ABSTRACT
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.
Acknowledgements
Andrea Beri, Wally Duncan, Jackie Greenfield, Jay Hoofnagle, Jake Liang, Vicky Liberty, Lynette Niemann, Dante Picchioni, Ann Smith, Sarah Smyth, Windy Wallin, Allison Weiss, Edythe Wiggs, NIDDK Liver Diseases Branch staff and patients.
Disclosure statement
No potential conflict of interest was reported by the authors.
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Notes on contributors
Michele M. Tana
Michele M. Tana was a Clinical Fellow in the Liver Diseases Branch.
Hawwa Alao
Hawwa Alao was a Clinical Fellow in the Liver Diseases Branch.
Nevitt Morris
Nevitt Morris was a Research Nurse in the Liver Diseases Branch.
Shanna Bernstein
Shanna Bernstein is a Dietician at the NIH Clinical Center.
Jacob Hattenbach
Jacob Hattenbach was an Intramural Research Assistant at the NIH.
Rahiya B. Rehman
Rahiya B. Rehman was a Student Researcher at the NIH Clinical Center.
Robert Brychta
Robert Brychta is an Investigator in the Diabetes, Obesity, and Endocrinology Branch.
Souvik Sarkar
Souvik Sarkar was a Clinical Fellow in the Liver Diseases Branch.
Xiongce Zhao
Xiongce Zhao was a Statistician for the NIDDK.
Mary Walter
Mary Walter leads the NIDDK Clinical Core.
Ashura Buckley
Ashura Buckley is Neurologist in NIMH.
Kong Chen
Kong Chen is an Investigator in the Diabetes, Obesity, and Endocrinology Branch.
Yaron Rotman
Yaron Rotman leads the Liver and Energy Metabolism Unit of the Liver Diseases Branch.