Association Between Viral Hepatitis Infection and Parkinson's Disease

A Population-based Prospective Study

Hwa-Young Choi; Thi Ha Mai; Kyung-Ah Kim; Hyunsoon Cho; Moran Ki

Disclosures

J Viral Hepat. 2020;27(11):1171-1178. 

In This Article

Discussion

The epidemiology of PD and the association of PD with viral hepatitis infection need to be examined closely. In this study, we determined the incidence of PD and evaluated the association between PD and HCV/HBV infection by analysing extensive nationwide population-based data. We found that the incidence of PD per 10 000 person-years was the highest in the HCV (8.0), HBV/HCV (6.8) and HBV (5.0) infection groups, while the 11-year cumulative incidence of PD was the highest in the HCV, HBV and noninfection groups, in that order. The risk of PD increased proportionally with increasing age and with the presence of comorbidities, including hypertension, ischaemic heart disease, epilepsy, stroke and depressive disorder in all groups.

Hepatitis C virus and HBV, members of the Hepadnavirus family, have outer lipid envelopes and icosahedral nucleocapsid cores composed of protein.[13] HCV and HBV infections might lead to neurodegeneration in many ways such as by direct killing of the neurons through viral replication or by activating both innate and adaptive immune responses, leading to neuronal damage.[14] The innate immune response increases the expression of toll-like receptor (TLR) 2, TLR 5 and CD14 in the central nervous system of PD patients and activates natural killer cells, whereas the adaptive immune responses increase CD4 + T cells that then infiltrate the brain in PD patients.[14] Chronic neuroinflammation is also seen in the brains of PD patients.[15] In addition, HBV infection might induce severe inflammation through mediators such as interleukin-8 (IL-8), IL-29 and IL-22.17.[16] In a population-based cohort study in Taiwan, HCV infection was associated with PD as shown by an adjusted HR of 1.29 for age, sex and some comorbidities.[7] Another study also demonstrated a significant association between HCV and PD, as shown by an OR of 1.39 (95% CI: 1.07–1.80.11). Besides, a study showed that HCV induced the death of 60% of dopaminergic neurons in the midbrain neuron-glia co-culture system in rats, and the toxicity of HCV was similar to that of 1-methyl-4-phenylpyridinium; these features are but not caused by HBV.[6]

The annual incidence density of PD in our study was lower than that observed in Taiwan (85.88 in the noninfection, 91.16 in the HBV, 213.84 in the HCV and 110.19 in the HBV/HCV groups).[6,8] This difference might be attributed to various reasons. Firstly, the definition used for viral hepatitis infection in our study (only chronic hepatitis infection) differs from the one used in Taiwan (both acute and chronic hepatitis infections). Secondly, patients diagnosed with secondary PD and PD-related diseases till the end point were excluded from this study. Thirdly, using the Fine and Gray competing risk regression model analysis, we adjusted for all-cause mortality before the diagnosis of PD.

We found that the HBV, HCV and HBV/HCV groups showed increased risk of PD, which was higher in participants with HCV infection than in those with HBV infections. Unlike our results, a previous study suggested that the standardized rate ratio of PD was higher among patients with HBV infections (RR: 1.76, 95% CI: 1.28–2.37) than among those with HCV infections (RR: 1.51, 95% CI: 1.18–1.90).[5] Another study showed that the HRs adjusted for age, sex and comorbidities were 1.03 (95% CI: 0.85–1.25) for patients with HBV infections, 1.29 (95% CI: 1.06–1.56) for patients with HCV infections and 0.97 (95% CI: 0.67–1.40) for patients with HBV/HCV infections.[6,8] Also, the cross-sectional design study showed that the OR of PD were 0.79 (95% CI: 0.54–1.17) with HBsAg group and 1.95 (95% CI:1.02–3.72) with Anti-HCV group.[17] However, our study showed that the HRs were significantly higher HBV, HCV and HBV/HCV groups compared to noninfection groups, except for the crude HRs in HBV groups. Also, our study showed that most of the comorbidities, including hypertension, ischaemic heart disease, epilepsy, stroke and depressive disorder, were associated with an increased risk of PD in all groups. However, Tsai et al showed that in the HBV infection group, only hypertension was related to a high risk of PD, whereas in HCV group, ischaemic heart disease and head injury were found to be associated with an increased risk of PD.[7]

