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Hepatic encephalopathy: Pathogenesis

Hepatic encephalopathy: Pathogenesis
Author:
Peter Ferenci, MD
Section Editor:
Bruce A Runyon, MD, FAASLD
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Literature review current through: Dec 2022. | This topic last updated: Apr 05, 2022.

INTRODUCTION — Hepatic encephalopathy (HE) or portosystemic encephalopathy (PSE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver failure. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis".)

However, HE is not a single clinical entity. It may reflect either a reversible metabolic encephalopathy, brain atrophy, brain edema, or any combination of these conditions. The mechanisms causing brain dysfunction in liver failure are still unknown. In advanced coma, the effects of brain swelling, impaired cerebral perfusion, and reversible impairment of neurotransmitter systems cannot be distinguished. Furthermore, these events overlap, at least in models of acute liver failure.

Data on cerebral function in HE are usually derived from animal studies since brains of patients with HE cannot be studied with neurochemical or neurophysiologic methods. It is beyond the scope of this review to discuss each of the animal models in detail, but it must be appreciated that they may not accurately reflect human disease.

The metabolic factors that contribute to the development of HE will be reviewed here [1]. Ammonia is clearly implicated; in addition, there may be a role for inhibitory neurotransmission through gamma-aminobutyric acid (GABA) receptors in the central nervous system and changes in central neurotransmitters and circulating amino acids. These hypotheses are not mutually exclusive, and multiple factors may be present at the same time. Therapies for hepatic encephalopathy are based upon these hypotheses. (See "Hepatic encephalopathy in adults: Treatment".)

Some precipitating factors are directly related to liver failure (eg, decreased metabolism of ammonia). Concurrent disorders can also contribute to the development of HE. These factors include (table 1):

Decreased oxygen delivery, which can result from a variety of issues including gastrointestinal bleeding, sepsis, the effects of cytokines or compounds released from necrotic liver tissue [2]. In particular, proinflammatory cytokines may have a pivotal role in impairing several brain functions [3,4]. The effects of hypotension on cerebral perfusion may be magnified in liver failure because of an associated impairment in the autoregulation of cerebral blood flow [5,6].

Functional and structural changes in the brain that are independent of the liver failure, such as changes seen in patients with alcohol use disorder, patients who inject drugs, or patients with Wilson disease.

Creation of a portosystemic shunt to treat portal hypertension, as with a transjugular intrahepatic portosystemic shunt, precipitates HE in approximately 30 percent of patients. (See "Transjugular intrahepatic portosystemic shunts: Postprocedure care and complications".)

Other events which can precipitate HE such as the administration of sedatives, hypokalemia, and hyponatremia (see "Hyponatremia in patients with cirrhosis").

The effect of hypokalemia is thought to be mediated by potassium movement out of the cells to replenish extracellular stores [7]. Electroneutrality is maintained in part by the movement of extracellular hydrogen into the cells; the ensuing intracellular acidosis in renal tubular cells increases the production of ammonia [8]. The often concurrent metabolic alkalosis may contribute by promoting the conversion of ammonium (NH4+), a charged particle which cannot cross the blood-brain barrier, into ammonia (NH3) which can enter the brain [8].

NEUROTOXINS

Ammonia — Ammonia is the best characterized neurotoxin that precipitates HE. The gastrointestinal tract is the primary source of ammonia, which enters the circulation via the portal vein. Ammonia is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested protein and secreted urea. Another source of ammonia may be urea digested by Helicobacter pylori in the stomach [9], although the role of H. pylori in HE is unclear [10]. The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation. However, glutamine is metabolized in mitochondria yielding glutamate and ammonia, and glutamine-derived ammonia may interfere with mitochondrial function leading to astrocyte dysfunction [11].

The increase in blood ammonia in advanced liver disease is a consequence of impaired liver function and of shunting of blood around the liver. Muscle wasting, a common occurrence in these patients, also may contribute since muscle is an important site for extrahepatic ammonia removal. Increasingly, gut microbiota are recognized as a main source of ammonia [12].

The arterial concentration of ammonia is increased in about 90 percent of patients with HE. Proof of the pathogenetic role of ammonia in HE has come from the efficacy of therapies aimed to lower plasma ammonia in improving HE (table 2). Ammonia interferes with brain function at several sites, each of which can contribute to the development of encephalopathy. In addition, other toxins, such as mercaptans or short-chain fatty acids (C4 to C8), may potentiate ammonia toxicity [13]. However, studies using positron emission tomography have illustrated that cerebral ammonia metabolism is not the only causal factor related to the development of hepatic encephalopathy [14]. Some of the other factors that have been implicated will be described below. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Magnetic resonance spectroscopy and positron emission tomography'.)

