Portal-Systemic Encephalopathy Neurological Complications of Liver Disease

Sherlock, Sheila; Summerskill, W.H.J.; White, LaurensP.; Phear, ElizabethA.

doi:10.1016/s0140-6736(54)91874-7

Cited by 436 publications

(172 citation statements)

References 7 publications

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“…[1][2][3][4] The effects of experimental porta-caval anastomosis with or without pharmacological manipulations of ammonia metabolism have been examined in rat brain, [5][6][7][8][9][10][11][12][13] and the effects of excess ammonia have been tested in astrocyte cell cultures. 14 Human studies of cerebral uptake and metabolism of ammonia included postmortem examinations of brain tissue from patients dying of HE 15 and biochemical analysis of jugular vein blood samples.…”

mentioning

confidence: 99%

Brain metabolism of13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography

et al. 2005

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, PS BBB , was 0.21 mL blood/min/mL tissue in patients with HE, 0.31 in patients without HE, and 0.34 in healthy controls; similar differences were seen in basal ganglia and cerebellum. Metabolic trapping of blood 13 N-ammonia in the brain showed neither regional, nor patient group differences. Mean net metabolic flux of ammonia from blood into intracellular glutamine in the cortex was 13.4 mol/min/L tissue in patients with cirrhosis with HE, 7.4 in patients without HE, and 2.6 in healthy controls, significantly correlated to blood ammonia. In conclusion, increased cerebral trapping of ammonia in patients with cirrhosis with acute HE was primarily attributable to increased blood ammonia and to a minor extent to changed ammonia kinetics in the brain. (HEPATOLOGY 2006;43:42-50.) T he role of ammonia in the pathogenesis of hepatic encephalopathy (HE) and possible deleterious effects on brain energy metabolism and neurotransmission has been extensively studied. [1][2][3][4] The effects of experimental porta-caval anastomosis with or without pharmacological manipulations of ammonia metabolism have been examined in rat brain, 5-13 and the effects of excess ammonia have been tested in astrocyte cell cultures. 14 Human studies of cerebral uptake and metabolism of ammonia included postmortem examinations of brain tissue from patients dying of HE 15 and biochemical analysis of jugular vein blood samples. [16][17][18] More recently, ammonia metabolism has been tested in positron emission tomography (PET) studies of monkeys, 19 healthy humans, [19][20][21][22] and patients with cirrhosis and minimal HE. [20][21][22][23] The 13 N-ammonia PET technique can, in conjunction with proper compartmental analysis, give quantitative estimates of kinetic parameters in awake subjects.Results of early PET studies by Phelps et al. 19 indicated the presence of regional variations in cerebral 13 N-ammonia uptake in normal human subjects. Lockwood et al. 20 subsequently emphasized that the metabolism of ammonia to glutamine in brain influences cerebral ammonia uptake and later calculated a global rate of cerebral 13 Nammonia metabolism in patients with cirrhosis with minimal HE and healthy controls. 21,22 Recently, Ahl et al., 23 using dynamic PET studies, found no significant difference of the permeability-surface area product of the trans-

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confidence: 99%

Brain metabolism of13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography

et al. 2005

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“…19 In at least two studies, an association between excessive sleepiness and the presence/degree of HE was also observed. [24][25][26] In addition, sleepiness has been shown to be more common in cirrhotic patients with a history of HE and documented portal-systemic shunt, 28 and to be positively correlated with the amount of slow activity on the wake EEG.…”

Section: Sleepiness and Hepatic Encephalopathymentioning

confidence: 96%

“…the combination of restless nights and excessive daytime sleepiness) as a feature of severe HE. 19 Subsequent, anecdotal evidence suggests that sleep abnormalities worsen following the insertion of portal-systemic shunts, 20 and improve after the institution of treatment with ammonia-lowering drugs. 21 These few findings, together with a tradition of grouping central nervous system complications of cirrhosis, have lead to the belief that the pathogenesis of sleep-wake disturbances exhibited by these patients is closely related if not identical to that of HE.…”

Section: Sleepiness and Hepatic Encephalopathymentioning

confidence: 99%

Hepatic Encephalopathy and Sleepiness: An Interesting Connection?

Montagnese

Turco

Amodio

2015

Journal of Clinical and Experimental Hepatology

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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...

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“…It was assumed that such substances are absorbed and are normally extracted from portal venous blood and metabolized by the liver. It was further assumed that in liver failure appreciable amounts of these substances gain access to the systemic circulation and ultimately the brain as a result of passage through portal-systemic venous collateral channels and/or impaired hepatic extraction [44]. As an alternative to hepatic encephalopathy, the term portal-systemic encephalopathy was introduced to embrace these concepts, and this term has withstood 306 the test of time.…”

Section: Gaba-ergic Neurotransmission In Liver Failurementioning

confidence: 99%

The GABA Hypothesis of the Pathogenesis of Hepatic Encephalopathy: Current Status

Jones

Schafer

Ferenci

et al. 1987

Assessment and Management of Hepatobiliary Disease

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Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter of the mammalian brain, can induce coma. Outside the central nervous system it is synthesized by gut bacteria and catabolized largely in the liver. GABA and its agonists, as well as benzodiazepines and barbiturates, induce neural inhibition as a consequence of their interaction with specific binding sites for each of these classes of neuroactive substances on the GABA receptor complex of postsynaptic neurons. In a rabbit model of acute liver failure: (i) the pattern of postsynaptic neuronal activity in hepatic coma, as assessed by visual evoked potentials, is identical to that associated with coma induced by drugs which activate the GABA neurotransmitter system (benzodiazepines, barbiturates, and GABA agonists); (ii) the levels of GABA-like activity in peripheral blood plasma increase appreciably before the onset of hepatic encephalopathy, due at least in part to impaired hepatic extraction of gut-derived GABA from portal venous blood;(iii) the blood-brain barrier becomes abnormally permeable to an isomer of GABA, a-aminoisobutyric acid, before the onset of hepatic encephalopathy; and (iv) hepatic coma is associated with an increase in the density of receptors for GABA and benzodiazepines in the brain. These findings are the bases of the following hypotheses: (i) when the liver fails, gut-derived GABA in plasma crosses an abnormally permeable blood-brain barrier and by mediating neural inhibition contributes to hepatic encephalopathy; (ii) an increased number of GABA receptors in the brain found in liver failure increases the sensitivity of the brain to GABA-ergic neural inhibition; and (iii) an increased number of drug binding sites mediates the increased sensitivity to benzodiazepines and barbiturates observed in liver failure by permitting increased drug effect. INTRODUCTIONHepatocellular failure, whether acute or chronic, is characterized by jaundice, fluid retention, a hemorrhagic diathesis, and hepatic encephalopathy [1]. Of these four complications of liver disease the pathogenesis of hepatic encephalopathy is least well understood. It has not even been established whether hepatic encephalopathy occurs as a result of failure of the liver to synthesize a substance that is necessary for the maintenance of normal brain function or failure of the liver to metabolize adequately neuroactive substances that are capable of inducing encephalopathy.

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Portal-Systemic Encephalopathy Neurological Complications of Liver Disease

Cited by 436 publications

References 7 publications

Brain metabolism of13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography

Brain metabolism of13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography

Hepatic Encephalopathy and Sleepiness: An Interesting Connection?

The GABA Hypothesis of the Pathogenesis of Hepatic Encephalopathy: Current Status

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