adjusted HR = 10.7 for those aged 65–74 years (95% CI = 8.12–14.1), adjusted HR = 12.3 (95% CI= 9.29–16.2) for the oldest patients comparedwith the youngest patients). After adjusted for gender and age, individuals with cholangitis had a 1.18-fold higher risk for ACS (95% CI = 1.03–1.35).
Fig. 1 presents the 13-year cumulative incidence curves of ACS by cholangitis status without any adjustment (A) and adjusted for age and sex (B). The difference in the cumulative incidence curves of ACS between the patients with cholangitis and those without cholangitis during the 13 years of follow-up was more pronounced in the adjusted curves (P = 0.04) than the unadjusted curves (P= 0.07).
4. Discussion
The present study is the frst to address the long-term risk of ACS
in patients with cholangitis. This population-based cohort study demonstrates that the long-term risk of ACS is signifcantly increased in
patients with cholangitis, with an adjusted HR of 1.18 (95% CI: 1.03,
1.35) for ACS within 13 years, after adjusting for confounding factors. Moreover, we found that the association is the most signifcant in
patients younger than 50 years. These results highlight an association that has not been previously considered in managing cholangitis. This warrants further investigation of the underlying pathophysiological association between ACS and cholangitis. Furthermore, preemptive screenings and treatments are needed to reduce the increased risks of ACS in cholangitis patients, especially in patients who are middle-aged and older.
The exact mechanisms that predispose patients with cholangitis to ACS remain unknown, but long-term infammation could play a role. Regardless of the underlying etiology, cholangitis is associated with sustained infammation in a substantial proportion of patients. Cholangitis is primarily caused by cholelithiasis or the stricture of the biliary tract [11], which can lead to benign or malignant obstructions of bile duct and aggravate cholangitis [11]. For cholelithiasis, removal
of the biliary stone, via either endoscopy or surgery, is the gold standard of treatment [2,3]. However, approximately 5.3–17.3% of the patients would have recurrent common bile duct (CBD) stones and required further intervention [2,3]. Predictive factors for recurrent biliary stones included dilated CBD (maximal diameter more than 22 mm) [2] and
gallbladder stone in situ [3]. Not only cholelithiasis itself but also intervention for stone removal can induce repeated cholangitis and sustained
infammation.
Biliary stricture may impede bile fow and predispose cholangitis. Approximately 15% of biliary strictures result from benign etiologies, which include injury during hepatobiliary surgery, chronic pancreatitis, primary sclerosing cholangitis, repeated cholangitis and idiopathic conditions [12,13]. It has been reported that 15.5% of the biliary stricture patients exhibited cholangitis [5]. If untreated, patients can suffer biliary cirrhosis, hepatic failure and eventually death. Even after a successful drainage or bypass, some patients however still exhibit recurrent cholangitis and chronic infammation that can persist throughout their lifetimes [13].
Primary sclerosing cholangitis (PSC) is characterized with slowly progressive and extensive infammatory fbrotic injuries of intraand extrahepatic biliary systems [14]. PSC is one of the most common adult cholestatic diseases in the western countries, although it is less prevalent in Asia. To date, there exists no defnite medical therapy for PSC and liver transplantation may be required at the end stage [15]. It was reported that 37% of the PSC patients had symptoms of cholangitis, i.e. right upper quadrant pain and/or jaundice, at diagnosis [15]. In addition, PSC is associated with infammatory bowel disease [14,15], which
also leads to long-term systemic infammation. Several studies have indicated the role of infammation in the pathogenesis of atherosclerotic
coronary artery disease [6,16–18]; thus, it is reasonable to suggest that chronic infammation contributes to ACS in patients with cholangitis. Low-grade chronic infammation is associated with metabolic syndrome [19], which is diagnosed when patients present 3 or more of
the following indicators: obesity, hyperglycemia, hypertension, low high-density lipoprotein cholesterol levels, or hypertriglyceridemia [20–23]. Serum C-reactive protein, a common marker of infammation, has been shown to be associated with metabolic syndrome [24, 25]. The present study determined that cholangitis is signifcantly
associated with hypertension, diabetes, and dyslipidemia. The risk of developing metabolic syndrome should be further studied in patients with cholangitis.
The strength of this study is that it provides a nationwide populationbased prospective cohort study that demonstrates the increased risk of
ACS in cholangitis patients. Furthermore, the completeness of the NHIRD allowed us to control for confounding factors. Individuals with hypertension, dyslipidemia, and diabetes were excluded from the analysis. However, this study has limitations. First, the NHIRD does not provide detailed information on tobacco use, alcohol consumption, body mass index, physical activity level, socioeconomic status, or family history, all of which are potential confounding factors. Although we excluded peoplewith triple H (hypertension, hyperlipidemia, hyperglycemia
(DM)) to reduce the infuence of obesity, the residual confounding factors of obesity might infuence the association between cholangitis and ACS. Moreover, the Taiwan NHIRD comprises computerized insurant claim data, which enabled this investigation of a nationwide population over 13 years. We determined the occurrence of ACS by investigating hospitalized patients whose diagnoses were audited for
the purpose of reimbursement. Therefore, we could overlook patients with severe or mild cases who did not seek hospital care. Although
these scenarios could under- or overestimate the true number of ACS incidences, they should not bias the results of the present study because of the accessibility and high coverage rate of universal health insurance in Taiwan [26].
In summary, this study demonstrates that cholangitis patients possess a greater risk of developing ACS than non-cholangitis patients, and this risk increases with age. Awareness of the potential ACS risk for patients with cholangitis is important for patients and clinicians. Further study may be warranted.
