Relationships among neurotransmitters, cytokines and cognitive performance for individuals with hepatitis C achieving sustained virologic response: A pilot study

Highlights

• Relationships between cognitive performance and serum analytes are different pre-and post-HCV treatment.

• Visual memory (both immediate and delayed) correlates with kynurenine and TGF-B pre-treatment.

• Post-treatment, visual memory correlates with TGF-B while delayed visual memory correlates with GABA.

• Ten individuals improved working memory scores to a minimal clinically important difference.

• Those who improved in working memory had higher baseline levels of TNF and lower baseline levels of COMT.

Abstract

An important extrahepatic consequence of Hepatitis C is its adverse impact on the central nervous system and cognitive performance. We aimed to determine whether there is a significant relationship between selected neurotransmitters and cytokines and cognitive performance in patients with Chronic Hepatitis C before and after achieving sustained virologic response (SVR). Pre-SVR, elevated kynurenine was associated with increased immediate and delayed visual memory, whereas post-SVR the positive associations are between kynurenine and immediate and delayed verbal memory. TGF-B was consistently negatively associated with both immediate and delayed visual memory pre- and post-SVR. These concomitant changes may have important clinical relevance.

Introduction

Hepatitis C Virus (HCV) infection affects an estimated 64–103 million people worldwide and is considered a major health and economic burden to many countries (Gower et al., 2014). HCV infection is a systemic disease that may lead to both hepatic manifestations (e.g. cirrhosis and hepatocellular carcinoma) and extrahepatic manifestations involving multiple organ systems (e.g. integumentary, ocular, muscular, skeletal, nervous, endocrine, cardiovascular, respiratory, and urinary systems) (Gill et al., 2016). A particularly important extrahepatic consequence of HCV is its adverse impact on the central nervous system and cognitive performance (Cacoub et al., 2014; Fletcher and McKeating, 2012; Younossi et al., 2016). In fact, even after controlling for substance abuse, affective disorders, and cirrhosis, presence of HCV viremia is associated with neurocognitive impairments (Fletcher and McKeating, 2012; Monaco et al., 2012). About one-third of individuals with chronic HCV have decreased levels of cognitive performance (Hilsabeck et al., 2002, 2003), with specific deficits noted in attention, processing speed, working memory, verbal learning, mental flexibility, and problem solving (Huckans et al., 2009; Perry et al., 2008).

However, little is known about the temporal aspects of cognitive performance in people with HCV. In particular, there is little known about what happens after successful treatment of viremia. Additionally, contributors to this change in cognition have not been well characterized, specifically abnormalities in the regulation of metabolism and/or inflammation. Potential contributors may include neurotransmitter and cytokine dysregulation that is associated with prolonged immune system activation (McAfoose and Baune, 2009).

Current treatments for Chronic Hepatitis C (CHC) include direct-acting antivirals, which have been shown to achieve sustained virologic response (SVR) in 90% or more of patients (Kiser et al., 2013; Monaco et al., 2015). A systematic review found that HCV eradication leads to improved cognitive functioning, however, patients who attained SVR were still impaired compared with healthy, age matched individuals (Spiegel et al., 2005). More recent studies have confirmed modest improvements in functioning in individuals who have attained SVR post-treatment compared with individual baselines and to treatment nonresponders (Kuhn et al., 2017; Younossi et al., 2017). Overall, these results indicate that SVR decreases impairments but does not result in return to baseline levels of functioning in all individuals with HCV. Therefore, it is important to understand the potential relationship between serum neurotransmitters and cytokines and cognitive performance in individuals with HCV as potential treatment targets for future investigation. In this pilot study, we aim to investigate the relationship between cognitive performance and serum levels of selected neurotransmitters and cytokines before and after achieving SVR in patients with CHC.