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Disruption of the Diurnal Rhythm of Plasma Melatonin in Cirrhosis
Abstract
OBJECTIVES: To assess 24-hour plasma melatonin profile as a marker of output rhythm from the circadian clock and to study sleep diaries as reflections of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. SETTING: Clinical research center in a university hospital. PATIENTS: Seven patients with cirrhosis but not alcoholism and seven age-, sex-, and education-matched controls. MEASUREMENTS: Neuropsychological testing to confirm subclinical hepatic encephalopathy. Plasma melatonin levels measured every 30 minutes for 24 hours by radioimmunoassay. Sleep diaries kept for 1 week before admission. RESULTS: Patients with cirrhosis had markedly elevated melatonin levels during daytime hours; in addition, the time of onset of melatonin increase and the time at which melatonin levels peaked were consistently and significantly delayed in these patients. Sleep diaries indicated more nocturnal awakenings and more frequent daytime naps in patients with cirrhosis. CONCLUSION: Disruption of the diurnal rhythm of melatonin may reflect alterations of circadian function that could contribute to the disturbances of the sleep-wake cycle frequently seen in patients with cirrhosis.
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“Consequently, the distal-proximal temperature gradient indicative of heat dissipation is blunted, which contributes to the highly prevalent sleep disruptions reported for cirrhotic patients29, among other proposed mechanisms such as displaced melatonin secretion30.”
From Diurnal rhythms of wrist temperature are associated with future disease risk in the UK Biobank (2023) · cites this paper as [30]
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“Some attempt has been made to correlate the changes in the endogenous melatonin rhythm with the sleep disturbances observed in patients with cirrhosis, but the findings have been inconclusive.(39,43) It has been suggested that circadian rhythm delays may be associated with delayed sleep habits, although not necessaril…”
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“First, the rhythm of production of melatonin plasma level, a brain hormone with a role of circadian pacemaker, is altered with a delayed peak at night time (6).”
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“Both the time of onset of melatonin secretion and the peak of plasma melatonin levels are delayed in cirrhotic patients, in agreement with the shift in the sleep-wake cycle (Steindl et al., 1995; Blei and Zee, 1998; Velissaris et al., 2009).”
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Experimental Data on the Role of Melatonin in the Pathogenesis of Nonalcoholic Fatty Liver Disease
Terziev, D., & Terzieva, D. D. (2023) · Biomedicines · doi:10.3390/biomedicines11061722 · Cited by 15
“Melatonin is mainly metabolized in the liver and, to a lesser extent, in the kidney [46,47], and, therefore, severe liver or kidney disease can affect the melatonin rhythm [48].”
BackgroundTsai, L., Lin, C., Chiang, S.-C., Chen, C., Lan, S.-J., & See, L. (2014) · Gastroenterology Nursing · doi:10.1097/sga.0000000000000020 · Cited by 11
López, L., González-Pardo, H., Cimadevilla, J., Cavas, M., Aller, M., Arias, J., & Arias, J. L. (2002) · Experimental Neurology · doi:10.1006/exnr.2001.7840 · Cited by 13
“However, the elevated melatonin levels could be caused by an impaired hepatic catabolism in PCS rats (64).”
BackgroundResultManaging Sleep Disturbances in Cirrhosis
Zhao, X., & Wong, P. Y. N. (2016) · Scientifica · doi:10.1155/2016/6576812 · Cited by 10
“Earlier studies have shown that patients suffering from liver cirrhosis have higher melatonin levels throughout the day and delayed onset ofmelatonin peaking during the night [23].”
BackgroundRisk factors for hospitalizations among patients with cirrhosis: A prospective cohort study
Rogal, S. S., Udawatta, V., Akpan, I., Moghe, A., Chidi, A. P., Shetty, A., Szigethy, E., Bielefeldt, K., & DiMartini, A. F. (2017) · PLoS ONE · doi:10.1371/journal.pone.0187176 · Cited by 10
Gençdal, G., Günşar, F., Meral, C. E., et al. (2014) · Digestive and Liver Disease · doi:10.1016/j.dld.2014.08.031 · Cited by 10
The appropriate and inappropriate uses of saliva melatonin measurements
Kennaway, D. J. (2024) · Chronobiology International · doi:10.1080/07420528.2024.2428197 · Cited by 10
“Impaired liver function can also be expected to influence clearance of endogenous melatonin and produce elevated plasma levels and altered timing of the rhythm (Iguchi et al. 1982; Montagnese et al. 2010, 2015; Steindl et al. 1995, 1997).”
Sleep pattern changes in patients with liver cirrhosis
Mabrouk, A. A., Nooh, M. A., Azab, N. Y., et al. (2012) · Egyptian Journal of Chest Diseases and Tuberculosis · doi:10.1016/j.ejcdt.2012.09.012 · Cited by 9
Bengtsson, F., Bergqvist, P. B. F., & Apelqvist, G. (1997) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-5945-0_1 · Cited by 9
Cirrhosis does not shift the circadian phase of plasma fibrinolysis
Piscaglia, F., Hermida, R. C., Siringo, S., et al. (2002) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2002.05799.x · Cited by 8
“As far as melatonin is concerned, our findings in cirrhotics with severe liver impairment confirm findings by others, who reported a delayed peak time of melatonin in cirrhosis (2).”
BackgroundResultModifcation of sleep architecture in an animal model ofexperimental cirrhosis
Jiménez‐Anguiano, A., Díaz-Medina, V., Farfán-Labonne, B. E., Giono-Chiang, G., Kersenobich, D., Lorenzana, M. G., Gutiérrez‐Ruíz, M. C., & Velázquez‐Moctezuma, J. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.5176 · Cited by 8
Tana, M. M.-S., Alao, H., Morris, N., et al. (2017) · Fatigue Biomedicine Health & Behavior · doi:10.1080/21641846.2018.1408539 · Cited by 8
Patterns of energy intake in patients with cirrhosis and healthy volunteers
Madden, A. M., & Morgan, M. Y. (1999) · British Journal Of Nutrition · doi:10.1017/s0007114599001105 · Cited by 8
Rodrigo, R., Monfort, P., Cauli, O., et al. (2006) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.a813 · Cited by 7
“Alterations in the regulation of biological rhythms such as sleep, appetite, melatonin production, and in sexuality are common in patients with liver disease (Iguchi et al 1982; Steindl et al 1995; Garfinkel and Zisapel 1996; Cordoba et al 1998).”
Metadata
- Authors
- Steindl, P. E., Finn, B., Bendok, B., Rothke, S., Zee, P. C., & Blei, A. T.
- Affiliations
- Northwestern Memorial Hospital (US)
- Northwestern University (US)
- From Northwestern Memorial Hospital, Lakeside Veterans Affairs Medical Center, and the Rehabilitation Institute, Chicago, Illinois.
- ORCID
- Zee, Phyllis C.
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 1995-08-15
- Volume
- 123
- Issue
- 4
- Pages
- 274-277
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- OpenAlex
- W2091220140
- Cited by
- 140
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 7 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 9 · 2013: 8 · 2012: 9
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Research Resources (RR00048)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- liver cirrhosis, plasma melatonin, circadian rhythm, circadian clock, sleep-wake cycle, sleep quality, nocturnal awakenings, daytime napping, hepatic encephalopathy
- MeSH terms
- Adult, Circadian Rhythm, Female, Humans, Liver Cirrhosis, Male, Melatonin, Middle Aged, Prospective Studies, Sleep Wake Disorders, Biomarkers
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