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July2014 Vol.51 Issue:      3 (Supp.) Table of Contents
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Neuropsychiatric Disorders and Magnetic Resonance Spectroscopy in Chronic Hepatitis C Patients

Horeya M. Saad Allah1, Soha A. Ibrahim2, Amany S. Elyamany3, Mohamed E. Reda4

Departments of Neurology1, Psychiatry2, Internal Medicine3, Radiodiagnosis4, Alexandria University; Egypt



ABSTRACT

Background: Hepatitis C Virus (HCV) is widely prevalent in Egypt. There is an evidence of neurocognitive dysfunction even in the absence of advanced liver disease in patients with chronic HCV infection. The patients are more likely to manifest impairments in the quality of life, fatigue, and depression than patients with liver disease of other etiology. Objective: The work aimed to study the impact of HCV infection on cerebral functions using cerebral Magnetic-Resonance Spectroscopy (MRS). Patients and Methods: The study included two groups; A patients’ group composed of 20 chronic, drug-naïve HCV patients and a control group composed of 20 healthy subjects. MRS and Psychometric assessment were done including Mini-Mental State Examination (MMSE), Fatigue Severity Scale (FSS) and 17-Item Hamilton Depression Rating Scale (HDRS). Results: Chronic HCV patients scored worse on both FSS and 17- Item HDRS than Controls, and showed an altered spectroscopic metabolic ratio along white matter at the level of the centrum semiovale bilaterally. The choline/creatine, ratios and N-acetyl aspartate/creatine ratios were significantly higher in the white matter of the patients compared to healthy volunteers. There was a positive correlation between abnormal spectroscopic findings and the severity of fatigue and depression. Conclusion: The altered cerebral metabolism in patients with chronic hepatitis C infection (with preserved liver functions) suggested that HCV may exert a direct effect on brain function. [Egypt J Neurol Psychiat Neurosurg.  2014; 51(3): 345-350]

Key words: Cerebral Magnetic Resonance Spectroscopy, neuropsychiatric disturbances in chronic hepatitis C viral infection, MMSE, FSS, 17-items HDRS

Correspondence to Soha A. Ibrahim, Neuropsychiatry Department, Al Hadra University Hospital, Alexandria, Egypt. Email:sohaghobashy@hotmail.com






INTRODUCTION

 

The population of Egypt has a heavy burden of liver disease, mostly due to chronic infection with hepatitis C virus (HCV). Overall prevalence of antibody to HCV in the general population is around 15-20%.1 although evolution to chronic HCV infection is extremely common, only 30% of chronically infected patients progress to end-stage liver disease. 2

The occurrence of hepatic encephalopathy is well documented in patients with viral cirrhosis, as in patients with cirrhosis of other etiologies.2 Recently, there has been growing evidence that alterations in cerebral function in patients with chronic HCV infection may appear long before the development of severe liver fibrosis/cirrhosis. These alterations cannot be ascribed to hepatic encephalopathy. About 50% of patients with HCV infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease.3 These alterations do not seem to relate to HCV genotype or replication.4

Their 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.

Aim of work: To study the direct impact of HCV infection on cerebral functions by evaluating cerebral choline/creatine, N-acetyl aspartate/creatine, and N-acetyl aspartate/choline ratios using Magnetic-Resonance Spectroscopy (MRS).

 

PATIENTS AND METHODS

 

The study included two groups; a patients’ group composed of 20 chronic, drug-naïve HCV patients and a control group composed of 20 healthy subjects. They were recruited from Hepato-biliary unit and referred to Neuropsychiatric Department, Faculty of Medicine, Alexandria University, for evaluation. Informed consent was signed and dated by each subject prior to participation and the approval by Human Ethics Committee was obtained.

Exclusion criteria included patients with cirrhosis, other causes of chronic liver disease, hepatocellular carcinoma, marked elevation of transaminases, prior or active antiviral therapy, co-infection with hepatitis B virus or human immunodeficiency virus (HIV), patients with previous alcohol consumption, drug addiction, psychiatric disease and patients on psychoactive drugs, patients with cryoglobulinemia, organ transplantation, renal failure or insulin-dependent diabetes.

All patients underwent a clinical assessment, detailed neuropsychological examination, liver profile tests; serum albumin, serum bilirubin, serum aspartate and alanine aminotransferase (AST, ALT), prothrombin activity, HCV RNA levels in serum using real time polymerase chain reaction (PCR) assay5, and abdominal ultrasonography.

Core liver biopsies were obtained from all patients and assessment of necroinflammatory grade and fibrosis stage according to Ishak fibrosis score.6 Significant fibrosis was defined as Ishak score of 3 or more (presence of bridging fibrosis) and cirrhosis as Ishak score of 5 or 6.

