|Year : 2015 | Volume
| Issue : 4 | Page : 238-242
Impact of early stages of (mild) hepatitis C viral infection on neurocognitive functions in otherwise healthy patients: an Egyptian magnetic resonance spectroscopy study
Hatem Anwar ElMassry1, Nahla Elsayed Nagy MD 2, Walaa Mohamed Sabry2, Reem Hassan El-Ghamry2
1 Department of Neurology, Beni Sweif University, Beni Sweif, Egypt
2 Neuropsychiatry Department, Institute of Psychiatry, Ain Shams University, Cairo, Egypt
|Date of Submission||09-May-2015|
|Date of Acceptance||29-Jun-2015|
|Date of Web Publication||27-Nov-2015|
Nahla Elsayed Nagy
Department of Neuropsychiatry, Institute of Psychiatry, Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
The alterations in cerebral function in patients with chronic hepatitis C virus (HCV) infection may be due to a direct effect of HCV on the brain, or due to neurotoxic-related systemic inflammation.
This study aimed to assess central nervous system involvement through brain magnetic resonance spectroscopy (MRS) as well as cognitive functions in HCV-infected patients with mild liver disease.
Patients and methods
Twenty-eight HCV-infected patients with slightly elevated liver enzymes were recruited from the outpatient Hepatology Clinic, Beni Sweif University Hospitals and Ain Shams University Hospitals. They underwent cognitive examination by means of the Wechsler attention, concentration, and memory subscales, as well as cerebral MRS. The results of all investigations were compared with corresponding results of 15 matched normal controls.
The results showed mild but significant elevation of liver enzymes in the patient group compared with the control group with impaired levels of attention, concentration, and memory determined by the subscales. MRS findings showed elevated choline and myoinositol in the basal ganglia, decreased N-acetyl aspartate, and abnormal N-acetyl aspartate/creatine ratio.
Treatment plans for HCV should consider neuropsychological complications.
Keywords: cerebral magnetic resonance spectroscopy, hepatitis C virus, memory, neuropsychological
|How to cite this article:|
ElMassry HA, Nagy NE, Sabry WM, El-Ghamry RH. Impact of early stages of (mild) hepatitis C viral infection on neurocognitive functions in otherwise healthy patients: an Egyptian magnetic resonance spectroscopy study. Egypt J Neurol Psychiatry Neurosurg 2015;52:238-42
|How to cite this URL:|
ElMassry HA, Nagy NE, Sabry WM, El-Ghamry RH. Impact of early stages of (mild) hepatitis C viral infection on neurocognitive functions in otherwise healthy patients: an Egyptian magnetic resonance spectroscopy study. Egypt J Neurol Psychiatry Neurosurg [serial online] 2015 [cited 2017 Jun 23];52:238-42. Available from: http://www.ejnpn.eg.net/text.asp?2015/52/4/238/170654
| Introduction|| |
Hepatitis C virus (HCV) is the most common cause of chronic liver disease nowadays. HCV infection affects up to 2% of the world's population. According to the Egyptian Demographic Health Survey (EDHS)  , it is estimated that HCV prevalence in the 15-59-year age group is 14.7%  , and in the general population the presence of HCV antibody increases by around 15-20%. Accordingly, Egypt has the highest HCV prevalence in the world , . Today, HCV infection and its complications are among the leading public health challenges in Egypt  .
Although evolution to chronic HCV infection is extremely common, only 30% of chronically infected patients go on to develop end-stage liver disease and hepatocellular carcinoma  . The majority of patients with HCV remain asymptomatic or report a range of mild-to-moderate symptoms, including flu-like symptoms, cognitive difficulty, and psychiatric disorder  .
The alterations in cerebral function in patients with chronic HCV infection may appear long before the development of severe liver fibrosis/cirrhosis, which cannot be ascribed to hepatic encephalopathy. About 50% of patients with HCV infection complain of neuropsychiatric symptoms, 'brain fog', weakness, and fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease. The etiology is unclear but it has been hypothesized that it is related to a direct effect of HCV on the brain, or the neurotoxic effect of HCV-related systemic inflammation  .
