Postgrad Med J 2013;89:433-439 doi:10.1136/postgradmedj-2012-131185
Original article
Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function
+ Author Affiliations
- Correspondence to Dr Jefferson Abrantes, QRSW 07 Bloco A-12 Apto 303. CEP: 70675712. Sudoeste. Brasília, Distrito Federal, Brazil; jeffabrantes@uol.com.br
- Received 1 June 2012
- Revised 7 November 2012
- Accepted 3 April 2013
- Published Online First 26 April 2013
Purpose of the study
Hepatitis C virus (HCV) is associated with neuropsychiatric complaints. Previous studies have associated cognitive alterations with HCV infection but have often included confounding factors in their samples. This study compares the cognitive performance between patients with HCV infection (HCV patients) and a control group while excluding other factors that may cause cognitive impairment.
Hepatitis C virus (HCV) is associated with neuropsychiatric complaints. Previous studies have associated cognitive alterations with HCV infection but have often included confounding factors in their samples. This study compares the cognitive performance between patients with HCV infection (HCV patients) and a control group while excluding other factors that may cause cognitive impairment.
Study design
This cross-sectional study was conducted from March 2010 through June 2011. HCV infected patients and healthy individuals between the ages of 18 and 80 years were considered eligible. The exclusion criteria included well established causes of cognitive impairment such as depression and cirrhosis. Study participants underwent neuropsychological testing involving measures of attention, memory, abstraction, visuoconstructive abilities, and executive function.
This cross-sectional study was conducted from March 2010 through June 2011. HCV infected patients and healthy individuals between the ages of 18 and 80 years were considered eligible. The exclusion criteria included well established causes of cognitive impairment such as depression and cirrhosis. Study participants underwent neuropsychological testing involving measures of attention, memory, abstraction, visuoconstructive abilities, and executive function.
Results
Of 138 initial patients, 47 were excluded because of their medical records, three refused to participate, 23 did not attend the consultation, and 32 were excluded because of having Beck Depression Inventory (BDI) scores >11. In all, 33 patients underwent neuropsychological testing; however, three were excluded because of having hypothyroidism, and one was excluded because of having a cobalamin deficiency. For the control group, of the 33 healthy individuals that were selected, four were excluded because of having BDI scores >11. Thus, the final analysis included 29 HCV patients and 29 control participants. The groups did not differ in education, age, or gender. No statistically significant differences were found between the groups regarding cognitive performance.
Of 138 initial patients, 47 were excluded because of their medical records, three refused to participate, 23 did not attend the consultation, and 32 were excluded because of having Beck Depression Inventory (BDI) scores >11. In all, 33 patients underwent neuropsychological testing; however, three were excluded because of having hypothyroidism, and one was excluded because of having a cobalamin deficiency. For the control group, of the 33 healthy individuals that were selected, four were excluded because of having BDI scores >11. Thus, the final analysis included 29 HCV patients and 29 control participants. The groups did not differ in education, age, or gender. No statistically significant differences were found between the groups regarding cognitive performance.
Conclusions
In this study using strict selection criteria, there was no evidence of an association between HCV infection and cognitive impairment.
In this study using strict selection criteria, there was no evidence of an association between HCV infection and cognitive impairment.
