Hepatic Encephalopathy and Sleepiness: An Interesting Connection?

Abstract

Sleep-wake abnormalities in patients with cirrhosis have been traditionally associated with hepatic encephalopathy (HE). In recent years, a certain amount of work has been devoted to the study of this relationship. This has lead to a modified picture, with weakening of the association between HE and poor night sleep, and the emergence of stronger links between HE and excessive daytime sleepiness. This brief review focuses on the evidence in favor of the interpretation of HE as a sleepiness syndrome, and on the diagnostic, therapeutic and social implications of such an interpretation. ( J CLIN EXP HEPATOL 2015;5:S49-S53) S leepiness is the expression of a basic physiological need, not unlike hunger or thirst. 1 Its presence and its intensity can be indirectly measured by how readily sleep occurs, how easily it is disrupted, and how long it lasts. Sleep deprivation/restriction increase sleepiness, and sleep reverses it. Routine access to sleep, not unlike that to food or drink, is not only homeostatic, but is influenced by social and environmental factors. Thus subjective sleepiness and its indicators (yawning, nodding etc.) are reduced under conditions such as social interaction, exercise etc. 2 However, when sleepiness is severe, our ability to reduce its impact on behavior is reduced, and the likelihood of sleep increases. There is probably some degree of adaptation to chronic sleepiness, and successfully treated patients report that "they had forgotten the experience of complete alertness". 2 This could provide an explanation for our observation that induced hyperammonaemia results in significantly more pronounced subjective sleepiness in healthy volunteers compared to cirrhotic patients, who may be used to it. 3 The degree of daytime sleepiness is related to both the amount of nocturnal sleep (sleep deprivation/restriction results in increased sleepiness during the following day, 4 ) and its quality (night arousals of different etiology, fragmenting sleep, also result in increased daytime sleepiness. 5 ) Finally, there is a circadian element to sleepiness. Subjects who are allowed to nap in time-free environments do so in a biphasic pattern, with a nap in the middle of the 24-h cycle (or early in the afternoon). 6 Such rhythmicity is preserved in "jet-lagged" conditions, just like that of sleep and feeding.It is assumed that sleepiness is a central nervous system phenomenon with identifiable neural mechanisms. However, limited information is available on whether: 1) the neurochemistry of sleepiness is different to that of sleep; 2) sleepiness and alertness have common or separate neural and neurochemical correlates. The electroencephalogram (EEG) of behaviorally awake subjects who have been deprived/restricted of sleep documents microsleep episodes and increased amounts of theta activity. 7 These neurophysiological events are considered markers/correlates of sleepiness. Neurophysiological studies have implicated histamine, serotonin, catecholamines, and acetylcholine in the control of wakefulness, and gamm...

Impact of Hepatic Encephalopathy in Cirrhosis on Quality-of-Life Issues

“…the oral administration of a mixture of amino acids that mimics the composition of blood, and therefore the increase in ammonia levels and the neuropsychiatric changes that are observed after a variceal bleed) [28]. These observations fit with the hypothesis that HE may be interpreted, at least to some extent, as a syndrome of decreased vigilance [29]. This interpretation of the syndrome has led to the attempt to combine ammonia-lowering and vigilance-enhancing medication.…”

GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study

“…Hepatic encephalopathy (HE), a neurological disorder associated with cirrhosis and portal-systemic shunting in which elevated brain levels of allopregnanolone have been reported (Ahboucha et al 2005 ; Ahboucha et al 2006 ), is one example. The manifestations of HE comprise a wide spectrum that ranges from subtly impaired covert neuropsychiatric abnormalities detectable only by standardized testing to clinically overt abnormalities that include altered motor function, sleep disturbances with changes in the sleep-wake cycle, daytime drowsiness, slurred speech, inappropriate behaviour, impaired memory impairment, shortened attention span, altered mental status with disorientation, coma, and even death (Bajaj et al 2011 ; Montagnese et al 2015 ; Vilstrup et al 2014 ). Indeed, GR3027 has shown promise in two different animal models of HE, including rats with portacaval shunts and rats with chronic hyperammonemia, both of which are associated with increased brain concentrations of neurosteroids (Ahboucha et al 2008 ; Cauli et al 2009 ).…”

“…These include the identification of a population of GABAergic neurons in the ventral lateral hypothalamus that help mediate human wakefulness (Venner et al 2016 ), the identification of a putative GABA-A agonist in the CSF of patients with primary hypersomnia (Rye et al 2012 ), and the clinical observation that the GABA-A antagonist flumazenil can promote wakefulness in patients with EDS (Trotti et al 2016 ). Indeed, the clinical manifestations of HE and hypersomnolence disorders exhibit similarities, and HE has been considered a sleepiness disorder (Montagnese et al 2015 ).…”

Symptom Domain Groups of the Patient-Reported Outcomes Measurement Information System Tools Independently Predict Hospitalizations and Re-hospitalizations in Cirrhosis

“…These findings point toward the importance of assessing daily function concerns at each clinical visit, both physical and mental, along with communicating the plan of care with patients and their family members. Examples of this would be addressing nutritional status to improve sarcopenia and muscle strength [36], and sleep disturbances which can be a sign of impending HE [37] or undiagnosed obstructive sleep apnea [38].…”