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

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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.

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. "

Barb

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Son (Ken) 31 - UC 91 & PSC 99