Introduction PBC is characterised by loss of small intrahepatic bile ducts, and in a significant proportion of patients by persistent fatigue. Genes regulating inflammatory pathways have been strongly associated with PBC in population-scale genetic studies, implicating inflammation in disease pathogenesis. Animal models of cholestasis, a biological process in PBC, have demonstrated fatigue-like behaviour appearing to result from responses to inflammatory cytokine release in the brain. Elevation of inflammatory cytokines has therefore, unsurprisingly, been postulated as an underlying mechanism for fatigue in PBC as well as other chronic inflammatory conditions. However, more recently data demonstrating that fatigue is not proportional to liver disease severity in PBC has questioned this presumed correlation between inflammation and fatigue. This study aimed to explore the serum cytokine profile in PBC compared to healthy controls, and to correlate this picture of inflammation status with fatigue severity.
Methods 68 patients from the Newcastle sector of the UK-PBC cohort and 9 healthy controls provided a morning peripheral blood sample and completed the PBC-40, a validated disease-specific quality of life measure with a fatigue domain. Sera were derived using standard protocols and stored at –80°C prior to multiplex cytokine quantification using the MSD platform.
Results PBC patients showed significant elevation of IFN-γ (median 2.4pg/ml[IQR 1.6–15.4] v control 0.7[0.2–1.5], p < 0.0005), IL-6 (1.0pg/ml[0.4–3.3] v 0.5[0–1.5],p < 0.005) and TNF-α (7.1pg/ml[5.5–10.5] v 4.3[3.6–5.9],p < 0.001). IL-1β was elevated in patients but fell short of significance (2.3 pg/ml [0.2–2.3] v 0.5[0.1–0.8],p = ns). Within the PBC group cytokine levels were compared between 21 patients reporting mild fatigue (established using published cut-offs for PBC-40 fatigue domain severity) and 24 patients with severe fatigue. No significant differences were seen between mildly and severely fatigued patients, and for three of the four pro-inflammatory cytokines (IFN-γ,IL-1β and TNF-α) levels were in fact lower in severely fatigued patients.
Conclusion Serum inflammatory cytokine levels are significantly elevated in PBC, in keeping with inflammation playing a key role in disease pathogenesis. Although the study protocol cannot exclude central nervous system-specific inflammatory mechanisms, no evidence was found to implicate inflammation in the pathogenesis or expression of fatigue in PBC, suggesting a further factor independent of inflammatory disease pathogenesis predisposes certain patients to fatigue.
Disclosure of Interest None Declared.
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