Hepatitis C is caused by the hepatitis C virus (HCV), an RNA virus of the genus Hepacivirus and family Flaviviridae. Studies indicate that approximately 60–85% of people exposed to HCV develop chronic infection.1 Globally, the number of people infected with HCV is estimated to be between 130–170 million, and HCV infection is five times
more prevalent than human immunodeficiency virus (HIV) infection.1 Since the 1989 publication detailing the discovery of HCV, various diseases with different physiopathological and epidemiological
bases have been associated, most anecdotally, with chronic HCV infection.2 ,3 It is estimated that 40–74% of patients infected with HCV will experience at least one extrahepatic manifestation within
their lifetime.4
Cognitive changes have been well documented in patients with chronic hepatopathy, most often as a result of hepatic encephalopathy
related to uncompensated liver cirrhosis.5 However, a growing body of evidence has demonstrated that cognitive changes may also occur before the development of liver
cirrhosis.6 Neuropsychiatric symptoms such as ‘brain fog’, fatigue, and weakness occur in approximately 50% of patients with HCV, independently
of the severity of the hepatic involvement. These complaints do not seem to be related to HCV genotype or replication.7
Forton et al reported the first evidence of brain metabolic changes in patients with HCV, distinct from the alterations found in hepatic
encephalopathy.8 The occurrence of cognitive deficits in this group of patients may be due to the direct action of the virus in the central
nervous system (CNS) or indirectly through production of cytokines.7
Several studies have suggested that a relationship may exist between HCV and cognitive dysfunction. However, these studies
frequently included patients with well established causes of cognitive impairment, such as the use of illicit drugs, interferon,
depression, and cirrhosis.7
Given the lack of controls for these potential confounding variables in previous studies, broad and rigorous exclusion criteria
were employed in this study to avoid the inclusion of individuals with known risk factors for cognitive impairment. The objective
of the current study was to compare the cognitive performance in HCV patients and a control group of healthy individuals,
while excluding any participants with conditions that might interfere with cognitive performance.
Methods
Study design
Methods
Study design
The current study was an observational, cross-sectional study with paired controls.
Inclusion criteria
This study was conducted at the Gaffrée e Guinle University Hospital (HUGG) of Rio de Janeiro, Brazil, from March 2010 through
June 2011. The hospital's gastroenterology service reviews about 4800 patients with hepatitis C annually. All HCV infected
patients (with detectable serum HCV RNA) who were being tracked in the hepatology outpatient clinic between the ages of 18
and 80 years were considered eligible. The control group was composed of individuals accompanying the outpatients and inpatients
at the HUGG who were between 18 and 80 years old.
Exclusion criteria
Many factors can provoke cognitive changes.9 Therefore, in an effort to avoid confounding factors, the following exclusion criteria were established: education of less
than 4 years; history of encephalic vascular accident, encephalic cranial trauma, dementia, Parkinson's disease, multiple
sclerosis, neurodegenerative disease, chronic obstructive pulmonary disease, congestive cardiac insufficiency, other viral
infections (HIV, hepatitis B virus (HBV), human T lymphotropic virus (HTLV)), syphilis, significantly compromised liver function,
depression, psychiatric illness, illicit drug use, psychotropic drug use, alcoholism, hypothyroidism, cobalamin or folic acid
deficiency; and previous or current use of interferon.
Neuropsychological assessment
The cognitive evaluation was performed in a soundproof room under adequate lighting conditions. Two neurologists trained in
the administration of neuropsychological tests, who had knowledge of the blood status of the individuals, conducted the cognitive
assessment. Study participants were asked about the use of illicit drugs, alcoholic beverages and psychoactive substances
48 h before neuropsychological testing.
The patients underwent neuropsychological testing by answering questions regarding predefined cognitive complaints (poor memory,
dispersal/distractibility, difficulty in performing two tasks simultaneously, and difficulty driving) and were given additional
space for spontaneous complaints. The following tests were used.
