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Hepatitis C virus infection as a risk factor for Parkinson disease
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from Jules: these theories make sense as well as the theories proposed that HIV might increase PD risk, but further studies are needed. In HIV we NEED real-time studies and large global cohorts following aging patients to closely examine clinical events & neurologic diseases in aging HIV+.
Hepatitis C virus infection as a risk factor for Parkinson disease....."Additional clinical studies are required to confirm the association between HCV infection, neuroinflammation, and PD......Although a few studies have suggested that viral infection could elicit an inflammatory response in PD, a specific virus has not yet been formally identified"
"In the current study, we found a significantly increased risk of developing PD in patients with HCV infection using a large nationwide population-based cohort. Additional clinical studies investigating the link between HCV infection and PD are warranted."
from Jules: authors appear to suggest - HCV enters CNS, this may cause neuro-inflammation and be a first hit, but a 2nd hit increases PD risk: "A study proposed that a potential "second hit" might lead to the development of viral parkinsonism,19 suggesting that environmental exposures or other risk factors also have a role in this condition. In our study, the most significant association between HCV and PD was observed in patients who were younger (aged younger than 65 years), male, or exhibited a combination of any of the comorbidities."....these theories make sense as well as the theories proposed that HIV might increase PD risk, but further studies are needed. In HIV we NEED real-time studies and large global cohorts following aging patients to closely examine clinical events & neurologic diseases in aging HIV+.
"Although a few studies have suggested that viral infection could elicit an inflammatory response in PD, a specific virus has not yet been formally identified.29 The findings of the current study suggested that HCV is a possible candidate. An earlier imaging
study that involved using magnetic resonance spectroscopy to investigate the cerebral effect of HCV showed that chronic HCV infection was associated with elevated choline/creatinine ratios, a biomarker indicating inflammatory and infective conditions, in the basal ganglia and white matter"
A nationwide cohort study
1. Hsin-Hsi Tsai, MD*,
2. Horng-Huei Liou, MD,
3. Chih-Hsin Muo, MSc,
4. Cha-Ze Lee, MD,
5. Ruoh-Fang Yen, MD, PhD* and
6. Chia-Hung Kao, MD
Neurology Published online before print December 23, 2015
Abstract
Objective: To determine whether hepatitis C virus (HCV) infection is a risk factor for developing Parkinson disease (PD).
Methods: This nationwide population-based cohort study was based on data obtained from a dataset of the Taiwan National Health Insurance Research Database for the period 2000 to 2010. A total of 49,967 patients with viral hepatitis were included for analysis. Furthermore, 199,868 people without viral hepatitis were included for comparisons. Patients with viral hepatitis were further grouped into 3 cohorts: hepatitis B virus (HBV) infection, HCV infection, and HBV-HCV coinfection. In each cohort, we calculated the incidence of developing PD. A Cox proportional hazards model was applied to estimate the risk of developing PD in terms of hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: The crude HRs for developing PD was 0.66 (95% CI = 0.55-0.80) for HBV infection, 2.50 (95% CI = 2.07-3.02) for HCV infection, and 1.28 (95% CI = 0.88-1.85) for HBV-HCV coinfection. The association between HCV and PD remained statistically significant after adjustments for age, sex, and comorbidities (adjusted HR = 1.29, 95% CI = 1.06-1.56).
Among those with hepatitis infection, the HR for having PD was 0.66 (95% CI 5 0.55-0.80) for HBV, 2.50 (95% CI 5 2.07- 3.02) for HCV, and 1.28 (95% CI 5 0.88-1.85) for HBV-HCV coinfection, respectively (table 2). After adjustments for age, sex, hyperlipidemia, hypertension, ischemic heart disease, epilepsy, diabetes, cirrhosis, stroke, and head injury, the association between HCV and PD remained statistically significant (adjusted HR 5 1.29, 95% CI 5 1.06-1.56). Figure e-1 on the Neurology® Web site at
Neurology.org shows the proportion of PD-free patients in the 3 hepatitis cohorts.
