Increased Risk of Intracerebral Hemorrhage Among Patients With Hepatitis C Virus Infection.

Increased Risk of Intracerebral Hemorrhage

Among

Patients With Hepatitis C Virus Infection

Chun-Hung Tseng, MD, Chih-Hsin Muo, MSc, Chung Y. Hsu, MD, PhD, and

Chia-Hung Kao, MD

INTRODUCTION

I

ntracerebral hemorrhage (ICH) is one of the main causes of debilitation and death among adults.1–3 ICH patients consume

more socioeconomic resources and represent a greater health care burden than patients with ischemic stroke. ICH comprises approximately 10% to 20% of all strokes,1–3 and

some pathological changes in the cerebral arteriolar wall, such as death and proliferation of vascular wall smooth muscle cells, ectasia of arteriolar walls with formation of microaneurysms,2

and subsequent rupture of the microaneurysms,1–3 are frequently

observed in ICH. Some traditional risk factors for

ICH, including hypertension,1–6 diabetes,1,2,4–6 hyperlipidemia, 5,6 ischemic heart disease (IHD),4–6 atrial fibrillation

(AF),4,5 alcoholic liver disorder (ALD),1–3,6 and head injury,7,8

may trigger these pathological changes in the cerebral arteriolar walls. However, in approximately 10% to 25% of patients, the risk factors for ICH remain unclear,6,9 particularly among

younger patients.6,10

The role of chronic inflammation in increasing the formation of arterial ectasia and microaneurysms in coronary

arteries has been proven in the literature.11,12 Some studies

have also connected the development of ICH with chronic vasculitis in cerebral arterioles caused by viral infections such as human immunodeficiency virus (HIV)13,14 and varicellazoster

virus (VZV),13,15 and autoimmune diseases such as

systemic lupus erythematosus (SLE)16,17 and rheumatoid arthritis

cerebral arteriolar ectasia and subsequent generation and rupture of microaneurysms remains unknown.

Transmitted through the use of injection drug, blood

transfusions, and unsafe therapeutic injections, the hepatitis C virus (HCV) has infected approximately 130 million people globally and has become a major worldwide health issue.19,20

HCV can lead to chronic liver disease, hepatic cirrhosis, and hepatocellular carcinoma, thereby increasing the socioeconomic burden.19,20 A few clinical studies have linked chronic

HCV infection with the subsequent development of ICH, but the relevance of those studies is limited by their small sample sizes.21,22 Because the majority of the Taiwanese population

is enrolled in the National Health Insurance (NHI) program of Taiwan, this study used a subset of the NHI claims database for

the period of 2000 to 2010 to investigate the association between HCV infection and the risk of ICH with a 12-year

follow-up period.

MATERIALS AND METHODS

Data Source

This study enrolled patients from the 1 million insurants in the Longitudinal Health Insurance Database (LHID), which comprises data derived from the National Health Insurance Research Database (NHIRD) for the period of 2000 to 2011.23,24 The data in the NHIRD are derived from Taiwan’s

NHI program, which was implemented in 1995 and covers >98% of the population of Taiwan. The details in the LHID include the medical facilities where patients were enrolled, the types of medical services provided, and demographic information. When the data of outpatient and inpatient enrollments

were accessed into the LHID, they required the approval of the insurance authorities. Patient identification numbers, which are linked to data files, are scrambled before the release of files to researchers to ensure patient privacy. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012). Disease diagnoses were identified according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.

The HCV cohort comprised patients with HCV

(ICD-9-CM codes 070.41, 070.44, 070.51, 070.54, and V02.62) newly diagnosed between January 1, 2000 and December 31, 2010 without a previous history of stroke (ICD-9-CM codes 430– 438). Patients with a history of HCV and hepatitis B virus (HBV) infections (ICD-9-CM 070.20, 070.22, 070.30, 070.32, and V02.61) during 1996 to 1999, or age <20 years were excluded. The date of the initial diagnosis of HCV infection was defined as the entry date. The control group comprised randomly selected patients without hepatitis infection or a history of stroke, sex- and age-frequency-matched to those in the HCV cohort at a ratio of 4:1. The flow chart of patient selection in HCV and control cohorts was shown in Figure 1.

