Neuropsychiatric Symptoms in Hepatitis C Patients Resemble Those of Patients With Autoimmune Liver Disease but Are Different From Those in Hepatitis B Patients

Meike Dirks; Kim Haag; Henning Pflugrad; Anita B. Tryc; Ramona Schuppner; Heiner Wedemeyer; Andrej Potthoff; Hans L. Tillmann; Kajetan Sandorski; Hans Worthmann; Xiaoqi Ding; Karin Weissenborn

Disclosures

J Viral Hepat. 2019;26(4):422-431. 

In This Article

Discussion

Chronic fatigue is the most frequent extrahepatic manifestation of HCV infection.[22,23] In about one-third of the patients, it is accompanied by cognitive dysfunction.[1] Considering the fact that chronic fatigue is also an issue in patients with liver disease of different origin than HCV, it has been discussed that chronic fatigue is an intrinsic attribute of chronic liver disease irrespective of its cause. Thus, we decided to compare measures of fatigue, mood, health-related quality of life and cognition between groups of patients with noncirrhotic chronic liver disease of different origin—AIH, PBC, HBV and HCV infection. Importantly, liver cirrhosis was an exclusion criterion to avoid potential effects of minimal hepatic encephalopathy in cirrhotic patients. Considering the effect of HCV infection upon the cytokine/chemokine network and the frequency of autoimmune disease accompanying HCV infection,[12,13] we hypothesized that HCV patients show a similar neuropsychological pattern as AIH and PBC patients but differ from HBV patients. Indeed we found a neuropsychiatric profile in the HBV patients that differed from the other groups studied. Our data fit very well with recent findings from Evon et al[11] who assessed the prevalence of chronic fatigue in a sample of 948 HBV infected individuals, of whom a considerable part was inactive carriers (40.7%) and had limited comorbid illnesses (27.8%). Only 2% of participants had advanced fibrosis according to the APRI score. Of note, the fatigue score of the HBV cohort was significantly lower and thus better than that of the US norm. In contrast, fatigue is the most frequent presenting symptom in patients with HCV infection, AIH or PBC. About 50% of AIH patients suffer from fatigue at disease onset,[8] and 40%-80% of PBC patients[24] as well as 50%-60% of HCV patients[22,23] complain about chronic fatigue. For 50% of the PBC patients, fatigue is the most bothersome symptom of their disease.[9] Of interest, fatigue persists in about 50% of the AIH patients despite response to immunosuppressive treatment,[8] and for PBC patients, it has been reported that fatigue neither improves with successful medical therapy of the liver injury nor with liver transplantation.[25,26] The same holds true for part of the HCV-infected patients. Fatigue dissolves in only half of the patients after successful virus eradication with interferon-based therapy.[27] Thus, it must be considered that fatigue associated with HCV infection, AIH or PBC may be induced by the same agent as liver disease but finally becomes independent from the course of liver disease, due—for example—to an ongoing autoimmune response within the brain.

Of interest, both, AIH and PBC, are discussed to be due to molecular mimicry between pathogens and structural components of liver cells, finally leading to an autoimmune response.[28,29] Such autoimmune mimicry may result in ongoing impairment of well-being such as fatigue, even if the liver disease is controlled.

Eight patients in our study had a so-called overlap syndrome combining characteristics of autoimmune hepatitis and primary biliary cholangitis. We decided to include these patients as a further group into the analysis despite the low number of patients. Interestingly, these patients showed significant alterations that are prone to be underestimated due to the size of the group. Fatigue, for example, was most pronounced in patients with AIH/PBC overlap followed by patients with HCV infection, while HBV-infected patients achieved the lowest fatigue scores. One could speculate that AIH/PBC overlap patients may be hit by a dual mimicry resulting in their worse impairment.

