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

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.

KEYWORDS:

• Fatigue
• liver disease
• sleep
• circadian rhythms
• melatonin
• cortisol

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.

Additional information

Funding

This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the UCSF Liver Center [grant number P30 DK026743].

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.