Hepatitis C virus infection increases the risk of
developing
peripheral arterial disease: A 9-year population-based
cohort study
Yueh-Han Hsu
1,2,3,4, Chih-Hsin Muo
5,6, Chun-Yi Liu
1,2, Wen-Chen Tsai
1,2,
Chih-Cheng Hsu
7,8,_,
Fung-Chang Sung
9, Chia-Hung Kao
9,10,⇑,_Introduction
Hepatitis C virus (HCV) infection is endemic worldwide, with an estimated global prevalence of 3% (approximately 170 million infected people) [1], and 4.4% in Taiwan [2]. Numerous recent studies have shown evidence of various extrahepatic manifestations of HCV infection. HCV-infected patients are at high risk of
stroke, hypertension (HTN), metabolic syndrome, chronic kidney disease (CKD), and end-stage renal disease (ESRD) [3–6]. Furthermore, prospective and retrospective studies have consistently
reported excess risk of developing type-2 diabetes mellitus (DM) in HCV-infected patients [7].
Peripheral arterial disease (PAD) is an under-diagnosed and undertreated disease [8], causing considerable burden to health care systems worldwide. Previous studies have reported that the prevalence of asymptomatic PAD ranges from 4.3% to 5.4% in the general population of Taiwan and the United States
[9,10], reaching 12.2% in people older than 60 years [11]. According to an analysis of Medicare enrollees, 6.8% of elderly Medicare enrollees received PAD treatment [12]. From 2000 to 2011, the incidence of invasive PAD treatment in Taiwan doubled, and the number of percutaneous transluminal angioplasty procedures increased 15-fold [8]. The reported risk factors of PAD include older age, male sex, smoking, DM, HTN, hyperlipidemia (HL), CKD, albuminuria, and chronic obstructive pulmonary disease (COPD) [10,11,13–16].
HCV infection has been reported to have close relationship
with both carotid and systemic atherosclerosis [17,18]. Further- more, localization of HCV RNA in human carotid plaques provides
atherosclerosis [19]. Because PAD is an atherosclerotic process affecting non-coronary arteries, the relationship between HCV infection and PAD warrants further attention. However, no previous study has addressed this topic.
The aim of this research was to investigate the relationship between HCV infection and PAD, in a retrospective nationwide cohort, by using data from a representative health insurance database. We defined patients with PAD or HCV according to clinical diagnosis in the health care claims files. We hypothesized
that HCV infection might be associated with an increased risk of developing PAD.
Materials and methods Data source
Taiwan’s National Health Insurance (NHI) is a mandatory health care program that started in 1995. This single-payer program provides comprehensive coverage for health care services, such as ambulatory care, hospital services, and prescriptions drugs [20]. In 2008, the NHI Program provided coverage for more than 99% of the Taiwan’s population, and had signed health service contracts with more than 92% of health care organizations in Taiwan [21]. All insurance claims are scrutinized by medical reimbursement specialists and undergo peer review. The definition of HCV status and infection were based on ICD-9 codes determined by qualified clinical physicians during strict audits in the reimbursement process based on laboratory, imaging, and pathological data. Therefore, the definition of HCV status and infection are accurate and reliable even if they were diagnosed by different doctors.
The data analyzed in this study were retrieved from the Taiwan NHI Research Database (NHIRD), a database maintained by the Taiwan National Health Research Institutes (NHRI). The Longitudinal Health Insurance Database 2000 (LHID2000) is a subset of the NHIRD, which comprises detailed healthcare usage data, 1996 through 2011, of one million selected NHI enrollees who were randomly selected and proved representative of the distribution of Taiwanese population in 2000 [22]. We identified the investigated diseases according to the
diagnosis codes in the LHID2000 based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The personally identifiable information in the LHID2000 is scrambled to conform to the Personal
Information Protection Act.
This study was approved by the Institutional Review Board at China Medical University and Hospital, Taiwan (CMU-REC-101-012).
