In this uniquely sized North American study, we extend the previous work by using for the first time in selleck chemical this context a more sensitive and disease-specific QOL measure for use in PBC. Our study showed that a higher

number of comorbidities (>2) as well as a higher number of medications (>3) was associated with higher fatigue scores. The association with depression is notable. Clearly we are not able to distinguish between direct potential causes for fatigue (for example, beta-blocker use) and surrogate associations (e.g. the possible increased prevalence of functional bowel disorders in those using a proton pump inhibitor). Our study design prevents us from doing this but this does not detract from the concept that fatigue is not specific to PBC, nor does it make less relevant the message to clinicians to think broadly about fatigue and its cause, if they are to successfully intervene. Others before have shown,

for example, that 12% of patients with PBC fulfilled criteria for irritable bowel syndrome and had more gastrointestinal symptoms and higher fatigue scores.11 The pruritus reported by our patients was also associated with higher fatigue scores, and at the time of evaluation 33 patients were currently using antipruritic prescription. Despite that, we show that PCI-32765 mouse patients who were on these medications scored high on the Fatigue domain of PBC-40 (34.5 ± 10.8 versus 26.5 ± 11.0, P < 0.0001). This could be attributed to the symptom being in need of better control as well as speculatively poor sleep quality because of itching. The associations we demonstrate with disease severity are complicated by unknown confounders. Therefore, although at the time of survey disease severity does seem

to associate with fatigue, it had an inverse relationship when factored backwards with regards to stage at presentation. Confounders regarding modes of presentation may help explain 3-mercaptopyruvate sulfurtransferase this apparent paradox, as might age at presentation, for example. Our multivariate analysis went on to provide a model for fatigue association that included BMI, disease severity, and clinical symptoms. The association with calcium and vitamin D use is presumably a surrogate for an unknown factor. Of note, AMA status was not related to the presence of fatigue. It is well recognized that AMA titers can fall during the course of treated PBC, and our failure to demonstrate a relationship between AMA titers and fatigue argues against the hypothesis that there is a direct metabolic link between mitochondrial antibodies and changes in mitochondrial function in patients.22, 31 For the symptom of fatigue, we were also not able to show an effect of treatment response, although intriguingly some components of the PBC-40 domains, Symptom and Itch, did seem to improve. This provides further support to the complex interactions that underpin fatigue in patients with PBC.