Mini-Mental State Exam
This test is widely used as a brief screening instrument for cognitive impairment. The cognitive functions assessed in this
test are attention, calculation, language, praxis, orientation, memory, and attention span.10 The Mini-Mental State Exam was applied according to the adaptations and recommendations of the Brazilian Academy of Neurology.11
Simple Drawing Test
This test assesses visual identification and incidental, immediate, and delayed visual memory. The test sheet comprises 10
drawings. The score indicates the number of correct responses at each step of the test.12
Rey Auditory Verbal Learning Test
This test assesses immediate and delayed verbal memory and evaluates the patient's ability to learn. The Portuguese translated
and adapted version of the Rey Auditory Verbal Learning Test (RAVLT) was used.13 RAVLT scores include the sum of the number of words remembered after five repetitions of a list A (A1–A5) and measures of
retroactive interference (A6/A5), proactive interference (B1/A1), forgetfulness (A7/A6), and recognition
Reverse Numerical Order Test
This test is a component of the Wechsler Intelligence Scale for Adults-III (WAIS-III), which is used to investigate working
memory. The score indicates the number of numerical sequences that the patient correctly repeats in reverse order.10
Direct Numerical Order Test
The number of digits repeated (in forward order) on the WAIS-III provides an easily administered objective measure of the
ability to maintain auditory attention for a brief period.14
Trail-Making Test
The Trail-Making Test (parts A and B) represents one of the most widely used tests for assessing divided attention. The score
is based on the time taken to execute specific tasks. If this time exceeds 5 min, the test is discontinued.10 The ratio between the execution times of part B and part A provides an assessment of non-verbal executive function.15
‘A’ Random Letters Test
This test assesses sustained attention and consists of a series of random letters among which a target letter appears with
greater-than-random frequency. The score is the sum of the number of errors.14
Stroop Test
Stroop Test
The Stroop Test, as modified by Dodrill, is considered one of the best tests of selective attention.10 This test evaluates the performance of the individual (ie, time required to complete each of the two parts of the test) and
the difference between these times. The test is stopped if the time required to complete either task exceeds 5 min.10 ,16
Boston Naming Test
This test was used in the Brazilian version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD). In
this test, 15 designs are presented to the individual. One point is given for each correct answer, yielding a maximum score
of 15 points.10 ,17
Verbal Fluency Test
The Verbal Fluency Test of a semantic category (animals) was used to assess verbal executive function. The score is the number
of items spoken (excluding repetitions) in 1 min.12
Clock Drawing Test
Clock Drawing Test
In addition to evaluating non-verbal executive function, this test covers many other cognitive domains, including verbal comprehension,
attention, and constructive abilities. The method chosen was that described by Shulman.18
Copies of Geometric Shapes (CERAD)
This test is used to assess visuoconstructive skills.17 The criteria chosen for correction and punctuation have been published by Rosen et al.19
Symbol Search Test
The Symbol Search Test is a component of the WAIS-III that is used to investigate processing and learning speed. The test
is stopped upon reaching 120 s.20
Similarities Test
Similarities Test
The Similarities Test of the WAIS-III is used to evaluate conceptualisation and abstraction. The individual is asked to identify
the characteristic that is shared by two objects or concepts. The test is discontinued after four consecutive errors.20
Depression screening
The Portuguese language adapted version of the Beck Depression Inventory (BDI) was used to screen for depression. The BDI
has been used in many clinical trials involving patients with HCV.21–23
Holtzheimer et al23 reported that the BDI has a diagnostic sensitivity of 91% for depression using the traditional cut-off point >10 in a population
of drug users with HCV. Analysis of the receiver operating characteristic (ROC) curve showed that a cut-off of 11 has a sensitivity
of 91% and a negative predictive value of 92%. Low specificity (63%) and low positive predictive (59%) value are among the
limitations of using the BDI.
In the Brazilian version of the BDI, scores between 0 and 11 are indicative of the absence of depression.21 Therefore, to avoid the inclusion of patients with depression in the study (which could result in a type I error), a BDI
cut-off point of 11 was used.
Assessment of hepatic involvement
Biopsies performed in the 12 months before the study were considered valid for the evaluation of the degree of hepatic impairment.
The aspartate aminotransferase/platelet ratio (APRI) was calculated for all patients. An APRI ≥1.5 indicates the presence
of significant fibrosis, whereas levels ≤0.5 indicate the absence of significant fibrosis. Using a cut-off of ≤1.0 allowed
us to exclude the presence of cirrhosis with a sensitivity of 89% and a specificity of 75%.24 The presence of advanced fibrosis or cirrhosis in a liver biopsy sample (F3 or F4 in the METAVIR classification system, respectively)
or an APRI >1 defined a significantly compromised liver.
Blood tests
Blood tests were performed on all patients after the cognitive analysis. Serum sodium, thyroid stimulating hormone (TSH),
free thyroxine (T4), cobalamin, folic acid, VDRL (Venereal Disease Research Laboratory, syphilis), HIV, HBV, and HTLVI/II
tests were analysed.
Data analysis
The Kolmorov–Smirnov test was used to analyse the hypothesis of normality of the sample. Inter-group comparisons were made
with the Student t test or the Mann–Whitney test according to the distribution of variables.
Inter-group differences in reporting cognitive complaints and difference in gender were assessed by Fisher’s exact test.
