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Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver insufficiency and/or portosystemic shunting. HE is mostly episodic and as such reversible. Hyperammonemia clearly plays a key role in the pathophysiology, but the precise detrimental events in the brain leading to HE remain equivocal. Several pathogenic models have been proposed, but few have been linked to clinical studies and observations. Decreased oxygen metabolism is observed in both type A and C HE and in this review, we advocate that this reflects an actual reduced oxygen demand and not a primary cause of HE. As driving force, we propose that the hyperammonemia via astrocytic glutamine synthetase causes an increased γ-aminobutyric acid (GABA) mediated neuro-inhibition which subsequently leads to an overall decreased energy demand of the brain, something that can be enhanced by concomitant neuroinflammation. This also explains the reversibility of the condition., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background & Aims: Sleep disturbances are related to hepatic encephalopathy and hyperammonaemia in patients with cirrhosis. The circadian rhythm is regulated by light stimulation of the retina via melanopsin-containing ganglion cells. The study aimed to investigate whether induced hyperammonaemia affects the pupillary light response and sleep efficiency in patients with cirrhosis., Methods: The study was a single-blinded crossover trial including nine patients with cirrhosis. Sleep was evaluated by Pittsburgh Sleep Quality Index (PSQI) and monitored for twelve nights with wrist accelerometers and sleep diaries. On two experimental days, separated by one week, patients were randomized to ingest either an oral amino acid challenge (AAC) or an isocaloric glucose solution (GS). We measured pupillary light response, capillary ammonia, the Karolinska Sleepiness Scale (KSS), and two neuropsychological tests on both experimental days., Results: The patients had poor self-assessed sleep quality. The amino acid challenge led to a significant increase in capillary ammonia and KSS. The time spent in bed sleeping after AAC was longer and with a reduced movement index compared to baseline but not different from GS. We found no difference in the pupillary light response or neuropsychiatric tests when comparing the effect of AAC with GS., Conclusions: Patients with cirrhosis had impaired sleep quality. Induced hyperammonaemia led to increased sleepiness but had no acute effect on pupillary light response or the neuropsychiatric tests., Trial Registration: Registration number: NCT04771104., Competing Interests: The authors have declared that no competing interests exist.

In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. Astrocytes cultured in ammonia have shown mitochondrial dysfunction and in rat models of liver failure, de novo lactate production in the brain has been observed and has led to a hypothesis of compromised brain metabolism during ALF. In contrast, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen: glucose ratio of cerebral metabolic rates remains normal. To investigate this inconsistency we studied the mitochondrial function in brain tissue with respirometry in animal models of hyperammonaemia. Wistar rats with systemic inflammation induced by lipopolysaccharide or liver insufficiency induced by 90% hepatectomy were given ammonium or sodium acetate for 120 min. A cerebral cortex homogenate was studied with respirometry and substrates of the citric acid cycle, uncouplers and inhibitors of the mitochondrial complexes were successively added to investigate the mitochondrial function in detail. In a separate dose-response experiment cortex from healthy rats was incubated for 120 min in ammonium acetate in concentrations up to 80 mM prior to respirometry. Hyperammonaemia was associated with elevated ICP and increased tissue lactate concentration. No difference between groups was found in total respiratory capacity or the function of individual mitochondrial complexes. Ammonium in concentrations of 40 and 80 mM reduced the respiratory capacity in vitro. In conclusion, acute hyperammonaemia leads to elevated ICP and cerebral lactate accumulation. We found no indications of impaired oxidative metabolism in vivo but only in vitro at extreme concentrations of ammonium.

Introduction: Systemic inflammation may affect the brain by aggravating the stage of encephalopathy and increasing intracranial pressure (ICP) especially if liver insufficiency with hyperammonemia is present. The aim of this study was to determine if the influence of concomitant hyperammonemia and lipopolysaccharide (LPS) on the brain can be prevented by dexamethasone and cyclooxygenase (COX) inhibitors., Method: Fifty-four male Wistar rats, 6 in each group, were divided into the following groups: Saline+ saline; LPS (2 mg/kg)+saline; LPS+indomethacin (10 mg/kg); LPS+diclofenac (10mg/kg); LPS+dexamethasone (2mg/kg) in experiment A. Experiment-B included the following groups: LPS+NH3 (140 μmol/kg/min)+saline; LPS+NH3+indomethacin; LPS+NH3+diclofenac and LPS+NH3+dexamethasone. ICP was monitored via a catheter placed in cisterna magna and changes in CBF were recorded by laser Doppler flowmetry., Results: LPS with and without NH3 induced a similar increase in plasma 6-keto-prostaglandin-F1α (6-keto-PGF1α) concentration together with a concomitant rise in CBF and ICP. Indomethacin and diclofenac prevented the increase in ICP by LPS alone, and with the addition of NH3 the increase in both CBF and ICP, which was associated with a decrease in 6-keto-PGF1α. Dexamethasone only reduced the LPS induced increase in ICP but not CBF, and partly the 6-keto-PGF1α plasma concentration in the combined setup., Conclusion: These data indicate that activation of cycloooxygenases is of central importance for development of cerebral hyperemia and high ICP during concomitant systemic inflammation and hyperammonemia.