In the controls, most of the comorbidities were associated with an increased risk of having PD; however, in those with HCV infection, only ischemic heart disease (HR 5 1.65, 95% CI 5 1.11-2.45) and head injury (HR 5 2.03, 95% CI 5 1.32-3.13) remained statistically significant.
Conclusions: We conducted a large nationwide population-based study and found that patients with HCV exhibit a significantly increased risk of developing PD.
EXCERPTS
Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by the early prominent death of dopaminergic neurons in the substantia nigra pars compacta,1 leading to movement disorders characterized by bradykinesia, muscular rigidity, rest tremor, postural imbalance, and gait impairment.2 PD is considered the most common neurodegenerative disorder after Alzheimer disease, and its incidence rate ranges from 10 to 18 per 100,000 person years. 3
Emerging evidence shows that the hepatitis C virus (HCV) is neurotropic and can replicate in the CNS.4-6 Chronic HCV infection is often associated with cognitive dysfunction, fatigue, and depression.4 Parkinsonism is rarely a described feature in patients with HCV. However, a recent study has discovered that HCV can induce dopaminergic neuron death, suggesting a possible association between HCV infection and PD.7
In the current nationwide cohort study, we determined whether HCV infection is a risk factor for developing PD. We selected 249,835 people from the Taiwan National Health Insurance (NHI) database to investigate the association between hepatitis infection and PD.
Table 1 shows the demographic data and comorbidities for the patients with viral hepatitis and controls. Among 49,967 patients with viral hepatitis, 35,619 (71.3%) had HBV infection, 10,286 (20.6%) had HCV infection, and 4,062 (8.1%) had both HBV and HCV infections. The mean age of the hepatitis cohort and controls was 46.4 (615.3 years) and 46.2 (615.6 years), respectively.
Approximately 43.5% of the patients were women, which was not different among the various hepatitis groups and controls. Compared with the controls, a higher percentage of patients with hepatitis exhibited comorbidities, namely, hyperlipidemia (19.3% vs 14.4%, p , 0.0001), hypertension (25.6% vs 21.4%, p < 0.0001), ischemic heart disease (12.5% vs 9.73%, p < 0.0001), epilepsy (0.75% vs 0.62%, p = 0.002), diabetes (8.64% vs 7.93%, p < 0.0001), liver cirrhosis (6.8% vs 0.77%, p < 0.0001), and head injury (10.1% vs 8.37%, p < 0.0001).
DISCUSSION
HCV is a small, enveloped RNA virus belonging to the family Flaviviridae and genus Hepacivirus. Exposure to the virus in most cases leads to chronic infection, causing a progressive liver disease including hepatic fibrosis, cirrhosis, and hepatocellular carcinoma.8 The seroprevalence of HCV has a significant geographical variation, ranging from 0.5% to 24.3% because of different contributions of risk factors in different study regions.9 In developed countries, the HCV is transmitted largely by injection from illicit drug use.10 In Taiwan, the prevalence of anti-HCV seropositivity is approximately 5%, and a history of blood transfusion is the most important risk factor for the HCV infection.11
Although HCV mainly targets hepatocytes, its involvement in extrahepatic tissue has been frequently reported.12,13 The neurotropic characteristic of HCV is still controversial. Fletcher et al.14 recently indicated that essential HCV receptors including CD81, claudin-1, occluding, LDLR, and scavenger receptor-B1 were expressed on the brain microvascular endothelial cells, a major component of the blood-brain barrier (BBB). This result suggested that HCV infection might compromise the BBB integrity, implying the entry of CNS. This result was also supported by the detection of negative-strand HCV RNA sequence in 6 postmortem brain tissue samples obtained from patients with HCV infection.5 These findings confirm the extrahepatic target for HCV infection, and HCV may directly induce neuropathology in vivo.