All tests were two-tailed and statistical significance was set at p<0.05. Data were recorded and analysed using SPSS V.15
for Windows.
Ethical aspects
The research ethics committee of the HUGG approved the study, which adhered to the guidelines of the Helsinki declaration.
Study participants completed a free and informed consent form after receiving a detailed explanation of the study.
Results
A total of 138 patients met the initial eligibility criteria, and 47 patients were excluded because their medical records contained one or more of the previously determined exclusion criteria (figure 1).
Demographic data
Table 2
Neuropsychological comparison of the HCV and control groups
Study sample
A total of 138 patients met the initial eligibility criteria, and 47 patients were excluded because their medical records contained one or more of the previously determined exclusion criteria (figure 1).
Figure 1
Patients excluded after medical analysis. HBV, hepatitis B virus; HIV, human immunodeficiency virus; HTLV, human T lymphotropic
virus. Access the article online to view this figure in colour.
Consultations to apply the BDI were scheduled for the 91 remaining patients. Of these, 23 patients did not attend the consultation,
three patients withdrew from participation in the study, and 32 patients received a score >11 on the BDI. The 33 remaining
patients underwent neuropsychological testing and blood sample collection. Three patients were excluded because of hypothyroidism,
and one patient was excluded because of vitamin B12 deficiency (figure 2).
Figure 2
Flow diagram of the selection of patients in the hepatitis C virus group. BDI, Beck Depression Inventory. Access the article
online to view this figure in colour.
Thirty-four healthy individuals were chosen for the control group, of whom five were excluded due to BDI scores >11. The control
group was assessed following the same criteria of exclusion for the HCV group; however, these individuals were not subjected
to serological tests.
Demographic data
There were no statistically significant differences in sex, age, or education level between the HCV and control groups (table 1). There were no statistically significant differences in the reporting of cognitive complaints between the HCV and control
groups. Interestingly, 5/29 (17.2%) patients in the HCV group spontaneously reported complaints of fatigue, while none in
the control group reported fatigue (table 2).
Table 1
Descriptive statistics for age, education level, and gender
| Group | |||
|---|---|---|---|
| Control (n=29) | HCV (n=29) | p Value | |
| Age (years) | |||
| Mean (±SD) | 52.45 (±12.97) | 54.10 (±12.23) | Student t test 0.62 |
| Educational level (years) | |||
| Mean (±SD) | 9.8 (±4.0) | 9.7 (±3.3) | Mann–Whitney test 0.83 |
| Gender | n (%) | n (%) | |
| Male | 14 (48.3%) | 11 (37.9%) | Fisher's exact test 0.596 |
| Female | 15 (51.7%) | 18 (62.1%) | |
Table 2
Cognitive complaints of patients in the HCV and control groups
| Group | |||||
|---|---|---|---|---|---|
| Control (n=29) | HCV (n=29) | p Value | |||
| Complaints | n | % | n | % | Fisher's exact test |
| Poor memory | 13 | 44.8 | 13 | 44.8 | 1.000 |
| Dispersal/distractibility | 9 | 31.0 | 7 | 24.1 | 0.769 |
| Difficulties in performing 2 tasks | 2 | 6.9 | 3 | 10.3 | 1.000 |
- No participants in either group complained of having difficulty driving.
- Regarding other complaints, 5 individuals (17.2%) in the HCV group reported experiencing fatigue.
- HCV, hepatitis C virus.
Genotype 1 was responsible for 22/29 (78.6%) of the infections in the HCV group. A total of 17/29 (58.6%) individuals in the
HCV group had liver biopsies performed in the last 12 months. Of these, 5/17 (29%) were classified as F0, 10/17 (58%) as F1,
and 2/17 (11%) as F2, based on METAVIR scores. The mean and median APRIs in the HCV group were 0.41 and 0.38, respectively.
The source of HCV infection was blood transfusion in 18/29 (62%), an unknown source in 10/29 (34%), and a biological material
accident in 1/29 (4%) of the patients with HCV.
