Table 2.

Studies on pharmacological and non-pharmacological treatment strategies for sleep–wake disturbance in patients with cirrhosis

First author	Year	Title Journal	Treatment	Patients and methods	Results	Conclusions and notes
Steindl PE	1995	Disruption of the diurnal rhythm of plasma melatonin in cirrhosis Annals of Internal Medicine	Melatonin metabolism	7 cirrhotics and 7 controls. Neuropsychological testing to confirm subclinical HE. Plasma melatonin levels measured every 30 min for 24 h. Sleep diaries kept for 1 week before admission.	Markedly elevated melatonin levels during daytime hours in cirrhosis; significant delay in time of onset of melatonin increase and time at which melatonin levels peaked. More nocturnal awakenings and more frequent daytime naps.	Disruption of the diurnal rhythm of melatonin may reflect alterations of circadian function that could contribute to the disturbances of the sleep–wake cycle in cirrhosis.
Weyerbrock A	1996	Effects of light and chronotherapy on human circadian rhythms in delayed sleep phase syndrome: cytokines, cortisol, growth hormone, and the sleep–wake cycle Biological Psychiatry	Chronotherapy/Light-dark therapy	29-year-old patient with the diagnosis of DSPS: 3-day test session in the sleep laboratory, 3-week hospital chronobiological therapy, 2 nights in sleep laboratory after treatment. Interleukin-1β and γ-interferon determined in endotoxin-stimulated 48-h whole-blood cultures. Cortisol and GH plasma levels measured.	After treatment, the patient maintained a conventional sleep–wake schedule, sleep efficiency was increased and the number of wake periods was significantly reduced.	Chronotherapy effectively relieved symptoms and acceptably adjusted the sleep period. Cortisol and cytokine 24-h rhythms appear to be altered in DSPS and respond to light therapy.
Spahr L	2007	Histamine H1 blocker hydroxyzine improves sleep in patients with cirrhosis and minimal hepatic encephalopathy: a randomized controlled pilot trial The American Journal of Gastroenterology	Hydroxyzine	35 patients with MHE and sleep difficulties randomized to hydroxyzine 25 mg at bedtime (N = 17) or placebo (N = 18) for a 10-day period. Measurements of sleep behaviour using VAS and actigraphy, neuropsychological tests, protein s100beta serum levels, at baseline and at day 10.	Subjective improvement in sleep in 40% of hydroxyzine-treated patients but in none receiving placebo. > or = 30% increase in sleep efficiency (actigraphy) in 65% of hydroxyzine-treated patients versus 25% of patients under placebo. Acute episode of encephalopathy reversible upon cessation of hydroxyzine in one patient.	Hydroxyzine 25 mg at bedtime improved sleep behaviour in patients with cirrhosis and minimal HE. Risk of precipitating overt HE.
Prasad S	2007	Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy Hepatology	Lactulose	Psychometry and HRQoL (SIP) of 90 cirrhotics (61 with MHE) on inclusion and 3 months later. Randomly assigned in a 1:1 ratio to receive treatment (lactulose) for 3 months (n = 31) or no treatment (n = 30).	Mean number of abnormal neuropsychological tests decreased significantly in patients in the treated group, compared with the untreated group. Mean total SIP score improved in the treated group. Improvement in HRQoL related to the improvement in psychometry.	Treatment with lactulose improves both cognitive function and HRQoL in cirrhotic patients with MHE.
Velissaris D	2008	Pituitary hormone circadian rhythm alterations in cirrhosis patients with subclinical hepatic encephalopathy World Journal of Gastroenterology	Melatonin and cortisol circadian patterns	26 patients with cirrhosis. 13 patients with systemic diseases not affecting the liver as controls. Neurological assessment, EEG, MRI, assays of pituitary hormone, cortisol and melatonin.	Abnormalities in pituitary hormone and melatonin circadian patterns in cirrhotic patients without OHE. Absence of cortisol secretion abnormalities in any patient, but low basal cortisol levels, correlated with EEG and brain MRI abnormalities. Melatonin identified as the only hormone associated with severity of liver insufficiency.	Abnormal pituitary hormone and melatonin circadian patterns are present in cirrhosis before the development of HE. These abnormalities may be early indicators of impending HE.
Montagnese S	2009	Sleep and circadian abnormalities in patients with cirrhosis: features of delayed sleep phase syndrome? Metabolic Brain Disease	Light therapy	Sleep monitored for 2 weeks, at home, with sleep diaries and actigraphy, in 35 patients with cirrhosis and 12 healthy controls; urinary aMT6s measured over 56 h, to assess circadian rhythmicity.	Later wake up and get up time and more fragmented sleep in patients. Mean 24-h urinary aMT6s outputs comparable in patients and controls but significantly lower in decompensated patients. Significant 24-h urinary aMT6s rhythms observed in 26 of 33 patients; 20 patients with normally timed urinary aMT6s peak, while delayed (> or = 06:00) in the remainder. Correlations between abnormalities in the urinary aMT6s profile and indices of sleep timing; parallel delays in sleep habits and urinary aMT6s peaks.	Delayed circadian rhythms and delayed sleep habits is reminiscent of ‘delayed sleep phase syndrome’; condition managed by attempting to resynchronise the circadian clock by exposure to bright light shortly after morning awakening.