Outcome and Relevant Variables

Both the HCV and the control cohorts were followed up

until the end of 2011 to determine the incidence of ICH (ICD-9-CM code 431). Relevant factors to ICH were sex, age, annual outpatient visits during the study period, medicine for HCV treatment (Ribavirin and Peginterferon), and comorbidities of diabetes (ICD-9-CM code 250), hypertension (ICD-9-CM

codes 401–405), IHD (ICD-9-CM codes 410–414), hyperlipidemia (ICD-9-CM codes 272.0–272.4), AF (ICD-9-CM code

427.31), ALD CM code 571.2), and head injury (ICD-9-CMcodes 959.01, 432.1, 852.2, and 852.3). The risk of ICH was evaluated for patients with or without these variables.

Statistical Analysis

The t test and x2 test were used to compare the distributions

of continuous and discrete variables, respectively, between the HCV cohort and the control group. The incidence of ICH was estimated per 1000 person-years, measured from the entry date to the initial ICH diagnosis, death, withdrawal from the insurance program, or the end of 2011. The HCV cohort and the

control group were compared using the Cox regression model to determine the hazard ratios (HRs) and 95% confidence intervals (CIs), with stratification for sex, age (_55, 56–64, and _65 years), and comorbidity stratum (with and without anyone comorbidity including hyperlipidemia, hypertension, IHC, AF, diabetes, ALD, and head injury). The interaction tests

for HCVand age, HCVand sex, and HCVand comorbidity were estimated using Cox proportional hazard regression. Multivariable Cox proportional hazard regression was adjusted for age,

sex, annual outpatient visits, medicine for HCV treatment, and comorbidities.

The risk for ICH was further evaluated according to the severity of HCV infection, determined as HCV patients without (mild) and with hospitalization for HCV infection (severe). Incidence rates of ICH were measured for levels of severity, as well as adjusted hazard ratios (aHRs) relative to the control group. Trend test of ICH and the HCV severity was assessed using Cox proportional hazard regression. The effects of medical treatment on the ICH risk among HCV patients were also evaluated. The cumulative proportional incidences of ICH were further plotted for both cohorts by using the Kaplan– Meier model, and the log-rank test was used to determine the difference. A 2-tailed P<0.05 was defined as significant. SAS Version 9.1 (SAS Institute Inc, Cary, NC) was used for all statistical analyses.

RESULTS

Men were slightly more in the both cohorts of HCV and controls (51.9%). Approximately one-fourth of the patients

were >65 years old. After comparing with controls, the comorbidity correlated to ICH (such as diabetes, hypertension, hyperlipidemia, IHD, AF, ALD, and head injury) was significantly

higher prevalent in the HCV cohort. The annual outpatient visit for HCV cohort was significantly higher than controls (29.8% vs 18.0%) (Table 1).

The risk of ICH was higher for men and elderly patients (Table 2). The comorbidities of hypertension, diabetes, ALD, and head injury were associated with a higher risk of ICH in all patients (Table 2). However, the HCV cohort had a greater risk of ICH than the comparison group (aHR¼1.68, 95% CI: 1.24– 2.27 and 2.33, 95% CI: 1.36–3.98, respectively) regardless of comorbidities (Table 3). The overall risk of ICH was 1.83 times higher in the HCV cohort than in the control group (95% CI: 1.41–2.38). The incidence rates for ICH in the HCV and

respectively (Table 2). The incidence of ICH increased with age

in both cohorts (Table 3), but the age-specific risk for ICH was significantly higher in the 56 to 64 years old HCV patients

(aHR¼2.45, 95% CI: 1.51–3.98) (Table 3). The Kaplan– Meier plot showed that the cumulative incidence of ICH was higher in the HCV cohort than in the control group (log-rank P<0.0001) (Figure 2).

Comparing the correlation between the severities of HCV

infection with the risk of ICH revealed a dose–response association. The risk of developing ICH increased with the severity of

HCV infection (Table 4). Compared with the control group, the aHRs for patients with HCV infection increased from 1.66 (95% CI: 1.21–2.30) for those with mild infection to 2.12 (95% CI: 1.47–3.06) for those with severe infection. HCV patients with medical treatment had a relatively lower ICH risk than those without medical treatment, with aHRs of 0.19 (95% CI: 0.03– 1.38) and 1.83 (95% CI: 1.41–2.38), respectively (Table 4).

