New Pathways Link Liver Disease To Changes In The Central Nervous System

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http://www.sciencedaily.com/releases/2006/01/060106004614.htm

Source: Wiley & Sons, Inc.

Date: 2006-01-06

New Pathways Link Liver Disease To Changes In The Central Nervous System

Liver disease is often associated with " sickness behaviors, " such as

malaise, listlessness, anorexia, difficulty concentrating, and fatigue. In

cholestatic liver diseases (where bile production is impaired) such as

primary biliary cirrhosis, fatigue occurs in up to 86 percent of patients.

Previous studies have suggested that these symptoms originate from changes

to the central nervous system (CNS), but little is understood about how

these changes occur or the pathways involved.

In a study led by M. Kerfoot of the Immunology Research Group at the

University of Calgary in Canada and published in the January 2006 issue of

Hepatology, researchers speculated that cholestatic liver damage may be

associated with an immune response affecting the central nervous system,

specifically the brain, which could represent a novel and potentially

important pathway.

Hepatology, the official journal of the American Association for the Study

of Liver Diseases (AASLD), published by Wiley & Sons, Inc. is available

online via Wiley InterScience at

http://www.interscience.wiley.com/journal/hepatology.

The study involved creating cholestasis in mice by tying off the bile duct.

Cerebral endothelial cells (cells lining the blood vessels of the brain)

were then isolated and examined to see if they were activated, as activated

endothelium tends to interact with activated immune cells. In addition,

researchers analyzed TNF-alpha (a messenger protein involved in

inflammation) production by monocytes, a type of white blood cell, to

determine if a peripheral immune response was present.

The results showed an increase in TNF-alpha production by monocytes and

activated endothelial cells in the cholestatic mice versus the control mice.

The authors suggest that cholestasis is also associated with a broad

activation of other immune cells within the central nervous system that

produce TNF-alpha. " Given the significant behavioral effects of TNF-alpha

within the CNS (i.e. sickness behaviors), the production of TNF-alpha within

the brains of cholestatic mice is likely to be important in the alterations

in behavior, as well as in the changes in the neurotransmitter systems which

sub-serve these behaviors within the brains of cholestatic mice and may have

direct implications for these systems in cholestatic patients, " the authors

conclude.

In an accompanying editorial in the same issue, I. Aspinall and

H. of the Institute for Biomedical Research at the University of

Birmingham in England, note the difficulties in treating fatigue associated

with liver disease and the lack of understanding of the mechanisms that

cause it, adding that the University of Calgary study " provides a novel

mechanism to link cholestasis, inflammation and sickness behavior and is

potentially important in understanding this poorly characterized aspect of

chronic cholestasis. " They state that the fact that monocytes were found in

similar locations to those seen in inflammatory brain disease supports the

likelihood that they are linked to pathological effects. However, they note

that there are still unresolved issues in understanding sickness behaviors

and that it remains unknown whether the results from the animal study will

translate to cholestasis in humans. One key message from the study is that a

number of factors most likely affect the CNS leading to sickness behaviors.

" Identifying the mediators involved is important not only to complete our

understanding of the pathogenesis of sickness behaviors but also to inform

the development of appropriate therapeutic agents, " the authors state,

adding that the risks of anti-TNF-alpha therapy most likely outweigh the

potential benefits. They conclude: " It is to be hoped that a better

understanding of these processes may lead to the development of more

effective and rational therapies for this disabling symptom of cholestatic

liver disease. "

###

Article: " TNF-alpha-Secreting Monocytes Are Recruited Into the Brain of

Cholestatic Mice, " M. Kerfoot, Charlotte D'Mello, Henry Nguyen,

Maureen N. Ajuebor, Kubes, Tai Le, Mark G. Swain, Hepatology, January

2006 (DOI: 10.1002/hep.21003).

Editorial: " Sickness Behaviors in Chronic Cholestasis: An Immune-mediated

Process? " I. Aspinall, H. , Hepatology, January 2006

(DOI: 10.1002/hep.21032)

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