Why is fatigue so persistent in PSC - and what might help?
Fatigue is one of the most common and burdensome symptoms experienced by people living with primary sclerosing cholangitis (PSC). It can affect work, social life, physical activity and overall quality of life. We still know relatively little about why some people with PSC experience severe and persistent fatigue while others do not.
In our prospective SOMA.LIV study, we wanted to look beyond liver disease alone. We investigated a broad range of biological, psychological and behavioural factors that might contribute to fatigue in people with PSC. We followed participants over six months to examine which factors were associated with fatigue over time.
How common was fatigue?
The study included more than 200 people with PSC. At the beginning of the study, around one in five participants (19%) experienced clinically relevant fatigue.
One of the clearest findings was that fatigue tended to be quite stable over time. Among people who did not have clinically relevant fatigue at the beginning of the study, 92% remained below the threshold for clinically relevant fatigue six months later.
Alternatively, among those who started the study with clinically relevant fatigue, 79% continued to experience it six months later.
This suggests that for the majority of people with PSC, fatigue isn‘t just a temporary symptom that comes and goes. Once severe fatigue is present, it can be remarkably persistent.
Is fatigue simply a consequence of liver disease severity?
One important question was whether people with more severe liver disease also experienced more fatigue.
Conventional indicators of liver disease severity did not independently explain fatigue in our analyses. This does not mean that PSC itself is unrelated to fatigue. Rather, it suggests that the relationship between the underlying liver disease and the fatigue a person experiences is more complex than we might assume.
This is consistent with what many people with PSC tell us: the severity of their fatigue does not always seem to correspond to their latest liver test results or to how advanced their disease appears to be clinically.
We therefore need to consider a broader range of possible mechanisms.
A biopsychosocial view of fatigue
Our study was based on a biopsychosocial approach. This means we considered biological processes alongside psychological and behavioural processes, rather than assuming that fatigue has one single cause.
It is important to note that describing fatigue as “biopsychosocial” does not mean that the symptom is “all in the mind”. Psychological and behavioural factors can influence very real physical symptoms, just as biological processes can influence how we think, feel and behave. These processes continually interact.
At the beginning of our study, depressive symptoms and fear-avoidance beliefs were among the factors independently associated with greater fatigue levels.
Fear avoidance refers to concerns that physical activity could worsen symptoms or be harmful. Such concerns are understandable when activity repeatedly seems to be followed by exhaustion. However, they may sometimes contribute to a cycle in which people become increasingly cautious about activity, potentially leading to reduced activity and further fatigue.
When we looked at fatigue six months later, fear-avoidance beliefs were again important: higher fear avoidance at the beginning of the study was associated with greater subsequent fatigue, even when initial fatigue severity was taken into account.
This is particularly interesting because fear avoidance is potentially modifiable. Unlike characteristics such as age or the underlying diagnosis, beliefs about symptoms and patterns of activity can potentially be addressed through targeted interventions.
What about inflammation?
We also found some preliminary evidence that inflammatory processes may play a role.
Participants with detectable levels of the inflammatory marker interleukin-6 (IL-6) (a protein made by the body during infections and injuries) at the beginning of the study tended to report greater fatigue six months later.
This finding needs to be interpreted cautiously, particularly because biomarker data were not available for all participants and the result needs to be replicated in further studies.
Nevertheless, it is an interesting signal. It supports the idea that biological and behavioural or psychological processes should not be viewed as competing explanations for fatigue. Both may contribute, and they may also interact with each other.
What do these findings mean for people with PSC?
Our findings do not provide a simple answer to the question of what causes fatigue in PSC - and they do not yet provide a new treatment. Instead, they suggest that we may need to move away from searching for a single cause.
For some people, biological processes such as inflammation may be important. For others, psychological wellbeing, expectations about symptoms, or patterns of activity and avoidance may contribute. Most likely, several of these factors interact differently in different individuals.
This may also help explain why fatigue can be so difficult to treat.
At the same time, the findings provide reasons for optimism. If potentially modifiable factors, such as fear avoidance, contribute to the persistence of fatigue, there may be opportunities to develop interventions that help people manage fatigue even when the underlying PSC itself cannot be changed.
This does not mean simply telling people to exercise more or to ignore their symptoms. Any intervention needs to acknowledge the reality of fatigue and help people find an appropriate balance between activity and recovery. Psychological interventions can, for example, help people understand patterns between expectations, symptoms and activity, gradually regain confidence in what their body can do, and develop strategies for managing symptoms without allowing fatigue to increasingly restrict every-day life.
Where do we go from here?
The SOMA.LIV study is part of a broader research unit aimed at understanding persistent physical symptoms and identifying mechanisms that could eventually become targets for treatment.
Our next challenge is therefore not only to understand fatigue better, but to translate these findings into interventions that are useful to people living with PSC.
Further research will also need to examine the biological mechanisms underlying fatigue in greater detail and determine whether the factors identified in our study actually play a causal role. Our results show associations, so we cannot yet conclude that fear avoidance or inflammatory activity directly causes persistent fatigue.
What the study does show clearly is that fatigue deserves attention as an important aspect of PSC in its own right. Liver tests alone cannot tell us how much fatigue someone experiences or how much it affects their life.
For people living with severe fatigue, that may be one of the most important messages from our research: the symptom is real, its causes are complex, and understanding that complexity may ultimately give us more - rather than fewer - opportunities to help.
Many thanks to Dr Anne Toussaint for this summary.