New pathways linking 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 Steven 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 John Wiley & Sons, Inc. is available online via Wiley InterScience.

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, Alexander I. Aspinall and David H. Adams 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."