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Chronic mild encephalopathy caused by hepatitis C virus: The evidence for a common psychiatric illness.

R.E.Kast, MD
Department of Psychiatry
College of Medicine
University of Vermont
Burlington, Vermont
05401 USA


phone: 802-863-2462


Keywords: Hepatitis C, encephalopathy, mood lability


Hepatitis C virus, HCV, is common worldwide. Mood and behaviour difficulties often accompany chronic HCV infection. This note reviews data showing HCV replication probably occurs in the brain and damages neurons and activates glia, giving a chronic mild viral encephalopathy.


Hepatitis C virus, HCV, is a positive strand RNA virus that is a leading cause of chronic hepatitis worldwide, infecting an estimated 1- 3% of humanity- 140 to 170 million people (1, 2). Transmission appears to be primarily by blood, in most patients an iatrogenic (contaminated needles or equipment, transfusions) or illicit i.v. drug use infection source is evident. HCV is a common cause of death through liver failure and other sequellae, after decades of HCV hepatitis. Hepatocellular carcinoma can supervene in the clinical course of HCV cirrhosis. I here briefly review evidence leading to the conclusion that a large minority of HCV patients are also burdened by an ambulatory, chronic, HCV related encephalopathy.

There is some research support for the common clinical impression of lower quality of life in HCV hepatitis (3), disproportionate to the apparent degree of liver involvement. Non-lateralizing, poorly localizing signs and symptoms such as malaise, fatigue, diffuse headache, severe myalgia/arthralgia, weakness, irritability, abulia, depressed mood and mood lability are common in my HCV patient population, and these signs and symptoms have been noted by others (3, 4, 5, 6).

Virologic Evidence

Negative strand RNA is the replicative intermediary of HCV RNA (1, 2, 4) and when found in a given compartment is strong evidence of active replication there. It was found in the cerebrospinal fluid, CSF, of three of six HCV patients studied (4). In another report the CSF of all five patients studied who were dually infected with human immunodeficiency virus, HIV, and HCV hepatitis, were positive for HCV RNA (positive stand), while five of seven HIV negative, HCV positive patients had HCV RNA in their CSF (6). Others found five of 19 dually infected HIV-HCV patients positive for HCV RNA in their CSF (7), the authors suggesting the brain is a reservoir for HCV.

Radologic Evidence

Evaluation of patients with chronic mild HCV hepatitis, whose biopsy scores were in the mildest inflammatory and lowest fibrosis score groups had magnetic resonance spectroscopy determined abnormal basal ganglia and cerebral white matter choline/creatine ratios suggestive of ongoing minor cell damage (5). The authors note similar findings in a better-recognized encephalopathy, HIV, and suggest, "the hypothesis that hepatitis C virus itself affects cerebral function".

Patients with cirrhosis of any origin tend to show increased T1 weighted MRI signal from the globus pallidus consistent with elevated tissue manganese, Mn, concentrations, (8,9,10), also in the absence of coarse neurological abnormalities. Three of four HCV patients studied showed high T1 weighted signal from the globus pallidus (9) and then upon autopsy of those patients, extraordinarily high Mn tissue levels in the globus pallidus was found. Excessive Mn exposure has been recognized for over 100 years as having the potential to cause a range of psychiatric signs and symptoms (reviewed in 11) and the encephalopathy seen in chronic HCV hepatitis seems in part mediated by globus pallidus Mn deposition, as well as by metabolic and inflammatory consequences of viral replication within the CNS.

Electrophysiological evidence

A 1996 study of auditory evoked cortical potentials showed drastically abnormal values in HCV patients with normal hearing, reflecting axonal degeneration, damage, or demyelination in tissue between the basal ganglia and cortex (12).


A mild, chronic, slowly progressive over decades or non-progressive encephalopathy is common in patients with HCV hepatitis. This encephalopathy tends to generate psychiatric morbidity. The encephalopathy probably is caused by metabolic and CNS inflammatory consequences of HCV replication within the CNS as well as hepatitis related increased Mn concentration in the globus pallidus. Patients with past or currently active risk factors, or signs or symptoms suggestive of HCV should be screened for serologic markers of HCV infection as part of the initial psychiatric work-up.




1. Shi ST, Lai MMC. Hepatitis C viral RNA. Cell Mol Life Sci 2001; 58:1276-95
2. Rosenberg S. Recent advances in the molecular biology of hepatitis C virus. J Mol Biol 2001; 313:451-64
3. Bonkovsky HL, Wooley JM. Reduction of health related quality of life in chronic hepatitis C and 29:264-70improvement with interferon treatment. Hepatology 1999;
4. Radkowski M, Wilkinson J, Nowicki M, Adair D, Vargas H, Ingui C, Rakela J, Laskus T. 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; 76:600-8
5. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001;358;38-9
6. Maggi F, Giorgi M, Fornai C, Morrica A, Vatteroni ML, Pistello M, Siciliano G, Nuccorini A, Bendineli M. Detection and quasispecies analysis of hepatitis C virus in the CSF of infected patients. J Neurovirol 1999; 5:319-23
7. Morsica G, Bernardi MT, Novati R, Foppa C, Castagna A, Lazzarin A. Detection of hepatitis C virus genomic sequences in the CSF of HIV infected patients. J Med Virol 1997; 53:252-4
8. Awada A, Sullivan S, Palkar V, Sbeih F, Naufal R, Al Rajeh S. Brain MRI in non-alcoholic cirrhosis. Eur J Radiol 1995; 21; 84-8
9. Maeda H, Sato M, Yoshikawa A, Kimura M, Sonomura T, Terada M, Kishi K. Brain MRI in patients with hepatic cirrhosis: Relationship between high intensity signal in basal ganglia on T1-weighted images and elemental concentrations in brain. Neuroradiology 1997;39;546-50
10. Malecki EA, Devenyi AG, Barron TF, Mosher TJ, Eslinger P, Flaherty-Craig CV, Rossaro L. Iron and manganese homeostasis in chronic liver disease: Relationship to pallidal T1-weighted MR signal hyperintensity. Neurotoxicology 1999;20;647-52
11. Barceloux DG. Manganese. Clin Toxicology 1999;37;293-307
12. Malaguarnera M, Pistone G, Trovato BA, et al. Mapped auditory evoked potentials before and after interferon treatment. J Inter Cytokine Res 1996;16;441-6

Submitted: 3 November 2002

Published: 16th November 2002

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