The implementation of a non-pharmacological multimodal intervention program-including physical exercise, nutritional counseling, and psychological support-is expected to improve fatigue in patients with primary biliary cholangitis. Consequently, this improvement is anticipated to enhance quality of life and cognitive symptoms, while also positively impacting emotional, social, and occupational aspects.
From a pathophysiological perspective, it is hypothesized that chronic cholestasis and/or immune system activation, with the release of pro-inflammatory cytokines, leads to both central and peripheral alterations causing fatigue.
At the central level, systemic inflammation may induce neuronal senescence in the basal ganglia, resulting in altered functional connectivity networks dependent on these regions and/or structural and connectivity changes in areas involved in interoception, such as the insula and anterior cingulate cortex.
At the peripheral level, the hypothesis is that chronic inflammation mediated by anti-mitochondrial antibodies causes mitochondrial metabolic dysfunction in muscle cells, which would be reflected in changes observed in the gene expression analysis of these cells.
Improvement in fatigue following the multimodal intervention program is expected to be associated with normalization of the immunological profile, enhanced functional brain connectivity, and improved mitochondrial metabolism in muscle.
Age ≥18 years
PBC diagnosis according to EASL guidelines
Moderate - severe fatigue defined by ≥ 29 points in PBC-40 questionnaire
Age > 80 years
Severe pruritus
Decompensated cirrhosis
Other causes of liver disease than PBC
Crossover
Multimodal prehabilitation
Other interventionThe multimodal prehabilitation program will consist of: 1. twice-weekly supervised exercise training at the hospital gym for approximately 8 weeks (induction phase), followed by 16 weeks of telematic, supervised, home-based exercise (maintenance phase); 2. nutritional consultation, including diet optimization and supplementation if needed; 3. individual or group-based psychological support.
standard of care
Other interventionParticipants in the control group will follow the standard of care provided by the hospital and will receive general recommendations on physical activity, nutrition, and stress/anxiety management.
Change in Fatigue Severity Assessed by PBC-40
To evaluate the effect of a non-pharmacological multimodal intervention program on fatigue severity and its impact in participants with primary biliary cholangitis (PBC). Fatigue will be assessed using the Primary Biliary Cholangitis-40 (PBC-40) fatigue domain, which consists of 11 items scored from 1 to 5. Scoring Range: 11 to 55; higher scores indicate greater fatigue.
Change in Fatigue Severity Assessed by Visual Analogue Scale
To evaluate the effect of a non-pharmacological multimodal intervention program on fatigue severity and its impact in participants with primary biliary cholangitis (PBC). Fatigue will be assessed using the Visual Analogue Scale (VAS) for fatigue, which captures the participant's perception of fatigue severity. Scoring Range: 0 (no fatigue) to 10 (worst imaginable fatigue).
Change in Fatigue Impact Assessed by Fatigue Impact Scale (FIS)
To evaluate the effect of a non-pharmacological multimodal intervention program on fatigue severity and its impact in participants with primary biliary cholangitis (PBC). Fatigue will be assessed using the Modified Fatigue Impact Scale (MFIS), which assesses the impact of fatigue on physical, cognitive, and psychosocial functioning. Scoring Range: 0 to 84; higher scores indicate greater fatigue-related impairment
Change in Cognitive Symptoms Assessed by PBC-40
To evaluate changes in cognitive symptoms using the Primary Biliary Cholangitis-40 (PBC-40) questionnaire. The cognitive domain ranges from 6 to 30 points. Higher scores indicate worse symptoms.
Change in Extrahepatic Symptoms Assessed by PBC-40
To evaluate changes in extrahepatic symptoms using the Primary Biliary Cholangitis-40 (PBC-40) questionnaire. The symptoms domain ranges from 7 to 35 points. Higher scores indicate worse symptoms.
Change in Quality of Life Assessed by EQ-5D-5L Index Score
To assess health-related quality of life using only the EQ-5D-5L index score derived from five health dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The index score ranges from -0.594 to 1, where higher scores indicate better health status.
Change in Self-Perceived Health Status Assessed by EQ Visual Analogue Scale
To evaluate self-perceived overall health using the EQ Visual Analogue Scale (EQ-VAS), part of the EQ-5D-5L instrument, reported separately. The EQ-VAS ranges from 0 to 100, where 0 = worst imaginable health and 100 = best imaginable health.
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