Although fatigue was the symptom with the highest overall load in PBC, the symptom set with the greatest impact (compared to controls) were autonomic symptoms. These symptoms were prevalent in the PBC population (confirming earlier, smaller studies) but largely absent in age- and sex-matched controls. The etiology of autonomic dysfunction in PBC is unclear; there may be both central and peripheral effects. In the central model brain injury, perhaps arising as a consequence of inflammatory processes occurring as INCB024360 cost a result of cholestasis inflammation (a model supported by animal modeling data for cholestasis25),

would affect autonomic regulating areas of the brain, leading to secondary peripheral autonomic effects. In the peripheral model vasomotor changes associated with liver disease and/or specific cardiac dysfunction associated with cardiac muscle abnormality in PBC26, 27 would give rise to processes mimicking central autonomic dysfunction peripherally. These models are, of course, not exclusive. Evidence in favor of an organic CNS process in PBC comes from brain imaging data and neurophysiology studies which suggest the presence of

organic brain change.24, 28 In the current study autonomic symptoms associated strongly with cognitive symptoms, fatigue, and with sleep disturbance. The strong associations between autonomic dysfunction, fatigue, problems with cognition, and problems with sleep regulation all provide further support for at least some organic CNS element underpinning the symptom complex in PBC. Again, further work in this area is warranted.

Ultimately the goal of this work is this website to improve the QOL of PBC patients. Although fatigue represents a major burden for patients, the impact that it has on their lives is itself complex. Although the presence of fatigue shows strong overall association with QOL, there was a clear-cut group of patients (nearly 300 in the national cohort) who had significant fatigue but whose perceived QOL remained good. A striking contrast was seen between this group of patients and the larger group of patients with severe medchemexpress fatigue who perceived their QOL as being poor, and this related to significant symptoms of social function (a symptom domain that showed the strongest overall association with QOL). Whereas 89% of patients with severe fatigue and poor QOL showed social dysfunction symptoms, only 11% of patients with severe fatigue and good QOL showed social impairment. This observation, together with data linking social function symptoms to QOL, suggests that, whereas fatigue is an important symptom for putting patients at risk of impaired QOL, ultimately this can be modified by the extent to which they maintain social contacts and links. This observation builds on previous findings to suggest that coping strategies are important for perception of life quality in PBC.