Assessment of 6-sulfatoxymelatonin rhythms and melatonin response to light in disease states: Lessons from cirrhosis

Abstract

Circadian rhythmicity and non-visual sensitivity to light can be assessed, in healthy subjects, by measuring the rhythm of the urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) and by determining the response of plasma melatonin to nocturnal retinal light exposure, respectively. However, the validity of these techniques has not been assessed in disease states in which disruption of the circadian rhythm is known or suspected to occur. Thus, the aims of this study were as follows: (i) to assess the reliability of circadian aMT6s profile estimates derived from 36 h versus 56 h urine collections and (ii) to test different models for calculating melatonin suppression in response to light in healthy volunteers and patients with cirrhosis. Twenty patients with biopsy-proven cirrhosis and 10 matched healthy volunteers undertook: (i) separate 36 - and 56-h urine collections, under controlled conditions, for cosinor analysis of the urinary aMT6s profile; (ii) a melatonin suppression test, comprising of a baseline night, during which subjects were woken and asked to sit in front of a switched off light sphere, and an experimental night, identically executed, except that the light sphere was switched on and the subjects were exposed to white light (4.1 × 10(14) photons/cm(2)/s) for 30 min. Alternative approaches to the calculation of melatonin suppression were taken, with/without inclusion of the baseline night. Eighteen patients and eight healthy volunteers had matched analysable 36 - and 56-h urinary samples. Cosinor analysis showed a significant fit in 88% of the remaining 56 h collections, and 48% of the remaining 36-h collections. Thus, eight patients and five healthy volunteers had matched analysable samples for cosinor analysis. In the healthy volunteers, aMT6s profile indices obtained using the 36 - and the 56-h collections did not differ significantly. In contrast, considerably more variability was observed in patients [i.e. the difference in the aMT6s peak time was 0.5 ± 1.7 h (limits of agreement: -3.9; +2.9 h)]. No difficulties were encountered in obtaining suppression estimates by use of the experimental night only. In contrast, suppression estimates obtained by use of both nights were considered inaccurate in one (11%) healthy volunteer and in 5 (28%) patients, primarily because: (i) melatonin concentrations at the beginning of light administration were significantly different on baseline and experimental night; (ii) the rise in melatonin was inconsistent on baseline night; and (iii) the shape of the rising phase of melatonin was different on baseline and experimental night. In conclusion, shorter urine collections lead to a higher number of profiles with no significant cosinor fit, and differences in cosinor indices obtained from the 36 - and 56-h collections were considerable, especially in patients. Thus, 56-h collections are probably advisable. Use of both baseline and experimental nights to calculate melatonin suppression often resulted in increased variation and confounding, due to point oscillat...

Morning Bright Light Treatment for Sleep-Wake Disturbances in Primary Biliary Cholangitis: A Pilot Study

“…In the present study, patients with cirrhosis showed a very delayed aMT6s acrophase time compared to PBC and healthy volunteers, although the differences were not significant, most likely due to small sample size and considerable inter-individual variability, which has been documented before (Montagnese et al, 2015 ). Delayed sleep-wake (Córdoba et al, 1998 ), melatonin (Steindl et al, 1995 , 1997 ; Velissaris et al, 2009 ; Montagnese et al, 2010 ), urinary aMT6s (Montagnese et al, 2009 ), and cortisol rhythms (Montagnese et al, 2011 ) have all been previously observed in these patients.…”

Skin temperature variability is an independent predictor of survival in patients with cirrhosis

“…Systemic disorders can affect the dynamics of heat loss and cellular heat production via multiple mechanisms such as vasodilatation (Charkoudian, 2010) and mitochondrial dysfunction (Argyropoulos & Harper, 2002), respectively. Furthermore, many systemic diseases such as liver cirrhosis have a significant impact on one's circadian rhythm (Blei & Zee, 1998;De Rui et al, 2015;Montagnese, Middleton, et al, 2015;Montagnese, Middleton, Mani, Skene, & Morgan, 2010) and 24-hr body temperature fluctuations (Garrido et al, 2017). Alterations in skin temperature dynamics and its link with poor outcome is documented in acute clinical settings such as sepsis (Papaioannou et al, 2012(Papaioannou et al, , 2013(Papaioannou et al, , 2019.…”

Nocturnal light pollution and underexposure to daytime sunlight: Complementary mechanisms of circadian disruption and related diseases

“…The widely used electric lights of today, like the Cool White and Daylight White Fluorescent and energy-saving Compact Fluorescent ones, are richer in blue and able to suppress melatonin synthesis when used within 1 h of bedtime (Wahnschaffe et al, 2013). Carefully conduced research over the past two decades demonstrates retinal exposure to as little as 1 lux monochromatic blue 440-460 nm light, 100 lux broad spectrum fluorescent light, or other conventional sources of ALAN can markedly attenuate nocturnal melatonin synthesis (Brainard et al, 2001;Giménez et al, 2014;Glickman et al, 2002;Montagnese et al, 2015;Obayashi et al, 2014a), phase shift the CTS (Gooley et al, 2011;Lockley et al, 2003;Zeitzer et al, 2000), and elevate alertness and disrupt sleep (Brainard et al, 2001;Cajochen et al, 2000;Lockley et al, 2006). Blocking the blue spectrum of light sources prevents such effects (Rahman et al, 2013;van de Werken et al, 2013).…”