The 23 patients who did not attend the neuropsychological testing exhibited the following characteristics: (1) a mean of 9.2
(±3.2) years of schooling; (2) a mean age of 54.3 (±12.1) years; (3) 12/23 (52.1%) were male and 11/23 (47.9%) were female.
Neuropsychological comparison of the HCV and control groups
Statistical analyses revealed no significant differences between the groups in any of the neuropsychological tests applied
(table 3).
CNS involvement is observed in many viral infections, and HIV infection is currently one of the most studied. Moreover, the
HCV family (Flaviviridae) includes several viruses with known neurotropic effects, such as the West Nile virus, Saint Louis
encephalitis virus, Murray Valley virus, and Japanese encephalitis virus.25 Several hypotheses have been proposed to explain the occurrence of cognitive impairment in HCV infections:
HCV.26
In this study there was no apparent relationship between HCV in patients without liver dysfunction, and cognitive impairment. Further studies with greater numbers of participants followed up prospectively over at least 12 months, with careful consideration for potential confounders including depression in the outcome variable analysis, are required to answer the question of a causal association between HCV and cognitive impairment in patients without liver dysfunction.
-
The direct action of the virus in the CNS, through a ‘Trojan horse’ effect: The infection of the CNS begins with HCV virus replication in peripheral blood mononuclear cells in the bone marrow, which subsequently serves as precursors of macrophages and microglial cells of the CNS.7 The production of tumour necrosis factor α (TNFα) and interleukin 8 (IL8) in macrophages/microglia infected with HCV may be responsible for cognitive impairment. However, data about the association between the virus in the brain and impaired cognitive function are still lacking.7
-
The direct action of the virus in the CNS through viral replication in neurons: Several factors suggest that this is not the case; for example, viral replication is very low within the brain, and HCV RNA is almost undetectable in the cerebrospinal fluid. Moreover, there is no correlation between viral load and cognitive impairment in patients with HCV infection.7
-
A side effect of the inflammatory process: The cytolytic effects of HCV within the liver activate the immune system. The chronic activation of the inflammatory system results in the production of cytokines, such as IL6, IL4, and TNFα, which are then responsible for the neuronal changes that can result in cognitive impairment.7
This study, which was developed with strict selection criteria, indicated no differences in performance on cognitive tests
between patients with HCV and the control group. The groups were similar in gender, age, and education, which are known to
influence cognitive testing.
The control group presented higher rates of memory problems (45%) as shown in table 2, which can raise questions about the health state of this group. However, when comparing the means obtained from both groups
with the cut-off values suggested on national studies, it was observed that the performance of this group is within the normal
range (table 4).11–13
Table 4
Mean obtained in cognitive testing in the study participants and cut-offs in national studies
| Cognitive tests | Control group Mean | HCV group Mean | Cut-off in national studies |
|---|---|---|---|
| MMSE | 28 | 27.4 | 25 |
| Direct order | 7.96 | 7.93 | >4 |
| Reverse order | 4.31 | 4.58 | >2 |
| Verbal Fluence Test | 19.13 | 18.55 | >12 |
| Simple Drawing Test | |||
| Incidental memory | 5.86 | 6.34 | >4 |
| Immediate memory | 8.65 | 8.75 | >6 |
| Later memory | 8.89 | 9.10 | >4 |
| Rey Auditory Verbal Learning Test | |||
| Sum of A1-A5 | 41.86 | 41.34 | >29.6 |
| Retroactive interference (A6/A5) | 0.83 | 0.79 | >0.61 |
| Proactive interference (B1/A1) | 0.95 | 1.04 | >0.48 |
| Forgetting (A7/A6) | 0.98 | 1.01 | >0.73 |
| Recognition | 11.58 | 11.27 | >9.42 |
| Trail-Making Test part A | 46.34 | 53.65 | <120 |
- HCV, hepatitis C virus; MMSE, Mini-Mental State Exam.
Other cognitive tests used in this study were not applied previously in Brazilian studies and therefore not included.