Montagnese S	2010	On the origin and the consequences of circadian abnormalities in patients with cirrhosis American Journal of Gastroenterology	Circadian clock function and hepatic melatonin metabolism	20 patients with cirrhosis and 9 healthy volunteers. Plasma melatonin/cortisol concentrations measured hourly, for 24 h, in light/posture-controlled conditions. Urinary aMT6s measured simultaneously (clearance). Ability of light to suppress nocturnal melatonin synthesis assessed. Habitual sleep quality/timing evaluated using questionnaire, actigraphy, and sleep diaries.	Evidence of central circadian disruption in patients vs controls: delayed peak plasma melatonin/cortisol times and reduced plasma melatonin response to light. However, non-significant difference in mean 24 h plasma melatonin clearance between patients and volunteers. Misalignment between sleep and circadian timings in patients but no association between circadian abnormalities and impaired sleep quality.	Patients with mild to moderately decompensated cirrhosis present plasma melatonin profile abnormalities, predominantly central in origin but substantially unrelated to sleep disturbances.
De Rui M	2011	Bright times for patients with cirrhosis and delayed sleep habits: a case report on the beneficial effect of light therapy The American Journal of Gastroenterology	Light therapy	Sleep time/quality monitored with sleep diaries, KSS and EEG - appropriately timed light administration.	Sleep–wake rhythms progressively improved, with reduced daytime sleepiness and fewer night awakenings.	Should the observed, beneficial effect of light therapy be confirmed by formal trials, a rational, non-pharmacological, and side-effect-free treatment might become available.
De Rui M	2014	Sleep and circadian rhythms in hospitalized patients with decompensated cirrhosis: effect of light therapy Neurochemical Research	Light therapy	Complete sleep–wake assessment, with qualitative and semi-quantitative (actigraphic) indices of night-time sleep quality, daytime sleepiness, diurnal preference, habitual sleep timing, quality of life, mood and circadian rhythmicity (i.e. aMT6s). 5 patients randomly assigned to a single room with controlled lighting in relation to timing, spectral composition and intensity; 7 in identical rooms with standard lighting.	Sleep diaries and actigraphy: poor sleep quality, prolonged sleep latency and a reduced sleep efficiency. Quality of life globally impaired, mood moderately depressed. Serial urine collections in 7 patients: no circadian aMT6s rhythm detected in any of them, neither at baseline, nor during the course of hospitalization in either room.	Sleep and circadian rhythms in hospitalized, decompensated cirrhotic patients extremely compromised. No obvious, beneficial effects after treatment with bright light therapy, most likely in relation to the severity of disturbance at baseline.
Casula EP	2015	Acute hyperammonaemia induces a sustained decrease in vigilance, which is modulated by caffeine Metabolic Brain Disease	Caffeine	10 healthy volunteers, two-hourly measurements of capillary ammonia, subjective sleepiness (KSS) and vigilance (PVT), in relation to the intake of breakfast (+/−coffee), AAC and AAC + coffee.	AAC resulted in increase in: capillary ammonia levels (with highest values at approximately 4 h after the administration), subjective sleepiness ratings, PVT-based reaction times. When caffeine administered after AAC, subjective sleepiness and slowing in RTs significantly milder.	Acute hyperammonaemia induces an increase in sleepiness and decrease in vigilance, attenuated by caffeine.
Liu C	2015	Health-related management plans improve sleep disorders of patients with chronic liver disease International Journal of Clinical and Experimental Medicine	Lavender hot-bathing and foot-soaking, progressive relaxation	317 subjects. Initially, 197 CLD patients divided randomly into four groups for receiving lavender hot-bathing and foot-soaking, progressive relaxation, or the combination of both methods, and controls. Sleep state questionnaires to assess sleep qualities and SRSS to assess sleep disorder. Another cohort with 120 CLD patients also investigated for further confirming related findings.	The SRSS scores were significantly higher in patients with CLD than those of domestic common model and internal medicine inpatients. All three methods of intervention improved SRSS scores.	Health education could reduce risk factors and implement intervention strategies; effectively decreased occurrence of sleep disorder related symptoms.
Cassidy S	2016	Diet, Physical Activity, Sedentary Behaviour and Sleep in 1289 Adults with Liver Disease; A Cross Sectional Study of Data from the UK Biobank Journal of Hepatology	Diet and physical activity	Diet, physical activity, sedentary behaviour and sleep across several liver disease groups: 1. liver/biliary/pancreas disease, 2. alcoholic liver disease, 3. liver cirrhosis, compared to healthy controls.	Low physical activity, high sedentary behaviour and poor sleep as high risk characteristics of liver disease.	Lifestyle interventions should focus on targeting multiple lifestyle behaviours in the prevention and management of liver disease.
