Montagnese, S.; (2009) Sleep and circadian rhythms in patients with cirrhosis. Doctoral thesis , UCL (University College London).

Abstract

Circadian regulation synchronises the sleep-wake cycle to the light-dark cycle. Light cues reach the hypothalamus, the site of the circadian clock, via the retino-hypothalamic tract. In turn, the hypothalamus projects to the pineal, regulating melatonin synthesis, which is high at night. The rhythms of plasma melatonin, its urinary metabolite 6-sulphatoxymelatonin (aMT6s) and plasma cortisol are reliable markers of ihe phase of the clock. Sleep-wake abnormalities are common in patients with cirrhosis and have traditionally been attributed to hepatic encephalopathy. Melatonin rhythm abnormalities have also been observed in these patients, and generally ascribed to impaired hepatic melatonin metabolism; their impact on sleep-wake behaviour remains unknown. The purpose of this thesis was to clarify the relationship between sleep-wake and neuropsychiatric disturbance in patients with cirrhosis and to determine the contribution of the circadian regulatory mechanisms. • Almost 70% of patients with cirrhosis showed significant sleep-wake disturbance. However, no relationship was observed between sleep-wake indices and the presence/degree of hepatic encephalopathy. • Patients with cirrhosis showed. evidence_ of impaired hepatic melatonin metabolism, namely reduced nocturnal melatonin clearance, delayed aMT6s peaks and significant correlations between circadian markers and indices of hepatic failure. • Patients with cirrhosis also showed evidence of central circadian disruption, with parallel delays in the onset of plasma melatonin/plasma cortisol rhythms and attenuated melatonin sensitivity to lignt. • Circadian rhythm delays were associated with delayed sleep habits, but not with impaired sleep quality. A subgroup of patients also exhibited a degree of desynchronisation between sleep and circadian timing. The association between circadian and sleep timing abnormalities observed in patients w]th cirrhosis is reminiscent of ‘delayed sleep phase syndrome', and probably susceptible to treatment. However, circadian deregulation does not offer a comprehensive explanation for the sleep quality impairment exhibited by these patients and alternative pathophysiological pathways should be explored.

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