Research sample
From the LHID2000, during the period 1998–2011, we identified 9631 patients with clinical diagnosis of chronic HCV (ICD-9-CM 070.41, 070.44, 070.51, 070.54, and V02.62) and the date for HCV diagnosis was defined as index date. Patients were defined to have PAD by clinical diagnosis (ICD-9-CM 440.0, 440.2, 440.3, 440.8, 440.9, 443, 444.0, 444.22, 444.8, 447.8, and 447.9) obtained from the LHID2000. The exclusion criteria were: age younger than 20 years, history of chronic hepatitis B virus (HBV) infection (ICD-9-CM 070.20, 070.22, 070.30, 070.32, and V02.61) or PAD before the index date. The remaining 7641 HCVinfected patients were classified as the HCV cohort. The HCV cohort was further
divided into two statuses: patients without cirrhosis (ICD-9-CM 571.5) or liver cancer (ICD-9-CM 155.0) before the index date (Class 1, n = 6771), and those with cirrhosis or liver cancer before the index date (Class 2, n = 870). LHID2000 beneficiaries with no HCV, HBV, or PAD history before the index date were selected
under a 4:1 age- and gender-match, to form a comparison cohort (Fig. 1). Endpoint and covariates
All patients were followed from the index date until the date of PAD diagnosis, withdrawal from the NHI program, or the end of 2011. The adjusted covariates
comprised various sociodemographic and comorbidity characteristics. The sociodemographic characteristics contained gender, age (20–34, 35–49, 50–64, and
P65 yr), and urbanization level of residency. Urbanization level was grouped into four levels based on a National Health Insurance report, ranging from Level 1 (the most urban areas) to Level 4 (the most rural areas). The comorbidities (ICD-9-CM) investigated in this study were HTN (401-405), HL (272), DM (250), ischemic heart disease (IHD, 410-414), COPD (490, 491, 495, and 496), CKD/ESRD (585), ischemic stroke (433-438), acute alcoholic hepatitis (571.2), and cirrhosis. Statistical analysis
The differences between the covariates of the HCV and comparison cohorts were analyzed using the Chi-square test for categorical variables or t test for continuous variables. The incidence of PAD was calculated for each HCV subgroup (Classes 1 and 2) and the comparison cohort. The Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of PAD development in the two cohorts. The multivariate-adjusted models included all statistically significant covariates identified by the crude models. In addition, we assessed the joint effects of HCV with HTN, DM, HL, ischemic stroke, and IHD, on the risk of PAD in the adjusted regression models after controlling age, gender, and urbanization level. Furthermore, we estimated the risk of developing PAD over various follow-up periods. All statistical analyses were performed
using SAS 9.3 software (SAS Institute, Cary, NC, USA) for Windows. The level of significance was set at 0.05, and the tests were 2-tailed.
Results
We collected data on 7641 HCV-infected patients (the HCV cohort), 6771 in Class 1, and 870 in Class 2 patients. Moreover, 30564 age- and gender-matched patients were selected as controls (the comparison cohort). The mean age of the HCV cohort
was 53.5 years (standard deviation = 14.6), with 51.2% of women. Compared with the comparison cohort, the HCV cohort was more likely to have all of the listed comorbidities shown in Table 1. Compared with the patients in Class 1, those in Class 2 were more likely to have comorbidities.
With a mean follow-up period of 5.96 years, the risk of developing PAD was higher in the HCV cohort (HR = 1.51), Class 1
(HR = 1.51), and Class 2 patients (HR = 1.56) compared with those in the comparison cohort (Table 2). After adjusting for age, gender, urbanization level, and comorbidity (HTN, HL, DM, IHD,
COPD, CKD/ESRD, ischemic stroke, and acute alcoholic hepatitis),
the risk of PAD development remained higher among patients in the HCV cohort (HR = 1.43, 95% CI = 1.23–1.67), Class 1
(HR = 1.49, 95% CI = 1.27–1.75), and Class 2 (HR = 1.04, 95% CI = 0.67–1.62). Compared with the 20–34 year-old patients, the risk of PAD development was 3.96-fold higher in those aged 35–49 years, and 11.7-fold higher in those aged 65 years and above; thus, the risk of developing PAD increased with age. Level of residence urbanization did not increase the risk of PAD.