Impaired blood to brain transport of amino acids — Hyperammonemia may increase the cerebral uptake of neutral amino acids by enhancing the activity of the L-amino acid transporter at the blood-brain barrier. This effect may be the consequence of the blood to brain transport of glutamine, which is formed in excess for ammonia detoxification [15]. Consistent with this hypothesis is the observation that transport of tryptophan into the brain is increased by ammonia infusions [16]. The ensuing elevation in the cerebral concentration of neutral amino acids tyrosine, phenylalanine, and tryptophan may affect the synthesis of the neurotransmitters dopamine, norepinephrine, and serotonin [17].

Increase in intracellular osmolarity in astrocytes — Brain edema has been observed in acute hyperammonemia [18], in animal models of hepatic encephalopathy [19] and in patients with cirrhosis and HE [20]. One possible explanation for brain edema is an increase in intracellular osmolarity resulting from the metabolism of ammonia in astrocytes to form glutamine. Inhibition of glutamine synthetase prevents brain swelling in rats infused with ammonia [21] and inhibits cellular swelling in cultures of astrocytes incubated with ammonia. In other experiments, portacaval shunted rats, but not control rats, developed encephalopathy associated with a significant increase in intracranial pressure after infusions with ammonium acetate [21,22]. Both groups had similar elevations in blood and brain ammonia concentrations, but brain and cerebrospinal fluid (CSF) concentrations of glutamine and aromatic amino acids were higher in the portacaval shunted rats.

These data are supported by in vivo measurements in cirrhotic patients in which proton magnetic resonance spectroscopy of the brain showed depletion of myoinositol (a sign of increased osmolarity) and increased glutamine [23]. Thus, as mentioned above with transjugular intrahepatic portosystemic shunt (TIPS) insertion, portosystemic shunting adds an essential contribution to the pathogenesis of encephalopathy.

Some studies have implicated a role of ammonia-induced oxidative stress and changes in mitochondrial permeability in inducing cell swelling (see 'Oxidative stress' below).

Furthermore, oxidative stress activates mitogen-activated protein kinases (MAPKs), which may lead to astrocyte swelling [24]. One protein strongly implicated is the water channel protein aquaporin-4 (AQP-4), which is abundantly expressed in astrocytes. Several observations support a potential role of AQP-4 in brain edema in in-vivo models of HE and in ammonia-induced cell swelling in cultured astrocytes [25]. Hepatocyte mtAQP8 channels facilitate the mitochondrial uptake of ammonia and its metabolism into urea, mainly under glucagon stimulation. This mechanism may be relevant to hepatic ammonia detoxification and in turn avoid the deleterious effects of hyperammonemia [26].

In addition to cell swelling, vasodilatation may contribute to the increase in intracranial pressure in acute liver failure. Ammonia-induced glutamate release and impaired glutamate clearance may elevate extracellular glutamate levels and cause overstimulation of N-methyl-D-aspartate (NMDA) receptors. NMDA receptor activation triggers nitric oxide synthetase (n-NOS) via a calmodulin-mediated mechanism. NOS catalyzed synthesis of nitric oxide (NO) produces vasodilatation [27]. Thus, ammonia-induced cerebral water accumulation (probably due to astrocyte swelling) triggers cerebral hyperemia [28]. The detrimental effects of the inhibition of NOS on HE in acute liver failure [29] are consistent with this hypothesis. In contrast, mild hypothermia may be effective in the prevention of brain edema in experimental acute liver failure by reducing blood-brain transfer of ammonia and/or reduction of extracellular brain glutamate concentrations [30].

Swelling of astrocytes may be a key event in the development of HE [31]. It has been assumed that one major pathogenetic effect in the development of HE in chronic liver disease is an increase in astrocyte hydration without clinically overt increase in intracranial pressure, but sufficient to trigger multiple alterations of astrocyte function. Such changes in cell size interfere with various basic cell functions [32] and may also lead to brain edema.