HCV patients with advanced stages of fibrosis or cirrhosis were excluded because these patients have a high frequency of cognitive
impairment. In addition to the hepatic encephalopathy that may occur in patients with significant liver impairment, some patients
may have minimal hepatic encephalopathy that is detectable only through neuropsychological testing. The prevalence of minimal
hepatic encephalopathy in cirrhotic patients is estimated to be between 30–80%. These patients exhibit cognitive changes that
involve executive function, attention span, working memory, and visuoconstructive abilities—symptoms that are frequently reported
in patients infected with
HCV.26
Because of the high prevalence of depression in patients suffering from HCV, a major concern was avoiding the inclusion of
depressed participants in this study. Although there is a debate about cognitive impairment in patients with depression, two
recent meta-analyses support the presence of cognitive impairment in patients with major depression. These studies demonstrate
that executive function and the prefrontral cortex are affected by depression, which may impact cognitive performance.27 ,28
A recent study demonstrated the presence of cognitive changes involving working memory and verbal fluency in patients minor
depression.29 Various studies have reported cognitive changes in HCV infected patients that include deficits in attention, psychomotor
speed, working memory, and executive function; this pattern of frontal–subcortical cognitive dysfunction is similar to that
found in patients infected with HIV. However, the inclusion of depressed patients in these studies may invalidate the assumption
of an association between HCV and cognitive deficit.
Conversely, the high rates of depression reported in patients with HCV may be a neuropsychiatric manifestation resulting from
the direct or indirect action of the virus in the CNS. Therefore, the exclusion of these patients may have resulted in selection
bias toward patients with fewer cognitive manifestations of HCV infection.
Other factors that may affect cognitive performance in some studies of HCV patients is the inclusion of patients with a history
of alcohol and/or illegal drug abuse, and the inclusion of patients using psychotropic drugs or interferon. Lack of rigorous
selection criteria in previous studies may have resulted in an overestimation of the prevalence of cognitive impairment associated
with HCV.
This study has the following limitations: (1) it was not a longitudinal study, which limits the authors’ hypothesis that the
association may not exist; (2) the number of study participants was small, thus limiting the statistical power of the study;
(3) the control group was composed of persons accompanying the patients—these individuals may experience anxiety disorder
due to the health conditions of those patients, resulting in a negative impact on cognitive performance; (4) the control group
did not undergo blood testing—thus, one cannot exclude the presence of comorbidities such as subclinical hypothyroidism that
can alter the performance in cognitive assessment; (6) the examiners were not blinded to the serological status of the participants,
which may influence the outcome of testing; (7) self-reporting is not the most reliable way of ensuring participants did not
use illicit drugs or alcoholic beverages—the inclusion of these individuals may have had an impact on the neuropsychological
tests; (8) the use of the BDI as a screening tool for depression may have resulted in the exclusion of individuals without
depression, due to its low specificity.
In this study there was no apparent relationship between HCV in patients without liver dysfunction, and cognitive impairment. Further studies with greater numbers of participants followed up prospectively over at least 12 months, with careful consideration for potential confounders including depression in the outcome variable analysis, are required to answer the question of a causal association between HCV and cognitive impairment in patients without liver dysfunction.
Main message
In this study there is no evidence of cognitive dysfunction in hepatitis C virus carriers without comorbidities.
Current research questions
Prospective studies with large numbers of participants, with careful consideration for potential confounders, are necessary to establish the relationship between HCV infection and cognitive impairment.
Acknowledgments
In this study there is no evidence of cognitive dysfunction in hepatitis C virus carriers without comorbidities.
Current research questions
Prospective studies with large numbers of participants, with careful consideration for potential confounders, are necessary to establish the relationship between HCV infection and cognitive impairment.
Acknowledgments
We thank Carl B Dodrill, Emeritus Professor in the Department of Neurology at the University of Washington Medical School,
for his kind permission to translate the Stroop test into Portuguese.
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Funding The Gaffrée e Guinle University Hospital, part of the Federal University of the State of Rio de Janeiro, Brazil, paid for the laboratory tests. This is a publically financed hospital.
-
Competing interests None.
-
Patient consent Obtained.
-
Ethics approval The research ethics committee of the Gaffrée e Guinle University Hospital approved the study according to the guidelines of the Helsinki Declaration. Study participants completed a free and informed consent form after receiving a detailed explanation of the study.
-
Provenance and peer review Not commissioned; externally peer reviewed.
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