Hepatitis C Linked to Parkinson's Disease

Pauline Anderson

December 23, 2015

Infection with the hepatitis C virus (HCV) significantly increases the risk for Parkinson's disease (PD), new research shows.

"The risk of developing PD is obviously multifactorial, and our study shows that hepatitis C virus infection can be one of the risk factors," said lead investigator Hsin-Hsi Tsai, MD, Neurology Department, National Taiwan University Hospital, Taipei.

The positive association between HCV infection and PD has clinical implications in high endemic HCV areas such as Taiwan, said Dr Tsai. "More detailed neurological tests and functional images might help us detect early PD in anti-HCV–positive patients."

The study was published online December 23 in Neurology.

Possible Mechanism

In most cases, exposure to HCV, a small, enveloped RNA virus, leads to chronic infection, causing progressive liver disease, including hepatic fibrosis, cirrhosis, and hepatocellular carcinoma.

In developed countries, HCV is transmitted largely by injection from illicit drug use. In Taiwan, a history of blood transfusion is the most important risk factor for the HCV infection, according to the authors. That country has a prevalence of anti-HCV seropositivity of about 5%.

For the study, researchers used the National Health Insurance Program, a mandatory single-payer program covering more than 99% of Taiwan residents, and the Longitudinal Health Insurance Database, which houses information on 1 million persons randomly selected from the National Health Insurance database.

The analysis included 49,967 patients with viral hepatitis: 35,619 (71.3%) with hepatitis B virus (HBV) infection, 10,286 (20.6%) with HCV infection, and 4062 (8.1%) with both infections.

The mean age of the patients was about 46 years, and 43.5% of patients were women. Patients were followed for 12 years.

The investigators found a 2.5-fold increased risk for PD in patients with HCV infection compared with controls (no HCV or HBV) (hazard ratio [HR], 2.5; 95% confidence interval [CI], 2.07 - 3.02).

After adjustment for age, sex, and comorbidities, including hyperlipidemia, hypertension, ischemic heart disease, epilepsy diabetes, cirrhosis, stroke, and head injury, the association between HCV and PD remained statistically significant (adjusted HR, 1.29; 95% CI, 1.06 - 1.56; P < .05).

The adjusted HRs for HBV and coinfection were not statistically significant. However, the authors pointed out that there were too few patients with PD in the "both" category to attain statistical significance.

An analysis stratified by age, sex, or comorbidity found that a positive association between HCV and PD was maintained in patients under age 65 years, men, or those with a combination of any of the comorbidities. Being male and having comorbidities could represent "hits" in the "second hit" theory of PD.

The theory, she said, is that HCV enters the central nervous system (CNS) by disrupting the integrity of the blood-brain barrier, altering dopaminergic neuronal transmission in the midbrain, and triggering neuro-inflammation, which results in neuronal damage. This damage could be the first "hit," with second "hits" possibly including age, male sex, other environmental exposures (such as pesticides), and head injury.

The link between HCV infection and PD is supported by findings that this infection might release inflammatory cytokines, such as sICAM-1 and RANTES signaling, which may play a role in the pathogenesis of PD, said Dr Tsai.

Dementia Link

HCV infection has also been linked to dementia, another neurodegenerative disease. Although the mechanisms here are not well understood, it's believed that a similar pathogenesis may be at play, said Dr Tsai.

In contrast to HCV, there is no evidence that HBV, which belongs to the Hepadnaviridae family, is neuroinvasive. An earlier study on rats by Dr Tsai and colleagues showed that HBV does not induce dopaminergic neuronal toxicity.

But other viruses have been linked to PD. One of the best-known examples is the type A H1N1 influenza virus that caused the 1918 influenza pandemic.

"It has been shown that people born during the time of the pandemic influenza outbreak of 1918 have a 2- to 3-fold increased risk of Parkinson's disease than those born prior to 1888 or after 1924," Dr Tsai told Medscape Medical News.

Another example is HIV, the retrovirus that causes AIDS. HIV can quickly infect astrocyte and microglia (monocytic lineage), causing CNS involvement, said Dr Tsai. "It has been reported that 5% to 50% of all AIDS patients have some motor dysfunction, such as bradykinesia, cogwheel rigidity, and tremor."

Several other viruses, including Coxsackie, Japanese encephalitis B, western equine encephalitis, and herpes, may also be linked to parkinsonism.

A limitation of the study was that it used healthcare codes to identify PD and viral hepatitis instead of clinical assessment, laboratory data, or neuroimaging. In addition, the database the authors used doesn't contain information on the duration of viral hepatitis and some HCV risk factors.

"Unfortunately, we were unable to investigate the association between IV [intravenous] drug users and HCV infection in the current study because there were no data regarding the use of illicit drug or associated behaviors" in the database that was used, said Dr Tsai.

Interpret With Caution

Reached for a comment, Michael S. Okun, MD, chairman, University of Florida Health Neurology, Gainesville, and national medical director, National Parkinson Foundation, said the idea that viruses such as HCV can cross the blood-brain barrier, cause inflammation, and lead to death of cells important to PD isn't new.

"However, this study is one of the few to offer well-documented evidence of at least an association," said Dr Okun. One of the strengths of the study, he noted, is its large sample size.

Nevertheless, because of the lack of diagnostic certainty of PD and the missing details, such as transfusion history and drug abuse, the results must be interpreted cautiously, he said.

"This study should be easily reproduced by data from other countries, and we look forward to verification of the result."

For clinicians, the new information should make them more aware that HCV may be a risk factor for the later development of PD, added Dr Okun. "The threshold for ordering a neurological consultation in HCV cases should be lower."

He noted that the authors didn't explore whether treatment for HCV infection could change the risk.

Also commenting on the findings for Medscape Medical News, Beth Vernaleo, PhD, associate director of research programs, Parkinson's Disease Foundation, said, "the epidemiological study builds upon previous lab research that identifies hepatitis C as a possible risk factor for Parkinson's. There's no cause for alarm for individuals with hepatitis C — for most people, several risk factors must be present for Parkinson's to develop. But we are hopeful that these results will spur additional studies to understand brain changes that might underlie both diseases, which in turn may advance research and treatments in the future."

The authors and Dr Okun have disclosed no relevant financial relationships.

Neurology. Published online December 23, 2015. Abstract


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