Garrido M	2016	Vigilance and wake EEG architecture in simulated hyperammonaemia: a pilot study on the effects of L-Ornithine-L-Aspartate (LOLA) and caffeine Metabolic Brain Disease	L-Ornithine-L-Aspartate (LOLA) and caffeine	6 cirrhotics and 6 volunteers. Hourly capillary ammonia, hourly subjective sleepiness, psychometry and wake EEG at 12:00, i.e. at the time of the maximum expected effect of the AAC.	In volunteers, post-AAC increase in capillary ammonia levels contained by both the administration of LOLA and caffeine. Reduction in subjective sleepiness and in the amplitude of the EEG after administration of caffeine. Changes in ammonia levels, subjective sleepiness and EEG less obvious in patients.	AAC-induced increase in capillary ammonia, contained by both LOLA and caffeine, especially in healthy volunteers. Caffeine also counteracted the AAC effects on sleepiness/EEG amplitude.
Singh J	2017	Sleep disturbances in patients of liver cirrhosis with minimal hepatic encephalopathy before and after lactulose therapy Metabolic Brain Disease	Lactulose	100 cirrhotics (n 50 MHE, n 50 no-MHE). Sleep disturbances measured with PSQI, ESS and polysomnography. HRQoL measured with SF-36(v2) questionnaire. All parameters repeated after 3 months of lactulose therapy in patients with MHE.	Poor quality of sleep and excessive daytime sleepiness more common in patients with MHE, compared to those without MHE. With lactulose therapy, improvement in MHE in 21 patients (arterial ammonia levels, CFF, PHES, PSQI, ESS, HRQoL).	Excessive daytime sleepiness and impaired sleep quality in patients with MHE correlate with neuropsychiatric impairment. Improvement in MHE with lactulose also leads to improvement in sleep disturbances and HRQoL.
Bajaj JS	2017	Mindfulness-based stress reduction therapy improves patient and caregiver-reported outcomes in cirrhosis Clinical and Translational Gastroenterology	Mindfulness-based stress reduction therapy	20 patient/caregiver dyads included. Cirrhotic outpatients with mild depression on screening with an adult caregiver enrolled. At baseline, BDI, sleep (PSQI, ESS), anxiety and HRQoL for both patients/caregivers; caregiver burden and patient CHE status measured. Structured MBSR program with four weekly hour-long group sessions interspersed with home practice using CDs.	Significant improvement in BDI, PSQI and overall HRQoL but not in anxiety or CHE rates in patients. Similarly caregiver burden and depression reduced while caregiver sleep quality improved.	A short program of mindfulness and supportive group therapy significantly improves PRO and caregiver burden in patients with depression. This non-pharmacological method could alleviate psychosocial stress in patients with end-stage liver disease and their caregivers.
Bruyneel M	2017	Improvement of sleep architecture parameters in cirrhotic patients with recurrent hepatic encephalopathy with the use of rifaximin European Journal of Gastroenterology and Hepatology	Rifaximin	15 patients. 24-h polysomnography and 7-day actigraphy. REM sleep: indicator of good sleep quality. Questionnaires assessing the quality of sleep and sleepiness. The same assessment repeated after a 28-day course of rifaximin	Polysomnography: long TST and limited REM sleep. Actigraphy: impaired number of steps. Questionnaires: impaired sleep quality and excessive daytime sleepiness. After rifaximin, decrease of HE scores, increase of REM sleep, no changes for TST, number of steps, and on questionnaires.	Rifaximin improves objective sleep architecture parameters on polysomnography, with no changes in the subjective quality of sleep and sleepiness.

AAC, amino acid challenge; aMT6s, 6-sulphatoxymelatonin; BDI, Beck Depression Inventory; CFF, critical flicker frequency; CLD, chronic liver disease; DSPS, delayed sleep phase syndrome; EEG, electroencephalogram; ESS, Epworth Sleepiness Scale; GH, growth hormone; HE, hepatic encephalopathy; MHE/CHE, minimal/covert hepatic encephalopathy; OHE, overt hepatic encephalopathy; HRQoL, health-related quality of life; KSS, Karolinska Sleepiness Scale; MBSR, mindfulness-based stress reduction; MCTQ, Munich ChronoType Questionnaire; MRI, magnetic resonance imaging; NAFLD, non-alcoholic fatty liver disease; NPV, negative predictive value; PFC, plasma free cortisol; PRO, patient-reported outcomes; PSQI, Pittsburgh Sleep Quality Index; PSS, porto-systemic shunt; PVT, psychomotor vigilance task; REM, rapid eye movement; RTs, reaction times; SIP, sickness impact profile; SRSS, self-rating scores of sleep; STSQS, sleep timing and sleep quality screening; TST, total sleep time; VAS, Visual Analogue Scale