Acute liver failure (ALF) can lead to brain edema, cerebral hyperperfusion and intracranial hypertension. These complications are thought to be mediated by hyperammonemia and inflammation leading to altered brain metabolism. As increased levels of adenosine degradation products have been found in brain tissue of patients with ALF we investigated whether hyperammonemia could induce adenosine release in brain tissue. Since adenosine is a potent vasodilator and modulator of cerebral metabolism we furthermore studied the effect of adenosine receptor ligands on intracranial pressure (ICP) and cerebral blood flow (CBF). We measured the adenosine concentration with biosensors in rat brain slices exposed to ammonia and in a rat model with hyperammonemia and systemic inflammation. Exposure to ammonia in concentrations from 0.15-10 mM led to increases in the cortical adenosine concentration up to 18 µM in brain slices. In vivo recordings showed a tendency towards increased adenosine levels in rats with hyperammonemia and systemic inflammation compared to a control group (3.7 ± 0.7 vs. 0.8 ± 0.2 µM, P = 0.06). This was associated with a significant increase in ICP and CBF. Intervention with the non-selective adenosine receptor antagonist theophyllamine, the A2A receptor antagonist ZM241385, or the A1 receptor agonist N6-Cyclopentyladenosine did not reduce ICP or CBF. In conclusion, our results show that the adenosine concentration in cortex increases during exposure to ammonia, and is associated with a rise in intracranial pressure and cerebral perfusion. However adenosine receptor antagonism/agonism did not reduce the ICP or CBF which indicates that adenosine may not be of direct importance for these cerebral complications in ALF.

Unlabelled: Intravenous infusion of magnesium sulfate prevents seizures in patients with eclampsia and brain edema after traumatic brain injury. Neuroprotection is achieved by controlling cerebral blood flow (CBF), intracranial pressure, neuronal glutamate release, and aquaporin-4 (Aqp4) expression. These factors are also thought to be involved in the development of brain edema in acute liver failure. We wanted to study whether hypermagnesemia prevented development of intracranial hypertension and hyperperfusion in a rat model of portacaval anastomosis (PCA) and acute hyperammonemia. We also studied whether hypermagnesemia had an influence on brain content of glutamate, glutamine, and aquaporin-4 expression. The study consisted of three experiments: The first was a dose-finding study of four different dosing regimens of magnesium sulfate (MgSO4) in healthy rats. The second involved four groups of PCA rats receiving ammonia infusion/vehicle and MgSO4) /saline. The effect of MgSO(4) on mean arterial pressure (MAP), intracranial pressure (ICP), CBF, cerebral glutamate and glutamine, and aquaporin-4 expression was studied. Finally, the effect of MgSO4 on MAP, ICP, and CBF was studied, using two supplementary dosing regimens. In the second experiment, we found that hypermagnesemia and hyperammonemia were associated with a significantly higher CBF (P < 0.05, two-way analysis of variance [ANOVA]). Hypermagnesemia did not lead to a reduction in ICP and did not affect the brain content of glutamate, glutamine, or Aqp-4 expression. In the third experiment, we achieved higher P-Mg but this did not lead to a significant reduction in ICP or CBF., Conclusion: Our results demonstrate that hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in rats with PCA and hyperammonemia., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Acute liver failure (ALF) is a condition with an unfavourable prognosis. Multiorgan failure and circulatory collapse are frequent causes of death, but cerebral edema and intracranial hypertension (ICH) are also common complications with a high risk of fatal outcome. The underlying pathogenesis has been extensively studied and although the development of cerebral edema and ICH is of a complex and multifactorial nature, it is well established that ammonia plays a pivotal role. This review will focus on the effects of hyperammonemia on neurotransmission, mitochondrial function, oxidative stress, inflammation and regulation of cerebral blood flow. Finally, potential therapeutic targets and future perspectives are briefly discussed.