DISCUSSION

Previous studies have shown that patients with viral infections, such as HIV13,14 and VZV,13,15 and autoimmune diseases,

such as SLE16,17 and RA,16,18 are at a higher risk of ICH. In the

present study, HCV patients were compared with patients without this infectious disease in a 12-year follow-up period, and the HCV patients had a 1.60 times higher risk of ICH. A dose–response association with the severity of HCV infection was also observed. Persistent inflammation due to HCV infection might cause pathological changes in cerebral arterioles,

which might trigger ICH development, as noted in some viral infections (eg, VZV and HIV infections) and autoimmune disorders (eg, RA and SLE). HCV-related chronic liver disease, hepatic cirrhosis,19,20 and hepatocellular carcinoma might

impair the human coagulation functions that might further enhance the risk of ICH noted in the present study.

More than 50% of our study patients were men and >75% were <65 years of age (Table 1). This is consistent with prior studies, noting that middle-aged men or younger are at higher risk of HCV infection.20,25,26 Men were more susceptible to the

proven in prior studies.1–6,27 The most critical risk factor for

ICH is age.1–6,27,28 The incidence rates of ICH increased with

age in both the HCV and control groups in this study. Nevertheless, the observed age-specific aHRs for the HCV cohort and

the control group were higher for relatively younger patients, with the higher aHRs of 1.92 and 2.54 noted in the _55 and 56 to 64 years age groups, respectively, decreasing to 1.33 in the _65-year age group (Table 3). Because the younger patients had fewer comorbidities associated with ICH, HCV is a more critical risk factor for younger patients than older patients. It is clear from this research that the risk of ICH increased in conjunction with HCV severity. These findings suggest a causal role of HCV in the development of ICH.

Comorbidities for Intracerebral Hemorrhage

Numerous studies have shown that the development of ICH risk is positively associated with older age,1–6,27,28 male

sex,1–6,27 and the comorbidities of hypertension,1–6,27,28 diabetes, 1,2,4–6,27,28 hyperlipidemia,5,6,27–29 IHD,4–6,27 AF,4,5,27,28

ALD,1–3,6,28 and head injury.7,8 In this study, the risk of ICH

increased in participants with the comorbidities of hypertension, diabetes, ALD, and head injury (Table 2).

Strengths and Limitations

This study had the advantages of a large sample size and a

longitudinal design with minimal loss to follow-up. The large sample size enabled stratified analysis of data for examining the differences among sex, age, comorbidities, and severity of HCV. The dose–response relationship correlating to severity of HCV reinforces the validity of this research. Insurance claims for health care reimbursements in the Taiwan NHI program are under rigorous surveillance to prevent fraud. The NHI investigation system helps validate the diagnoses listed in insurance

claims.

Nevertheless, this study also had limitations. First, information on some risk factors for cardiovascular diseases was not available in the claims data, including physical activity, lifestyle factors, and alterations of patients’ immunity associated with HCV infection. Second, the results of laboratory data, for example, liver function tests (eg, alanine aminotransferase, aspartate aminotransferase, g-glutamyl transferase, alkaline

phsosphatase, and bilirubin), serum levels of HCV antigen titers and anti-HCV antibodies, serum C-reactive protein level and erythrocyte sedimentation rate, are unavailable in the NHIRD. Therefore, it was impossible to measure the relationship between various immune conditions in different HCV patients and the risk of ICH. Third, information regarding patients’

personal habits and behaviors, such as alcohol consumption and cigarette smoking, are unavailable in the database. However, the relatively low smoking rate (<3.5%) among Taiwanese women30 and the similar prevalence of ICH in men and women

imply that cigarette smoking and alcohol consumption were unlikely to be confounders that would bias the correlation between HCV infection and ICH. This study estimated the risk of ICH in patients with HCV infection and revealed a higher prevalence of comorbidities in the patients with HCV infection

than in the control group. However, after adjustment for these confounding factors, the risk of ICH remained higher in the

HCV cohort than in the comparison group. Thus, HCV infection is likely a causal factor in the development of ICH. The exact pathogenic mechanisms involved in this relationship warrant further research.

CONCLUSIONS

This study revealed a significant relationship between the risk of ICH and HCV infection. The results also showed that the risk of ICH increases with the severity of HCV infection.

Further research is required to confirm our results, particularly regarding younger patients and more severe cases of HCV infection. The findings in this study could lead to a useful method of preventing ICH for patients with HCV infection, particularly those of a younger age.