Other theories postulated that cognitive impairment may be related to medical or substance use history or due to antiviral treatment rather than HCV itself  .
As these variables may serve as confounding factors, previous studies have tried to control for them as current or recent substance abuse, advanced liver disease, and current or past interferon therapy.
However, few published studies have ruled out history of alcohol or drug use disorders as a confounding factor. This could be mainly attributed to the difficulty of finding a good sample of HCV-positive patients with no history of substance use disorder in different countries; however, this is not the case in Egypt.
The prevalence of injecting drug use in Egypt is estimated at 0.21% ,, , with HCV prevalence among them being 63%  . Considering that HCV prevalence in the population is 14.7%  , injecting drug use may explain at most only about 1% of the national HCV prevalence in Egypt. As HCV transmission in Egypt is mainly due to medical exposures, the possibility of finding cases with hepatitis C with no recent or past history of substance abuse is greater.
| Aim|| |
The study aimed to assess central nervous system involvement through brain magnetic resonance spectroscopy (MRS), as well as cognitive functions, in HCV-infected patients with mild liver disease.
| Patients and methods|| |
This study is a cross-sectional, case-control trial. The participants were divided into two groups: the patient group and the control group.
The patients included in the study were recruited from the Hepatology Outpatient and Inpatient Departments of Beni Sweif and Ain Shams University Hospitals, after obtaining approval of the study protocol from the concerned ethical committee in both medical departments. The control group was recruited from among employees working in the hospitals' outpatient clinics.
This work has been carried out in accordance with the code of ethics of the World Medical Association, and written informed consent was obtained from all participants to participate in the study.
All participants in the patient group were examined by a specialist for evaluation of their laboratory test results and diagnosis of liver disease. The specialist then referred them to the Neuropsychiatry Department to complete the relative medical history and cognitive function tests.
Adult patients of both sexes with complaints of mild HCV infection were included in the study. Of 80 examined patients, as calculated by Graphpad StatMate (USA), with clinical mild HCV infection, a total of 28 (12 women and 16 men) patients aged 20-45 years participated in the study. This group of patients agreed to complete the cognitive tests included in the study. Those with marked liver impairment and with other concomitant chronic medical or cerebral illnesses were excluded from the study. The control group comprised 15 normal volunteers matched for age, sex, and education. They had no clinical liver disease or changes in liver enzymes, nor other medical disease or neuropsychiatric disorders.
Both groups underwent psychiatric examination using the Structured Clinical Interview for DSM-IV-TR Axis I disorder - clinician version (SCID-CV)  to exclude any psychiatric disorder. Then a cognitive examination was carried out using the Wechsler Memory Scale-Revised (WMS-R)  attention, concentration, and memory subscales, in addition to brain MRS. Liver disease was diagnosed using laboratory tests, complete blood count, liver function tests including alanine transaminase, aspartate transaminase, total bilirubin, direct bilirubin, total proteins and serum albumin, and bleeding profile (prothrombin time, partial thromboplastin time, international normalized ratio). MRS was performed on a 1.5 T super conducting system with a 30 minT/min gradient head coil, using single and multivoxel for the basal ganglia, and pertinent metabolic ratios were calculated.
Collected data were analyzed using the statistical package for social sciences (SPSS, version 17; SPSS Inc., Chicago, Illinois, USA). Qualitative variables were described as number and percentages and quantitative variables as mean and SDs. Pearson's χ2 -test was used to detect the presence or absence of significant association between two categorical variables. The independent sample t-test was used to compare between the means of different groups of patients. ANOVA was used to compare quantitative data between more than two groups. P value was used to indicate the level of significance (P < 0.05 was considered significant, and P < 0.01 was considered highly significant). Linear relationships were examined with Pearson's correlation coefficient.
| Results|| |
At the beginning of the study, 80 patients aged 20-45 years were examined for HCV infection by a specialist in the Medical Department. They were referred to the Neuropsychiatry Department for cognitive test assessment. Only 28 patients agreed to complete the study procedures. Their mean age was 28.1 ± 6.3 years and the male to female ratio was 16/12. The control group was composed of 15 normal individuals; their mean age was 23.4 ± 5.1, and the male to female ratio was 9/6. Both groups were compared for age (P = 0.33) and sex (P = 0.21) and showed no statistical significance.