Glutamine is not just an osmolyte. Much of the newly synthesized glutamine in astrocytes is transported from the cytoplasm into mitochondria via a histidine-sensitive glutamine carrier and is metabolized by phosphate-activated glutaminase (PAG), yielding glutamate and ammonia. The generation of ammonia by PAG in the relatively small mitochondrial compartment may reach extremely high levels leading to the induction of the mitochondrial permeability transition (MPT) [33], production of free radicals and potentially to oxidative damage of mitochondrial constituents. MPT is a calcium-dependent process associated with a collapse of the inner mitochondrial membrane potential due to the opening of the permeability transition pore. Thus, glutamine acts like a "Trojan horse" serving as a carrier of ammonia into mitochondria [11]. The glutamine-derived ammonia within mitochondria leads to the phenomena known to bring about astrocyte dysfunction, including cell swelling.

Altered neuronal electric activity — Ammonia directly affects neuronal electric activity by inhibiting the generation of both excitatory and inhibitory postsynaptic potentials [34-36]. The effects of ammonia on glutamatergic neurotransmission and on altered brain energy metabolism [37,38] will be discussed below.

Oxidative stress — Oxidative stress has a major role in cerebral ammonia toxicity and the pathogenesis of hepatic encephalopathy. Ammonia induces rapid RNA oxidation in cultured rat astrocytes, mouse brain slices, and rat brain in vivo [39]. Ammonia-induced RNA oxidation in cultured astrocytes may modulate the N-methyl-D-aspartic acid (NMDA) receptor activation [40]. Because hypo-osmolarity, tumor necrosis factor alpha (TNF-alpha), and diazepam increase RNA oxidation in cultured astrocytes, it is conceivable that the action of different HE-precipitating factors converges at the level of RNA oxidation. The messenger RNA (mRNA) coding for the glutamate/aspartate transporter (GLAST) and 18S-rRNA have been identified among the oxidized RNA species. Oxidized RNA species may participate in postsynaptic protein synthesis, which is a biochemical substrate for learning and memory consolidation [39]. In one study, oxidative stress markers in the brain of patients with cirrhosis with severe HE included elevated levels of protein tyrosine-nitrated proteins, heat shock protein-27, and 8-hydroxyguanosine as a marker for RNA oxidation [41]. Glutamine synthetase activity was decreased while protein expression of the glutamate/aspartate cotransporter was up-regulated.

Since oxidative stress promotes astrocyte swelling, a self-amplifying signaling loop between osmotic and oxidative stress triggers protein tyrosine nitration (PTN), oxidation of RNA, mobilization of zinc, alterations in intra- and intercellular signaling, and multiple effects on gene transcription. PTN can affect the function of a variety of proteins, such as glutamine synthetase. PTN and RNA oxidation are also found in the postmortem human cerebral cortex of patients with cirrhosis with HE but not in those without HE, supporting a role for oxidative stress in the pathophysiology of HE. More recent observations made in whole genome microarray analyses of post mortem human brain tissue point to a hitherto unrecognized activation of multiple anti-inflammatory signaling pathways [42].

Oxindole — Oxindole is a tryptophan metabolite formed by gut bacteria (via indol) that can cause sedation, muscle weakness, hypotension, and coma. It appears to be produced in the intestine and cleared by the liver, which is similar to ammonia [43]. Cerebral concentrations of oxindole are increased 200-fold in rats with acute liver failure, an effect that was partially reversed by oral neomycin [44].

In a study in humans, indole levels were significantly higher in patients with overt HE and higher in patients with cirrhosis compared with controls [45]. In another report, indole and ammonia levels increased after placement of a TIPS [43]. Psychometric performance deteriorated in four patients, all of whom had higher indole plasma concentrations compared with patients whose psychometric performance remained stable.

IMPAIRMENT OF NEUROTRANSMISSION — Hepatic encephalopathy (HE) is characterized by biochemical alterations in functions associated with neural membranes, such as the changes in the uptake of neurotransmitters, in enzyme activities, and the expression of neurotransmitter receptors. A possible common pathway for these changes may be alterations in membrane properties in HE. Gross alterations in cerebral cortical membrane lipid composition (including a decrease in cholesterol, phosphatidylserine, sphingomyelin, mono- and polyunsaturated fatty acids) and the annular membrane fluidity were documented in rats with TAA-induced HE [46,47].

GABA-benzodiazepine neurotransmitter system — A role has been proposed for increased tone of the inhibitory gamma-aminobutyric acid (GABA)A-benzodiazepine neurotransmitter system in the development of HE. As an example, visual evoked potentials in rabbits with HE are similar to those induced in normal animals by drugs acting through the GABAA-benzodiazepine receptor complex [48].

