This study presents further evidence underlining that fatigue is a significant problem in the lives of patients with PBC. However, one of the conclusions of this article—fatigue in PBC is nonspecific and multifactorial—gives rise to a number of important issues. First, the conclusion that fatigue in Akt inhibitor PBC is associated with comorbidities is unsurprising and underlines the necessity of excluding patients with comorbidities from mechanistic studies (of the kind recently

reported by our group4-6) exploring the pathophysiology of fatigue in PBC. Second, although fatigue can arise in PBC in association with comorbidities or because of medications (it occurs with a number of other chronic liver diseases and most, if not all, chronic inflammatory processes), it is no less of a problem to the patients who experience it. Furthermore, it is clear that the fatigue profile for PBC patients is significantly greater than that for age-matched community controls experiencing all the comorbidities identified by Al-Harthy et al.1 in PBC patients.7 Recent studies have also confirmed that fatigue in PBC is associated not only with impaired quality of life but also with reduced length of life.8, 9 Therefore, although fatigue may be a ubiquitous symptom in chronic BAY 73-4506 clinical trial disease; it is associated with PBC and is perceived by patients as a disease-associated problem. Although fatigue may not always be specific to PBC,

it is vital for this fact not to be used as a rationale by clinicians managing PBC patients to avoid addressing this symptom. To do so because fatigue is in some way “not a PBC-specific problem” can contribute to a disappointing patient experience if clinical management is not relevant to the patient’s perceived problems. The third issue is the important question of why PBC patients experience, MCE at a seemingly enhanced frequency, the problem set

that underpins fatigue; Al-Harthy et al.1 quite correctly stated that this requires study in centers other than our own. The fatigue phenotype seen in PBC is strikingly similar to that seen in other chronic inflammatory conditions, and PBC-associated problems, such as autonomic dysfunction and sleep disturbance, are themselves associated with fatigue in multiple different settings. Each of these can in turn be associated with the comorbid processes identified by Al-Harthy et al. This raises the intriguing question whether PBC is in fact a paradigm for complex fatigue in chronic disease. Because of the advantages that PBC holds for the study of phenomena such as fatigue (e.g., robust diagnostic criteria and validated assessment tools), it might represent an important and exciting context in which to study fatigue in ways that will be highly relevant to other disease settings. We believe that Al-Harthy et al.1 have provided further support for the consensus that fatigue is a problem experienced by a significant proportion of PBC patients.