A possible association between HCV and parkinsonism was discovered. A previous study revealed that dopaminergic neurotransmission is altered in patients with HCV infection.15 HCV was also reported to induce dopaminergic neuronal toxicity in the midbrain cell culture in rats.7 From the epidemiology perspective, a recent study on a community-based cohort in Taiwan concluded that patients with anti-HCV(1) exhibited a significantly increased risk of developing PD.7
Similarly, in the current study, which was conducted using larger samples in a nationwide population-based cohort, we observed that HCV infection was significantly associated with PD and that this infection could be one of its risk factors. This association was not observed in HBV infection or HBV-HCV coinfection. However, there were too few cases of HBV-HCV coinfection with PD development to attach the statistical difference.
The risk of developing PD is obviously multifactorial. Similar to several neurodegenerative disorders, age is a clear risk factor for developing PD and they were reported to exhibit an adequately established causal relationship.16 In our study, we confirmed that age was a consistent risk factor for developing PD. Sex is another well-established risk factor, with studies reporting that men tend to have a higher incidence of PD than women do17,18; however, we did not observe this trend in our current study. Environmental exposures such as pesticide and previous head injury have also been considered as a possible risk factor for PD.1,16
A study proposed that a potential "second hit" might lead to the development of viral parkinsonism,19 suggesting that environmental exposures or other risk factors also have a role in this condition.
In our study, the most significant association between HCV and PD was observed in patients who were younger (aged younger than 65 years), male, or exhibited a combination of any of the comorbidities.
The male sex or the comorbidities may serve as a second hit in our patient group, but the significant association between HCV and PD in the young age group indicates the possibility of HCV as a potential individual risk factor in patients aged younger than 65 years. Some of the risk factors for HCV infection, such as illicit drug use and associated behaviors, may be confounding factors in this age group. In Taiwan, the use of IV drugs is not one of its risk factors based on previous epidemiologic study, and history of blood transfusion is the most important risk factor for the HCV infection.
In addition to Lewy bodies, neuroinflammation is a characteristic feature of PD pathology.16,20 Both microglia and astrocyte activation may result in reactive gliosis within areas of neurodegeneration in PD.21 The release of numerous inflammatory mediators is known to disrupt BBB patency and allow entry of immune cells of the adaptive immune system into the CNS.22,23 The role of peripheral immune cell influx has not been completely explored. Several studies implicated that effector T cells cause microglial activation and are neurotoxic.24-26 In contrast, regulatory components of adaptive immunity affect neural repair and protection.27,28
Factors that trigger neuroinflammation in PD are debatable. Although a few studies have suggested that viral infection could elicit an inflammatory response in PD, a specific virus has not yet been formally identified.29 The findings of the current study suggested that HCV is a possible candidate. An earlier imaging study that involved using magnetic resonance spectroscopy to investigate the cerebral effect of HCV showed that chronic HCV infection was associated with elevated choline/creatinine ratios, a biomarker indicating inflammatory and infective conditions, in the basal ganglia and white matter.6 Additional clinical studies are required to confirm the association between HCV infection, neuroinflammation, and PD.
This study had limitations. First, we used ICD-9-CM codes, instead of clinical assessment, laboratory data, or neuroimaging study, for identifying PD and viral hepatitis profiles. This may lead to less accurate results, but all insurance claims in NHIRD were scrutinized by medical reimbursement specialists and peer review according to the standard diagnosed criteria.
Second, the LHID does not contain information regarding the duration of viral hepatitis and some of the risk factors for HCV infection (blood transfusion, illicit drug use, tattooing, etc.). These factors for HCV infection might have confounding effects on PD development, but could not be controlled for analysis in the current study. In addition, evidence derived from a retrospective cohort study is typically lower in statistical quality because of numerous sources of inherent bias such as medical surveillance bias and misclassification bias.
In the current study, we found a significantly increased risk of developing PD in patients with HCV infection using a large nationwide population-based cohort. Additional clinical studies investigating the link between HCV infection and PD are warranted.
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