More Evidence Links Hepatitis C and Parkinson's Disease

June 19, 2019

A possible link between hepatitis C infection and Parkinson's disease has been further strengthened by a new study from Taiwan.

The study shows that among patients with chronic hepatitis C, those who received therapy with interferon-based antiviral therapy had a lower risk of developing Parkinson's disease compared with those who did not receive antiviral therapy.

"The results seem to support the theory that hepatitis C virus infection is a risk factor for developing Parkinson's disease and antiviral therapy has potential in lowering this risk," the authors conclude.

The study was published online in JAMA Neurology on June 5. It was also presented at the 5th World Parkinson Congress, in Kyoto, Japan.

The researchers led by Wey-Yil Lin, MD, Landseed International Hospital, Taoyuan, Taiwan, explain that several epidemiologic studies have found an association between hepatitis C infection and Parkinson's disease, and hepatitis C has been suggested as a risk factor for Parkinson's disease. However, results have been inconsistent and more data are needed.

For the current study, they compared the incidence of Parkinson's disease in patients with chronic hepatitis C infection treated with antiviral therapy with similar patients who did not receive antiviral treatment.

Using the Taiwan National Health Insurance Research Database, they identified 242,568 patients with a diagnosis of hepatitis C infection between 2003 and 2013. Patients with an established history of severe liver disease, stroke, dementia, or Parkinson's disease were excluded, leaving a total of 188,152 individuals who were included in the final analysis.

They then divided the patients into two groups: those who received antiviral therapy (interferon/ribavirin), and those who did not receive antiviral treatment.

They performed propensity score matching with covariate adjustment to match the characteristics of patients between groups, with each treated patient paired with a corresponding untreated patient to minimize treatment selection bias with almost 40,000 pairs matched (45% female, mean age 52 years).

Development of Parkinson's disease was the main outcome. A Cox proportional hazards regression model was used to compare the risk of Parkinson's disease, and the hazard ratio (HR) was calculated at 1 year, 3 years, and 5 years after the index date and at the end of the cohort.

Results showed that the risk of developing Parkinson's disease was higher in the untreated group. Incidence density of Parkinson's disease was 1.00 (95% confidence interval [CI], 0.85 - 1.15) per 1000 person-years in the treated group vs 1.39 (95% CI, 1.21 - 1.57) in the untreated group.

The advantage of antiviral therapy reached statistical significance at the 5-year follow-up (HR, 0.75; 95% CI, 0.59 - 0.96), and this advantage continued to increase until the end of follow-up (HR, 0.71; 95% CI, 0.58 - 0.87).

The researchers say that, to their knowledge, this is the first cohort study to investigate the association between antiviral therapy and risk of Parkinson's disease in patients with chronic hepatitis C infection, with the results suggesting that hepatitis C infection is a risk factor for Parkinson's disease development, which can be lowered with antiviral therapy.

They point out that a direct protective effect of interferon-based antiviral therapy against the development of Parkinson's disease cannot be fully excluded, but the short exposure (16 to 48 weeks in most treated patients) makes this unlikely.

They note that in imaging studies, chronic hepatitis C infection has been associated with cerebral inflammatory response, cognitive impairment, and neuropsychiatric symptoms; it has also been linked to disrupted serotonin and dopamine transmission.

In an accompanying editorial, Adolfo Ramirez-Zamora, MD, Christopher Hess, MD, and David Nelson, MD, University of Florida, Gainesville, say: "The results of this study are relevant to both the fields of neurology and hepatology, as they reveal a potentially treatable hepatological risk factor for the development of Parkinson's disease."

The findings also add to the "evolving knowledge about the association between immunological and infectious factors in Parkinson's disease and related disorders," they comment.

They point out that the findings suggest mechanisms that may be responsible for this association, including neuroinflammation and clearance of hepatitis C infection.

"Although pathogenic mechanisms between hepatitis C infection and Parkinson's disease remain unconfirmed, it is possible that hepatitis C infection enters the brain through the microvasculature and then induces microglial and macrophages inflammatory changes, with damage associated with the release of neurotoxins such as nitric oxide and proinflammatory cytokines, including tumor necrosis factor, IL-1, and IL-6," they write.

"Other potential mechanisms include immune cross-reactivity between hepatitis C peptides and brain tissue antigens that leads to neurodegeneration," the editorialists suggest.

They point out some limitations of the study involving the fact that Parkinson's disease diagnosis — which can be challenging — was not confirmed by clinical, neuroimaging, or pathological findings.

They also point out that interferon has extensive immunomodulatory effects but modest viral eradication rates for hepatitis C infection, so future studies should evaluate the association between Parkinson's disease and those who cleared the virus as well as those who did not, and they should include newer more effective antiviral agents.

They conclude that: "While the search for a disease-modifying or neurorestorative therapies for Parkinson's disease continues, identification of potentially treatable Parkinson's risk factors presents a unique opportunity for treatment. Additional studies with detailed viral analysis and exposure are needed, including in other geographic and ethnic distributions."

This study was funded by grants from Chang Gung Medical Research Fund of Chang Gung Memorial Hospital, Linkou, and Chang Gung Memorial Hospital, Chiayi, Taiwan.

JAMA Neurol. Published online June 5, 2019. Full text, Editorial

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