Regarding risk factors, CKD/ESRD had the strongest risk of developing PAD (HR = 1.80, 95% CI = 1.29–2.53), followed by HL
(HR = 1.58, 95% CI = 1.35–1.84), HTN (HR = 1.41, 95% CI = 1.19– 1.66), DM (HR = 1.33, 95% CI = 1.13–1.58), ischemic stroke (HR = 1.29, 95% CI = 1.08–1.55), and IHD (HR = 1.19, 95% CI = 1.01–1.41).
Regarding the joint effects of various comorbidities on the risk of developing PAD, Table 3 shows the results of the age-, gender-, and urbanization-adjusted regression models. Compared with the patients without these 6 diseases, those with HCV alone were at higher risk of developing PAD (HR = 1.69, 95% CI = 1.21–2.29). Among the HCV-infected patients with one comorbidity, those
with ischemic stroke exhibited the highest risk (HR = 3.56, 95% CI = 1.14–11.2), followed by those with HTN, DM, HL and IHD (Supplementary data). The HCV-infected patients with any 4 comorbidities exhibited a substantial risk of developing PAD (HR = 9.25, 95% CI = 6.35–13.5) (Table 3).
Table 4 shows the associations between PAD and HCV infection over various lengths of follow-up under multivariable models. Compared with patients in the comparison cohort, those in the HCV cohort exhibited a significantly higher risk of developing PAD from 1 year (p <0.01) to three years (p <0.001) of follow-up, then the risk faded. Class 1 patients had a similar trend.
Discussion
This nationwide population-based retrospective cohort study was conducted in an area with high prevalence of both HCV and PAD [2,9]. After adjusting to control the effects of age, gender, urbanization level, HTN, DM, HL, IHD, COPD, CKD/ESRD, ischemic stroke, acute alcoholic hepatitis and liver cirrhosis, we observed that patients with HCV exhibited a 1.43-fold increased risk of developing PAD compared with those without HCV. The presence of cirrhosis did compound the risk of developing PAD in the HCVinfected patients. The other crucial risk factors associated with
PAD development include increased age, HTN, HL, DM, IHD,
CKD/ESRD, and ischemic stroke. With a mean follow-up period of 5.96 years, the excess risk of PAD development in HCV-infected
patients appeared within the first and the third follow-up year, and it faded thereafter.
Several potential factors may be considered as surrogates for PAD, to explain the relationship between HCV infection and atherosclerosis. Costantini et al. [23] reported that HCV RNA sequences have been isolated within carotid plaques, indicating that HCV might, by inducing arterial inflammation, play a direct proatherogenic role in atherosclerosis. Abbas et al. [24] reported
that HCV structural and non-structural proteins might play a major role in initiating and maintaining chronic inflammation.
HCV-infected DM patients have increased risk of developing insulin resistance and proinflammatory cytokine overproduction [25]. In addition, insulin resistance has been associated with increased oxidative stress and endothelial dysfunction, thereby contributing
to vascular injury [26].
Our data indicated that gender had no effect on the risk of PAD development. However, aging had a significant effect on the risk of developing PAD; moreover, the risk increased in conjunction with age. Similar findings have been reported by previous research on the relationship between HCV infection and increased risk of stroke, which is also a macrovascular disease
[3,27]. Regarding urbanization level, our data showed that more HCV-infected patients resided in rural areas. Both of these results were similar to those reported by previous research [5,6,27]. HCV typically progresses to cirrhosis or hepatic cancer. Therefore, we divided the HCV cohort into 2 patient groups (with and without cirrhosis and/or hepatic cancer), to determine whether this trend existed in our research sample. The
crude HR values (Table 2) supported the trend of increased risk in Class 1 (HR = 1.51) and Class 2 (HR = 1.56) patients; however, the adjusted regression models yielded a less severe
increase in risk. This reduction in risk could be explained by the following reasons: first, the case number in Class 2 patients was relatively small (n = 21); second, the involved pathogenic mechanisms of cirrhosis development might differ from those causing PAD.
The joint effects analyses revealed additive effects on risk of PAD with increased comorbidities; however, the analyses were under strict limitations by case numbers with different comorbidity, such as the cases for CKD/ESRD and for ischemic stroke.
Theoretically the adjusted HR for PAD in HCV with all 5 included comorbidity should be the highest, due to lower chances, the case number should become smaller, and the HR should become lower (Table 3).