Psychometric assessment using Mini-Mental State (MMSE) examination for global assessment of cognitive functions, 17-item Hamilton Depression Scale (HDRS) to rate the severity of a patients’ major depression, Fatigue Severity Scale (FSS) to explore fatigue symptoms and to evaluate the impact of fatigue on a person’s life. People with depression have a score above 7, people with fatigue have a score of above 6.5.7,8

All subjects underwent cerebral MRI and 1HMRS studies on a 1.5-tesla (Avento-Siemens, Germany using TE=135 msec.). The spectroscopic volume of interest (VOL) of 35×25×20 mm was positioned in the posterior cingulate gyrus, centrum semiovale and frontal lobe. This attempt was to determine the N-acetyl aspartate-to-creatine ratios (NAA/Cr ratio), Choline/Creatine ratios (Cho/Cr ratio), and N-acetyl aspartate-to-Choline ratio (NAA/Cho ratio).

 

Statistical Analysis

Statistical analysis was done using statistical package for social science (SPSS/version 17) software. Simple descriptive statistical tests as arithmetic mean, standard deviation, number and percent for each category were used. Person correlation coefficient was done to determine the level of association between two parameters. The metabolite differences between chronic HCV patients and healthy controls were tested using a two-tailed t-test. P-value <0.05 was considered statistically significant.

 

RESULTS

 

The patients’ group had a mean age of 40.47±7.49 years compared to the control  group who had a mean age 37.8±7.44 years with no statistical significant difference. In addition, there were 11(55%) males and 8(45%) females in the patients group compared to 12(60%) males and 8(40%) females in the control group with no statistical significant difference. No clinical abnormalities were observed in all subjects as regard medical and neurological examination. All patients had normal liver profile except for mildly elevated liver transaminases. HCV RNA by PCR ranged between 49.2-3672844.0 IU/mL, abdominal ultrasound revealed homogeneous echo-pattern of the liver with no focal hepatic lesions. Liver biopsies showed that necroinflammatory changes classified into stages of fibrosis without cirrhosis.

In chronic HCV patients, MMSE scores ranged between 23 and 30 (mean 27.67±1.50) compared to 28-30 (mean 29.6±0.70) in controls with no significant difference observed. Fatigue Severity Scale (FSS) showed significantly higher results in chronic HCV patients (mean 5.40±0.74) than controls (mean 3.05±1.09). FSS scores were not correlated with the level of HCV viremia. Seventeen-items HDS scores had a mean value of 27.67±0.74 in the patients’ group which was significantly higher than controls (mean 3.4±2.46) (p <0.001). In addition, it showed no correlation with the level of viremia (r =0.37 and p=0.17). FSS scores were significantly correlated with scores of 17-item HDS (r =0.76 and p =0.001).

No evidence of cerebral vasculitis or white-matter abnormalities was detected in MR images of both patients and controls. The MR Spectroscopic findings are summarized in Table (1). There were altered spectroscopic metabolic ratios along the centrum semiovale bilaterally in patients with chronic HCV.

Choline/Creatine ratios were significantly higher in the white matter of chronic HCV group with a mean of 1.42±0.29 on the right side and 1.41±0.24 on the left side compared to controls who showed a mean of 0.79±0.26 on the right and 0.70±0.25 on the left (p=0.001 and 0.001 respectively). The NAA/Cho ratios were significantly decreased in centrum semiovale bilaterally in chronic HCV patients (mean 1.53±0.37 on the right side and 1.55±0.37 on the left side) compared to controls who had a mean of 2.24±0.42 on the right and 2.31±0.46 on the left (p=0.001 and 0.001 respectively). The NAA/Cr ratios were significantly higher in the white matter of the chronic HCV patients with mean 2.49±0.53 on the right side and 2.43±0.53 on the left side compared to healthy volunteers in whom the mean value was 1.75±0.24 on the right and 1.74±0.27 on the left (p=0.001 and 0.001 respectively). Some findings are shown in Figures (1) and (2).

The correlation between altered spectroscopic metabolic ratios and other variables are summarized in Table (2). No correlation existed between the changes in cerebral metabolite ratios and the level of viremia or the hepatic histopathological changes. The score of FSS was significantly correlated with the Cho/Cr ratio on the left side and NAA/Cr ratio bilaterally. MMSE scores were significantly correlated with Ch/Cr and NAA/Cr ratios bilaterally. The 17-item HDS was significantly correlated with the NAA/Cr ratios bilaterally.

 

 


 

 

Figure 1.               Decreased NAA/Cho ratio on the right and left sides of centrum semiovale (white matter)

of a 32-years female patient with chronic HCV infection complaining of fatigue.

 

 

 

Figure 2. Altered spectroscopic findings along the centrum semiovale in

a 43-years male patient complaining of fatigue and depression.

