Fatigued patients with chronic liver disease have subtle aberrations of sleep, melatonin and cortisol circadian rhythms

Aims: We sought to examine whether disturbances in central and peripheral circadian rhythms were related to the experience of fatigue in patients with chronic liver disease (CLD). Methods: Fatigued and non-fatigued patients with compensated CLD were enrolled in a prospective pilot study. Patients underwent a one week evaluation of free-living sleep and physical activity patterns, followed by a 24-hour admission, during which they underwent serial blood sampling, polysomnography, a 6-minute walk test and continuous core temperature measurements under standardized conditions. Blood samples were analyzed for liver tests, melatonin levels, lipids, and cortisol. Circadian rhythms were analyzed using single cosinor analyses. Results: Six fatigued and six non-fatigued patients were studied; five participants had cirrhosis. Fatigue severity was positively associated higher peak melatonin levels (rho = 0.59, p = 0.04) and a delay in night-time melatonin peak and inversely associated with sleep efficiency (rho = -0.63, p = 0.04). Polysomnography, 6-minute walk test, and core temperature measurements did not differ significantly between the fatigued and non-fatigued patients. Although liver enzymes, bilirubin and albumin demonstrated a circadian pattern, it was not associated with fatigue. Fatigued patients showed a blunted and delayed cortisol rhythm and fatigue was strongly correlated with cortisol amplitude (rho = -0.77, p = 0.004) and phase (r = -0.66, p = 0.02). Conclusion: Subtle aberrations in melatonin and adrenal circadian rhythms, as well as reduced sleep efficiency, likely contribute to fatigue in patients with CLD. These abnormalities may ultimately be a therapeutic target to improve quality of life for fatigued patients with CLD.