Our analysis results indicated ischemic stroke as an independent risk factor of PAD development in HCV-infected patients
(HR = 1.29). This finding is supported by the reports from Lee et al. [3] and Liao et al. [27]. Furthermore, our data fill the gaps concerning concurrent associations of most major cardiovascular risk factors with PAD: HTN, DM, IHD, HL, CKD/ESRD, and ischemic
stroke. The findings of this study have several crucial clinical implications. First, the results indicated that HCV infection independently
increased the risk of developing PAD. Since HCV
infection has been associated with increased risk of stroke, coronary arterial disease, metabolic syndrome, HTN, and CKD/ESRD,
HCV infection should be considered a risk factor of cardiovascular disease. Further large-scale prospective studies, systemic review, and meta-analyses may be necessary to validate this finding. Second, HCV infection per se is an infectious disease, yet it exerts
many significant extrahepatic influences. Therefore, HCV infection should no longer be considered as a disease concerning hepatologists alone – all physicians should improve their knowledge
on HCV infection. Third, recent studies have confirmed that antiviral treatment of HCV infection can improve cardiovascular,
renal, and hepatic outcomes in HCV-infected patients [28,29],
indicating the potential for more optimistic outcomes of HCVassociated vascular complications. Accordingly, further research
is warranted to elucidate the effects of antiviral treatment on PAD. Fourth, the presence of multiple comorbidities in HCVinfected patients increases the risk of PAD development and
potential limb loss; accordingly, clinicians should be alert to
these conditions and provide appropriate evidence-based treatment timely.
Certain limitations were encountered. First, the study was
conducted on health insurance claims database and lacked information on patient behaviours and about certain important cardiovascular risk factors, like smoking, obesity/BMI, alcoholism,
exercise, and dietary habits. We were unable to control certain residual confounding factors. However, we included acute alcoholic hepatitis to adjust for the influence of alcohol intake. We
already included HTN, DM, HL (the Triple H) to adjust for the influence of BMI/obesity. In addition, we used an alternative way and adjusted for smoking related diseases (including IHD, COPD, and ischemic stroke), to minimize the potential confounding effect by smoking, which was used in a previous publication
[30]. Second, patients with asymptomatic PAD or HCV infection might not seek health care until they experience considerable discomfort; consequently, we may have under-estimated the risk of PAD development. However, the significant results may strengthen the relationship between HCV infection and PAD
development. Finally, we planned to include antiviral treatment (interferon plus ribavirin) in our analysis; however, because of changes in the prescription reimbursement policy of the NHI program
[31], a reliable prescription profile of antiviral treatments was unavailable.
The major strengths of this research are the following: first, novel approaches were adopted to analyze the relationship between HCV infection and PAD incidence, and to divide the severity of HCV infection into 2 levels (patients with and without cirrhosis/hepatic cancer), to confirm the existence of any trends. Second, we conducted a comprehensive adjustment to control multiple confounding factors including COPD, ischemic stroke, IHD, and cirrhosis. Third, a large research sample (7641 cases of HCV infection and 30,564 age- and gender-matched controls) and long follow-up periods (mean = 5.53 ± 3.75 and
5.96 ± 3.73 years for the HCV and comparison cohorts, respectively) increased the validity of the data. Fourth, we analysed
and discussed the joint effects of HCV-infected patients with increasing comorbidities. Because most PAD patients typically have multiple comorbidities [10], these results provided a more precise indication of the risk of PAD development in patients with diverse comorbidities combination. Fifth, because the database used in this study is managed by the Bureau of NHI for reimbursement purposes, it is reasonable to infer that the data are
both reliable and valid.
In conclusion, HCV-infected patients are at higher risk of developing PAD. Other significant risk factors include aging, and the presence of comorbidity, including HTN, HL, DM, IHD, CKD/ ESRD, and ischemic stroke. HCV-infected patients with concurrent comorbidity are at even higher risk of developing PAD.
Excess risk of PAD development in HCV-infected patients appears within the first and the third follow-up year. Although HCV infection per se is an infectious disease, it presents various cardiovascular manifestations. We recommend all physicians to be aware of their patients’ HCV infection status and potential extrahepatic sequelae.