 

Table 1. Comparison between Chronic hepatitis C patient and control as regard metabolites ratio in cerebral magnetic resonance spectroscopy.

 

 

Chronic HCV Patients

Control

P-value

Right NAA/Cr ratio

2.01-4 (2.49±0.53)

1.31-2.01(1.746±0.24)

0.001*

Left NAA/Cr ratio

1.99-4 (2.43±0.53)

1.29-2.05 (1.742±0.27)

0.001*

Right Cho/Cr ratio

1.1-1.9 (1.42±0.29)

0.23-1.06 (0.798±0.26)

0.001*

Left Cho/Cr ratio

1.09-1.79 (1.41±0.24)

0.34-1.02 (0.707±0.25)

0.001*

Right NAA/Cho ratio

1-2.3 (1.53±0.37)

1.89-3.16 (2.239±0.42)

0.001*

Left NAA/Cho ratio

0.9-2.3 (1.55±0.37)

1.89-3.16 (2.307±0.46)

0.001*

 Cho/Cr ratio Choline/Creatine ratios, HCV Hepatitis C Virus, NAA/Cho ratio N-acetyl aspartate-to-Choine ratio, NAA/Cr ratio N-acetyl aspartate-to-creatine ratios

*Significant at P<0.01

 

Table 2. Correlation between cerebral metabolite ratios and other variable.

 

 

Right NAA/Cr ratio

Left NAA/ Cr ratio

Right Cho/Cr ratio

Left Cho/Cr ratio

FSS

R

0.664(*)

0.681(*)

0.478

0.523(*)

P

0.007

0.005

0.071

0.046

MMS

R

-0.797(*)

-0.731(*)

-0.847(*)

-0.833(*)

P

0.000

0.002

0.000

0.000

HDRS

R

0.601(*)

0.646(*)

0.246

0.328

P

0.018

0.009

0.376

0.233

HCV/PCR

R

-0.218

-0.201

-0.130

-0.188

P

0.435

0.474

0.644

0.502

Grade of inflammation

R

-0.001

-0.045

0.143

0.154

P

0.996

0.874

0.612

0.584

Stage of fibrosis

R

-0.245

-0.290

0.016

-0.049

P

0.379

0.295

0.956

0.862

FSS Fatigue Severity Scale, MMS: Mini-Mental State, HDRS: 17-item Hamilton Depression Scale, HCV: Hepatitis C Virus, PCR: Polymerase Chain Reaction.

*Significant at P<0.05 **Significant at P<0.01

 


DISCUSSION

 

Infection with HCV is a major public health problem worldwide. Besides the late clinical sequelae of chronic liver disease, patients with HCV infection were reported to manifest neuropsychiatric impairments more than patients with liver disease of other etiology. 9-12   However, there is no clarification about the etiology behind these impairments.

We investigated whether the degree of fatigue and depression in patients with chronic HCV correlated with the histopathological changes. Firstly, we used the FSS to assess the severity of fatigue. A higher FSS scores were found in chronic HCV patients than in healthy controls. However, there was no correlation between the severity of fatigue and the viral load, no correlation of the FSS score with the histopathological changes. Secondly, depression were assessed with the mean score of 17-item HDRS, which was significantly higher in patients than controls. The severity of depressive symptoms did not correlate with the degree of histopathological changes.

In agreement with our study, Fontana and colleagues13 observed no relationship between neuropsychiatric manifestations as cognitive alterations and the degree of fibrosis or mood disturbances in patients with HCV.13Also, numerous studies have reported associations between chronic HCV infection and fatigue, depression and impairments in health-related quality of life, which are independent of the severity of liver disease.4,14 There has been recent interest in the possibility of a biological effect of HCV infection on cerebral function which maybe through direct infection of brain cell or indirectly via the systemic inflammatory process.15-19

In our work, the severity of fatigue was significantly correlated with the increase in Cho/Cr on left side and increased NAA/Cr ratios bilaterally. Moreover, there was a positive correlation between the severity of depression and increase in NAA/Cr ratio bilaterally and elevations in white matter Cho/Cr ratios and NAA/Cr ratios and decrease in NAA/Cho ratios in patients compared to controls, in the absence of hepatic cirrhosis. Spectroscopic studies of hepatic encephalopathy show globally reduced Cho/Cr ratios.20   Thus, proving a definite biological pathology going on in the brain of our patients regardless of their degree of infection or hepatic affection.

