Research ArticleLoss of capacity to recover from acidosis in repeat exercise is strongly associated with fatigue in primary biliary cirrhosis
Introduction
Patients with the autoimmune liver disease primary biliary cirrhosis (PBC) can experience systemic symptoms seemingly unrelated, in terms of their severity, to “classical” liver complications conventionally associated with disease progression. Patients can experience significant fatigue, cognitive symptoms, and social and emotional dysfunction related to symptom burden which can all significantly impair quality of life [1], [2], [3], [4], [5]. Whereas there are emerging data to suggest that central nervous system processes underpin at least some of the symptoms of PBC (in particular the cognitive symptoms which can have an association with mood and sleep disturbance [6]) there are also emerging data to suggest that peripheral processes are also taking place [7], [8]. There are data in PBC, therefore, to support both a peripheral and a central component to fatigue, the inter-relationship of which is currently unclear.
The concept that peripheral muscle dysfunction might contribute to the perception of fatigue in PBC started with qualitative research, with patients emphasising constructs related to power and physical capacity to undertake work (an example being an analogy frequently drawn by patients between their fatigue and “a battery running down”). This led us to address whether physical performance-related factors contribute to perception of fatigue. Were this to be the case this may open-up potentially exciting new approaches to physical therapy to reduce the impact of fatigue. In initial studies we demonstrated that PBC patients who reported fatigue showed an impaired capacity to perform sustained activity over a five minute period [7]. Non-fatigued PBC patients, in contrast, showed no deterioration in this capacity over and above that seen in age and sex matched controls. Although another study [9] did not replicate this finding the patient group studied was substantially less fatigued than the fatigue group in our study and would be better regarded as consisting of minimally-fatigued patients.
In order to address the mechanistic basis of this effect we have recently reported magnetic resonance spectroscopy (MRS) findings in peripheral muscle in PBC patients which indicated the possibility of two separate effects contributing to energetic abnormalities and subsequent fatigue in muscle in PBC [8]. PBC patients had excessive acidosis in peripheral muscle following controlled exercise, with pH levels achieved after relatively low levels of exercise that would be more typically associated with significant levels of exercise in normal controls. The level of pH achieved after controlled exercise did not, however, relate to severity of fatigue. In contrast, the rate of recovery from acidosis was significantly associated with fatigue severity. This led us to propose a “two hit” model for peripheral fatigue pathogenesis in PBC in which the “first hit” is excessive acidosis following exercise and the “second hit” represents an inadequate capacity to respond to this. A critical observation was that a number of patients who achieved very low pH following exercise did not experience fatigue. They were, however, characterised by extremely rapid pH recovery in the rest period following exercise.
Patient descriptions of fatigue in PBC, and our work on repeat exercise, suggest that it is not a single exercise episode that is difficult for patients but the capacity to perform sustained or repeat exercise. This type of exercise was not modelled in our original study. We therefore set out to extend these observations in a repeat-exercise study looking at minimum muscle pH following exercise, and the rate of pH recovery following a series of three linked, equal intensity exercise episodes from which patients were allowed to recover over a fixed recovery period before instituting the next episode. The findings of this study provide important new insights into the metabolic abnormality in PBC patients and, in particular, provide an important pointer to the potential value of physical therapy in symptom treatment.
Section snippets
Subjects
This study was performed in two phases. In phase 1, we explored the bioenergetic effects of repeat exercise in PBC patients (n = 16) and normal controls (n = 8). In the second phase we undertook a pilot study to explore the feasibility, acceptability and effects of exercise therapy in PBC patients (n = 4). Appropriate subject numbers were determined based on our previous observations in a single exercise session [8]. All participants were recruited through our specialist PBC out-patient clinic. All
Muscle bioenergetic function
No baseline differences were seen between the study groups in relation to the concentrations of phosphorus energy metabolites or muscle pH prior to commencement of exercise (Table 2). When non-fatigued patients were compared with normal controls minimum pH following the 1st exercise period was found to be significantly lower in the PBC group than in normals (Fig. 1A) with strikingly low nadir pH values being seen in some of the PBC group replicating our previous findings [8]. No association was
Discussion
We have previously demonstrated abnormalities in acid handling by exercising muscle in PBC patients [8]. Given the well characterised associations between acid accumulation in muscle during exercise and exercise limitation in normal individuals the implications for limitation of function and perception of fatigue in PBC are clear. The exercise protocol in our earlier studies consisted of a single period of exercise. In daily life, however, PBC patients describe symptoms suggesting difficulty in
Funding
Medical Research Council, UK NIHR Biomedical Research Centre in Ageing Liver Theme. None of the funders contributed to the design, performance or interpretation of the results of this study.
Conflicts of interest
None of the authors have any conflict of interest.
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