We found significant difference between patients and controls with regard to laboratory tests, mainly alanine transaminase (P = 0.02) and aspartate transaminase (P = 0.01). Yet, these differences indicated only mild liver impairment ([Table 1]).
Patients with HCV infection showed evidence of cognitive impairment, primarily attention and higher executive functions. There were significant differences between patients and controls as regards the attention, concentration, and verbal memory subscales (P < 0.05), as shown in [Table 2].
In addition, we found significant elevated choline and myoinositol in the basal ganglia, decreased N-acetyl aspartate (NAA), and abnormal NAA/creatine ratio (P < 0.05), as shown in [Table 3].
|Table 3 Mean value for the metabolic ratios in magnetic resonance spectroscopy findings |
Click here to view
| Discussion|| |
This study tried to examine the effect of HCV on the brain. We examined changes in metabolic ratios in brain MRS and changes in cognitive functions in patients with mild HCV liver impairment to detect the effect on higher brain functions even with mild elevation in liver enzymes.
Patients with HCV infection showed evidence of cognitive impairment, primarily attention and higher executive functions, and significant elevated choline and myoinositol in the basal ganglia, decreased NAA, and abnormal NAA/creatine ratio (P < 0.05) compared with normal controls.
Several studies showed that HCV affects the brain directly and the virus can replicate in the central nervous system even in patients with compensated liver. Radkowski et al.  analyzed the presence of the HCV-negative-strand RNA sequence, which is the viral replicative intermediary, in autopsy brain tissue samples from six HCV-infected patients. HCV-negative-strand RNA was searched for by a strand-specific Tth-based reverse transcriptase PCR, and viral sequences amplified from brain tissue and serum were compared by single-strand conformational polymorphism analysis and direct sequencing. HCV-negative-strand RNA was detected in brain tissue in three patients. In two of these patients, serum-derived and brain-derived viral sequences were different and classified as belonging to different genotypes.
In one of the latter patients, HCV-negative-strand RNA was detected in lymph nodes and, while being different from serum-derived sequences, was identical to those present in the brain. The results of this study suggest that HCV can replicate in the central nervous system, probably in cells of the macrophage/monocyte lineage.
This study explains our findings of elevated choline and myoinositol in the basal ganglia, decreased NAA, and abnormal NAA/creatine ratio in the MRS study of the brain of patients with mild HCV infection.
In contrast, one could not exclude the systemic effect of viral infection and drug treatment on the psychological and cognitive functions of these patients.
The cytolytic effect of HCV within the liver is responsible for the activation of the immune system. Evidence supports immune system-to-brain communication, with peripheral immune activation being associated with behavioral, affective, and cognitive disturbances. Peripheral proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are mostly the main mediators. They penetrate the blood-brain barrier directly through active transport mechanisms, especially in the prefrontal cortex and hippocampus, causing modulation of brain activity through stimulation of neurotransmitter systems. However, much of this evidence is derived from animal models  .
The prevalence of cognitive dysfunction in patients with chronic HCV was investigated by Hilsabeck et al.  . They found that the proportion of impaired performances ranged from 0% on a design copy task to 49% on a measure of sustained attention and concentration. The pattern of cognitive deficits was suggestive of frontal-subcortical dysfunction. Prevalence of cognitive impairment was found to range from 9% on a figure copy task to 38% on a measure of complex attention, visual scanning and tracking, and psychomotor speed. Severity of liver disease and fibrosis was associated with poorer cognitive functioning.
In our study, we found significant differences between patients and controls as regards the attention, concentration, and memory subscales (P < 0.05). Correlation of cognitive problems with liver functions was not applicable as we excluded those patients with severely impaired liver functions according to the scope of this work, to focus on cognitive functions in patients with mild (otherwise healthy) HCV infection. This exclusion of severely impaired liver function was to prove central nervous system affection even in clinically apparent stable cases.
Our findings coincide with the results of Lowry et al.  who studied neuropsychiatric function in a well-selected, homogeneous cohort of 20 female, iatrogenically infected patients. The authors showed that PCR-positive women had significantly poorer scores in the areas of memory, auditory recognition, and sustained attention compared with healthy controls.