Forton and colleagues, in two studies7,21, reported frontal-subcortical dysfunction in patients with mild chronic HCV infection using 1HMRS. They demonstrated elevations of Cho/Cr ratios in basal ganglia and white matter in patients with mild hepatitis C disease compared to control and patients with chronic hepatitis B infection. Increased choline and reduced NAA levels among HCV-positive patients relative to those of controls has been also reported.22,23

In the present study, none of the chronic HCV patients had overt cognitive dysfunction as indicated by normal scores in the Mini-Mental State examination (range 25-30, mean 27.67 ±1.50). However, the MMSE scores were significantly related to NAA/Cr ratio. Weissenborn and colleagues24 used 1HMRS to study 30 HCV-infected patients with normal liver function who underwent cognitive testing. They found decreased NAA/Cr in the cerebral gray matter compared to healthy controls, which can be attributed to either decreased NAA or increased Cr.  The NAA is a neuronal marker and Cr is a component of high-energy phosphate metabolism. Their finding was significantly related to cognitive dysfunctions among their patients. Our negative finding of cognitive dysfunctions maybe attributed to different patients’ selection and cognitive testing. 

Studies have showed significant alterations in cerebral Cho and NAA in HCV infected patients without cirrhosis.9-11,25 The findings of elevated Cho and reduced NAA mirror those reported in HIV infection4, a virus which is tropic to the CNS. Detection of replicative intermediates of HCV (negative strand RNA) within the CNS14, and different viral variants in the CNS, liver, and serum support the concept of low level HCV replication within the brain.16 Although the mild neurocognitive impairments seen in HCV infection are not progressive as in AIDS dementia, it has been suggested that they may result from cerebral immune activation, possibly as a result of CNS infection by HCV.10

Infection of cerebral microglia by HIV, possibly via infected monocytes, and subsequent microglial activation are thought to underlie the MRS changes. There is good evidence to suggest that HCV infects cells of monocytic lineage, raising the possibility that HCV too may infect the brain. An alternative explanation for these findings is a centrally mediated effect of peripherally derived cytokines, either via their transfer across the blood-brain barrier or through an interaction with the cerebral vascular endothelium and the generation of secondary messengers.21

 

Conclusion

Depression and fatigue are associated with biological changes in the CNS among patients with HCV independent of hepatic affection. This suggests a pathophysiological mechanism other than encephalopathy like direct HCV infection to brain cells or secondary systemic affection. Future large-scale studies should employ longitudinal methods to better characterize metabolic changes associated with HCV infection and determine whether elevations in choline precede significant decreases in NAA and nail down the HCV pathophysiological processes in the CNS. Understanding the attendant changes in cerebral metabolism could pave the way for better understanding of how HCV treatments alter the course of neurological functioning.

 

[Disclosure: Authors report no conflict of interest]

 

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الملخص العربى

 

الاضطرابات العصبية والنفسية والرنين المغناطيسي الطيفي في مرضى الالتهاب الكبدى المزمن سى

 

أدى انتشار الإصابة بفيروس الالتهاب الكبدى C إلى اهتمام زائد بالأعراض الغير كبدية. هناك آراء متباينة عن ارتباط الإصابة بفيروس الالتهاب الكبدى C والاضطرابات العصبية والنفسية. الهدف من إجراء هذه الدراسة هو معرفة ما إذا كانت الإصابة بهذا الفيروس  لها تأثير على الجهاز العصبى مما ينتج عنها الاضطرابات العصبية والنفسية.اشتملت الدراسة على عشرين مريضا بالالتهاب الكبدى C ممن يترددون على وحدة الكبد بكلية الطب جامعة الإسكندرية ويعانون بالتعب والاكتئاب وعشرين فردا من الأصحاء مماثلين لهم فى الجنس والسن كعينة ضابطة. وقد خضع المشاركين لمجموعة من الفحوص الطبية والعصبية مثل فحص الحالة العقلية المصغر MMSE))  واستبيان حدة الاكتئاب وحدة التعب وإجراء التصوير بالرنين المغناظيسى والتحليل الطيفى بالرنين المغناطيسى للمرضى والمجموعة الضابطة وتحليل نسبة الفيروس فى الدم وعينة من الكبد للمرضى. أسفرت النتائج  زيادة ذات دلالة احصائية فى حدة الاكتئاب والتعب فى المرضى بالمقارنة بالمجموعة الضابطة ولكن هذه النتائج لم تكن ذات دلالة إحصائية ارتباطيه بنتائج الفحوص المعملية  المرتبطة بوظائف الكبد ومنها كمية الفيروس بالدم. كما أظهرت نتائج الرنين المغناطيسى الطيفى وجود اضطرابات ذات دلالة احصائية فى نسبة الان أستيل أسبارتيت إلى الكرياتينين ونسبة الكولين إلى الكرياتينين وأيضا نسبة الان أستيل أسبارتيت إلى  الكولين وهذه الاضطرابات ذات دلالة إحصائية ارتباطيه بحدة الاكتئاب والتعب. ونستخلص من هذه  الدراسة أن فيروسC  له تأثير مباشر على الوظائف العصبية والنفسية حتى قبل ظهور مضاعفات المرض المؤثرة على الجهاز العصبى.



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