In addition, Tsai et al[8] showed no association between HBV infection and PD after adjusting for age, suggesting that further studies are required to clarify the relationship between HBV and PD. It is well-known that viruses such as HCV can invade the brain and lead to PD-related cell loss. The mechanism of the association between HCV infection and PD is described elsewhere.[6,7,18–21]

The findings that HCV infection, HBV infection, age, sex and comorbidities were associated with a high risk of PD have several implications. In osteoporosis, predictive models, such as the Garvan Fracture Risk Calculators[22] and the Fracture Risk Assessment Tool2, have been used for predicting fractures. Our finding suggests that a predictive model can be developed for predicting PD based on HCV infection, HBV infection, age, sex and comorbidities. Secondly, the finding implies that PD is partially preventable, because HBV infection, HCV infection and comorbidities are potentially modifiable factors. Thirdly, since HCV and HBV infections were found to increase the risk of PD, we emphasize that patients with viral infections should be considered for early diagnosis and treatment of PD.

The strength of this study was that the results were derived from a well-characterized cohort, with long-term follow-up and large sample size. Moreover, by using competing risk analysis[23] for analysing the association between viral hepatitis infection and PD, we were able to make refined predictions of an individual's risk for PD. However, there are some limitations. The first limitation is the use of the NHIS-NSC cohort database as the source of information for the group without hepatitis. However, Korean NHI claims data covers almost the entire Korean population (98.5%). In addition, the NHIS-NSC cohort database is representative because it was sampled by NHIS based on age, sex, and income level and includes data on 1 020 340 individuals, comprising approximately 2.2% of the population registered with NHIS in 2002. Secondly, this study participant was not ascertained by clinical assessment but by ICD-10 codes. The HBV and HCV diagnoses were defined as those who were treated for these conditions according to the ICD 10 codes. The viral hepatitis group only included individuals with chronic hepatitis and did not include those treated for acute hepatitis. In addition, individuals with viral hepatitis who did not seek health care, or who were not tested for viral hepatitis were not included. Furthermore, individuals diagnosed with PD may have had a greater number of opportunities to be diagnosed with viral hepatitis due to a greater number of hospital visits than individuals without viral hepatitis. However, the possibility of this bias was prevented by excluding individuals diagnosed with viral hepatitis after a diagnosis of PD. There is no information about HBsAg and anti-HCV test results in the NHIS-NSC cohort database. Hence, we could not consider or confirm these test results when defining the noninfection group. To complement this, participants who were diagnosed or treated at least once with acute or chronic viral hepatitis ICD-10 codes in the NHIS-NSC cohort database from 2002 to 2013 were excluded from the noninfection group. As a result, the noninfection group included participants who had never been diagnosed with, or treated for, acute or chronic hepatitis virus for 12 years, thereby compensating for the lack of HBsAg or anti-HCV test results. The last limitation is that the study did not include data on antiviral treatment, potential risk factors for PD such as family history of PD, cigarette smoking, alcohol, physiological factors (such as body mass index, fasting blood sugar and blood pressure) and drug abuse. Further studies should be conducted in other settings to further evaluate the association between HBV and HCV infections with PD. In conclusion, this study demonstrates that HCV and HBV infections are independent risk factors for PD development. Our findings also indicate that comorbidities and advancing age increase the risk of PD in patients with viral hepatitis infections. Taken together, our findings suggest that elderly patients with HBV or HCV infections who are diagnosed with HCV or HBV infections should be monitored for signs of PD so that early intervention and accurate treatment can be provided to minimize the development and consequences of PD.

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