The etiology of cognitive dysfunction exhibited by patients with HCV is unknown. Increasing evidence suggests that there may be a direct effect of the virus on brain functioning secondary to infection of monocytes, which are believed to replace microglial cells. Microglial cells are located predominantly in the cerebral white matter and are known to release excitatory amino acids that can induce neuronal cell death. Moreover, microglia can produce neurotoxins and other neurochemicals that can influence cognitive functioning  .
Indirect effects of HCV on brain functioning are also possible through the production of secondary cytokines (interferons and ILs). Cytokines may cross the blood-brain barrier and/or interact with the cerebral vascular endothelium and generate secondary messengers, which can affect cognitive functioning through multiple mechanisms that can influence arousal, initiation, working memory, psychomotor movements, and mood  .
Later in 2001, imaging studies tried to examine the specific role of HCV in causing cerebral function abnormalities. Forton et al.  detected cerebral metabolic abnormalities (elevated choline/creatine ratio) in the frontal white matter and basal ganglia of HCV-infected patients, using proton magnetic resonance spectroscopy ( 1 H MRS); these alterations were not present in either controls or patients with hepatitis B virus infection.
An important study by McAndrews et al.  examined cognitive functioning and MRS in patients with HCV. They confirmed the presence of attention deficits and impairment in verbal learning ability in their study of 37 HCV patients, in which 13% of patients with HCV infection showed impairment in verbal learning ability. They also detected an increase in choline and a reduction in NAA on MRS in the central white matter of patients compared with controls.
The similarities between the above results and those elicited in the current study point to the direct effect of HCV despite the source of infection (substance abuse vs. medical disease) and severity of liver involvement (severe vs. mild).
| Conclusion|| |
Research studies showed that about 50% of patients with HCV infection complain of neuropsychiatric symptoms that may affect their quality of life and cognitive functions. Their etiology may be related to the direct effect of HCV on the brain or neurotoxic effects of HCV-related systemic inflammation. Thus, treatment plans for HCV should consider neuropsychological complications.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, et al.
Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002; 35
Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011; 17
Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5
Strickland GT. Liver disease in Egypt: hepatitis C superseded schistosomiasis as a result of iatrogenic and biological factors. Hepatology 2006; 43
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy - definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35
Seeff LB, Hoofnagle JH. Appendix: The National Institutes of Health Consensus Development Conference Management of Hepatitis C 2002. Clin Liver Dis 2003; 7
Tillmann HL. Hepatitis C virus infection and the brain. Metab Brain Dis 2004; 19
Hilsabeck RC, Hassanein TI, Carlson MD, Ziegler EA, Perry W. Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. J Int Neuropsychol Soc 2003; 9
Mohamoud YA, Mumtaz GR, Riome S, Miller D, Abu-Raddad LJ. The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect Dis 2013; 13
First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV, Clinician Version (SCID-CV)
. Washington, DC: American Psychiatric Press Inc.; 1996.
Wechsler D. WMS-R: Wechsler Memory Scale-Revised
. San Antonio, TX: Psychological Corp; 1987.
Radkowski M, Wilkinson J, Nowicki M, Adair D, Vargas H, Ingui C, et al.
Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol 2002; 76
Palin K, Bluthé RM, McCusker RH, Moos F, Dantzer R, Kelley KW. TNFalpha-induced sickness behavior in mice with functional 55 kD TNF receptors is blocked by central IGF-I. J Neuroimmunol 2007; 187
Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 2002; 35
Lowry D, Coughlan B, McCarthy O, Crowe J. Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients. J Viral Hepat 2010; 17
Peterson PK, Hu S, Salak-Johnson J, Molitor TW, Chao CC. Differential production of and migratory response to beta chemokines by human microglia and astrocytes. J Infect Dis 1997; 175
Dunn AJ. Cytokine activation of the HPA axis. Ann N Y Acad Sci 2000; 917
McAndrews MP, Farcnik K, Carlen P, Damyanovich A, Mrkonjic M, Jones S, Heathcote EJ. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 2005; 41
[Table 1], [Table 2], [Table 3]