Of note, the HCV patients performed worse than any of the other "single" disease entity groups. This fits well with the literature suggesting that the neuropsychiatric extrahepatic manifestation of HCV infection might be due to a triggered neuroinflammatory response.[30] Recently, Blank et al[31] showed that single-stranded RNA viruses and type 1 interferons share an inflammatory pathway leading to interferon receptor chain 1 activation on brain endothelial and epithelial cells followed by the expression of CXCL10 and consecutive impairment of synaptic plasticity causing depressive behaviour and cognitive dysfunction. Liu et al[32] showed the induction of CXCL10 in human brain microvascular endothelial cells (HBMECs) by HCV infection. Type 1 interferon activation in HCV infection had been suggested before by Wilkinson et al[33] who observed significantly increased levels of IFN ß and myxovirus resistance protein A (MxA) transcripts in brain macrophage/microglia cells from autopsy samples of 7 patients with HCV infection compared to 8 patients without infection. In addition, they also observed an increased transcription of IL-8, lymphocyte chemoattractant factor (IL-16) and IP-10 (CXCL10) in the autoptic brain samples of HCV-positive patients. Thus, it is quite conceivable that the neuropsychiatric symptoms in HCV patients relate to the activation of the interferon receptor chain 1 pathway leading to upregulation of CXCL10 expression and alteration of synaptic plasticity.

Data upon cognitive function in AIH, PBC and HBV patients with noncirrhotic chronic liver disease are sparse. Quarantini et al[34] described worse visuo-spatial memory in HCV patients compared to HBV patients, but did not comment on patients' performance compared to healthy controls. Newton et al[10] assessed the prevalence of cognitive symptoms in 198 patients with PBC of who 28 underwent formal neuropsychological testing compared to 11 healthy controls. About 53% of the patients asked for cognitive symptoms reported deficits in attention and memory. These symptoms were independent from the grade of liver disease. The patients who underwent neuropsychological testing showed worse performance than controls in the digit span test, the symbol search test and the digit symbol coding test, which all three assess working memory, while the two latter in addition require perception and visual scanning. Zenouzi et al[35] observed worse lexical and semantic verbal fluency in 20 PBC patients compared to age-matched controls, but no effect on working memory or attention ability. To our knowledge, data upon cognitive function in AIH patients so far are missing. In contrast, there are several studies concerning cognitive function in HCV-infected patients with only mild liver disease indicating significant alteration of attention and memory in up to 1/3 of the patients.[1,36–38] The psychometric test results of the present study suggest that HCV patients differ in regard to neuropsychiatric symptoms from patients with HBV, while they show a profile similar to patients with autoimmune liver disease with alterations especially concerning alertness, working memory and recognition of words and figures (Figure 1). This finding is in accordance with the assumption that the neuropsychiatric symptoms in HCV-infected patients are due to a systemic and/or local (CNS) inflammatory response to the virus.[33,39] Data indicating the presence of neuropsychiatric symptoms despite clearance of the virus in the periphery point to the importance of neuroinflammation in the development of HCV encephalopathy.[27,30,40] Magnetic resonance spectroscopy and positron emission tomography studies prove neuroinflammation in HCV-afflicted patients.[38,39,41,42] Similar MRS studies of the brain comparing controls to HBV or PBC patients found no difference, though in very small patient groups.[43,44] So far, similar studies are missing for AIH.

A limitation of the study is that due to the time intensity of the study for both patients and provider, few patients were available for this study. Though—with 132 patients and 33 healthy controls—this study included a respectable number of subjects, after subdivision of the patient group according to diagnosis finally the subgroups were small. Nevertheless, the present study is the first to compare neuropsychiatric symptoms in patients with noncirrhotic chronic liver disease of different cause, thereby indicating that HCV infection, AIH and PBC share chronic fatigue as the most bothering symptom of extrahepatic manifestation combined with distinct alterations of memory and attention.

The fairly normal performance of our HBV patients in the neuropsychiatric tests as well as the significant impairment of the other groups despite absence of cirrhosis and the missing correlation between FIB4 score and FIS underlines the fact that it is not chronic liver disease per se that induces chronic fatigue, mood alterations and cognitive dysfunction.

In conclusion, the results of the present study suggest that the neuropsychiatric symptoms in HCV-infected patients are probably due to a systemic and/or neuroinflammatory response to the virus affecting brain function similar as in patients with autoimmune liver diseases.

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