Central nervous system dysfunction in primary biliary cirrhosis and its relationship to symptoms

Claire McDonald 1,2, Julia Newton 1, H. Ming Lai 3, Stuart N. Baker 2, David E. Jones 1

Received 15 December 2009; received in revised form 24 May 2010; accepted 26 May 2010. published online 18 August 2010.
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Background & Aims
Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally we determine the relationship of these indices to the symptoms of PBC.

Methods
16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF).

Results
PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF.

Conclusions
PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).

Keywords: Muscle, Trans-cranial magnetic stimulation, Twitch interpolation, Cortical inhibition, Liver cirrhosis, Biliary

Abbreviations: TMS, trans-cranial magnetic stimulation, ICI, intra-cortical inhibition, ICF, intra-cortical facilitation, ESS, Epworth Sleepiness Scale, PBC, primary biliary cirrhosis, MVC, maximal voluntary contraction
 
1 Institute of Cellular Medicine, Newcastle University, UK
2 Institute of Neuroscience, Newcastle University, UK
3 Department of Clinical Neurophysiology, Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK

Corresponding author. Address: Institute of Cellular Medicine, Newcastle University, 4th Floor William Leech Building, The Medical School, Newcastle University, Newcastle, NE2 4HH. Tel.: +44 191 222 5784; fax: +44 191 222 0723.

PII: S0168-8278(10)00699-9
doi:10.1016/j.jhep.2010.05.036
© 2010 Published by Elsevier Inc

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