Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?

Häussinger, Dieter; Kircheis, G.; Fischer, Richard; Schliess, Freimut; Dahl, Stephan Vom

doi:10.1016/s0168-8278(00)80110-5

Cited by 422 publications

(271 citation statements)

References 34 publications

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“…The reduced PS BBB in the patients with cirrhosis with HE might be linked to inflammatory factors 46 or increased diffusion distance through an increased extracellular volume in patients with cirrhosis with low-grade cerebral edema. 47 It also could be related to other abnormalities such as altered membrane properties attributable to long-term exposure to elevated blood ammonia in analogy with the decreased membrane fluidity observed in patients with chronic high alcohol intake. 48 Finally, the activity of specific transport proteins for NH 4 ϩ in the BBB 4 may be altered because of high ammonia concentrations.…”

Section: Discussionmentioning

confidence: 99%

Brain metabolism of 13N‐ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography†

et al. 2006

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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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Section: Discussionmentioning

confidence: 99%

Brain metabolism of 13N‐ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography†

et al. 2006

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“…43 Experimental models of CLF in rats have consistently shown no evidence of BBB breakdown, 28,44 however Chavarria and colleagues 45 have recently provided evidence for the presence of both cytotoxic and vasogenic edema in cirrhotic patients awaiting liver transplantation. It has been proposed that low-grade astrocyte swelling, as may be seen in CLF, 46 could have significant functional consequences despite the absence of clinically overt ICH, and impairment of the cross-talk between swollen astrocytes and neurones has also been suggested to alter cerebral function. 47 Evidence suggests that the neuropsychological effects of induced hyperammonaemia, and the subsequent elevation of astrocyte glutamine levels, are determined by the intrinsic ability of the brain to buffer these changes by losing key osmolytes such as myo-inositol 48 ; a process which may in itself be modulated by other factors such as hyponatraemia, a major risk factor for the development of overt HE in patients with CLF.…”

Section: Ammonia and The Brain: The Sick Astrocytementioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

246

190

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The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. ( J CLIN EXP HEPATOL 2015;5:S7-S20) H epatic encephalopathy (HE) is the term used to encapsulate the broad spectrum of neuropsychiatric disturbances associated with both acute and chronic liver failure (ALF and CLF, respectively), as well as porto-systemic bypass in the absence of hepatocellular disease. The clinical manifestations of HE can be extremely heterogeneous in nature, with symptoms presenting anywhere on a continuum spanning from seemingly normal cognitive performance, right the way through to states of confusion, stupor and coma. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleep-wake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia.ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease. 1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death. H...

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“…Similarly, this would entail that the increase in brain water found in CLD is less than the quantity found in ALF and, therefore, has been defined as "low-grade" brain edema (Fig. 1B, points A → B) (Häussinger et al, 2000). A second explanation could be that the quantity of accumulated water in the brain parenchyma is similar in both ALF and CLD, but the volume of other brain constituents is altered (Fig.…”

Section: Relationship Between Intracranial Pressure and Brain Edemamentioning

confidence: 99%

“…It is believed that small increases in astrocyte water content may have important functional consequences, including neuronal dysfunction, despite the absence of intracranial hypertension (Häussinger et al, 2000). Termed "low-grade" edema, this suggests that HE represents a clinical manifestation of astrocyte swelling.…”

Section: Role Of Brain Edema In Hementioning

confidence: 99%

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Bosoi

Rose

2013

Neurochemistry International

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Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed. HighlightsBrain edema is a common feature in ALF and CLD. HE is inconsistently associated with the presence of brain edema. Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. The pathogenesis of HE is multifactorial causing an array of neurological symptoms.

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Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema?

Cited by 422 publications

References 34 publications

Brain metabolism of 13N‐ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography†

Brain metabolism of 13N‐ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography†

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

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