Neurochemical studies — Multiple studies have examined the GABAA-benzodiazepine neurotransmitter system in liver failure. In contrast to initial reports of an increase in GABA and benzodiazepine receptors on cortical membranes [49], subsequent studies yielded conflicting results [50]. In most studies, GABA and benzodiazepine receptors and cerebral GABA concentrations are not changed in HE [51,52].

An increasing body of evidence supports the notion that activation of the astrocytic 18-kDa translocator protein (formerly referred to as the peripheral-type benzodiazepine receptors [PTBR]) contributes to the pathogenesis of the central nervous system symptoms of HE. Binding site densities for the PTBR ligand [3H-PK11195] are increased in autopsied brain tissue from PSE patients as well as in the brains of animals with experimental chronic liver failure. In the case of the animal studies, increased PTBR sites resulted from increased PTBR gene expression. This increase may be due to exposure to ammonia or manganese. Activation of PTBR results in increased cholesterol uptake and increased synthesis in brain of neurosteroids, some of which have potent positive allosteric modulator properties on the GABAA receptor system. Accumulation of such substances in the brain in chronic liver failure could contribute to the development of HE [53]. Downregulation of PTBR reduced cell swelling and prevented the ammonia-induced decline of the cyclosporin A-sensitive mitochondrial inner membrane potential. These findings highlight the important role of the PTBR in the mechanism of ammonia neurotoxicity [54].

Neurobehavioral studies — Rats with liver failure are more sensitive to the sedative effects of benzodiazepines than normal rats [55]. Furthermore, administration of antagonists of the GABAA-benzodiazepine receptor complex to animals with fulminant hepatic failure and HE has led to a transient clinical improvement which was associated with a normalization of abnormal visual evoked potentials [56,57].

Antagonists with partial inverse agonistic properties appear to be most effective for the amelioration of HE [58,59]. However, the beneficial effects of these compounds do not necessarily imply overactivity of the GABAA-benzodiazepine neurotransmitter system. An alternative explanation is an imbalance of excitatory and inhibitory neurotransmission.

Electrophysiologic studies — Single cell recordings from Purkinje neurons have revealed increased sensitivity in HE to the inhibitory effects of benzodiazepine agonists, a finding consistent with activation of the GABAA-benzodiazepine neurotransmitter system in HE [60]. In contrast, neuronal firing action was augmented in the cerebella of rabbits with HE but not of control rabbits when flumazenil or other benzodiazepine antagonists were added to the perfusion medium [60]. This observation is compatible with displacement from the GABAA-benzodiazepine receptor of a benzodiazepine-like ligand not present in normal brains.

Endogenous benzodiazepines — Endogenous benzodiazepines involved in the activation of the GABAA-ergic neurotransmission have been isolated, characterized, and positively identified by gas chromatography-mass spectroscopy as benzodiazepines in brain, sera, and CSF of experimental animals and humans with acute liver failure due to acetaminophen toxicity [61,62]. The brain concentration of these substances correlated closely with the degree of neurologic impairment in an animal model of HE [63]. In these drug-free animals, the presence of benzodiazepines (including diazepam and desmethyldiazepam) cannot be explained by exogenous benzodiazepine administration, which could occur in humans. However, the use of benzodiazepines prior to HE was carefully excluded in human studies [62].

Neurosteroids — Neurosteroids are metabolites of progesterone and are endogenous neuroactive compounds. Allopregnanolone and tetrahydrodeoxycorticosterone are potent selective positive allosteric modulators of the GABAA receptor complex. Administration of these steroids induces behavioral effects that include sedation, a property consistent with enhancement of the neuronal inhibition characteristic of HE. In one report, allopregnanolone and pregnenolone (a neurosteroid precursor) concentrations were increased in the brains of hepatic coma patients [64]. Concentrations of allopregnanolone comparable to those observed in hepatic coma brains are pathophysiologically relevant and correlated with the magnitude of induction of [3H] muscimol binding. Increased brain concentrations of pregnenolone and consecutively of allopregnanolone could be peripheral in origin. Both allopregnanolone and its precursors cross the blood-brain barrier and pregnenolone and progesterone are metabolized by the liver. TGR5 (Gpbar-1) is a novel neurosteroid receptor in the brain that may be involved in the pathogenesis of HE [65].

Glutamatergic neurotransmission — There is increasing evidence that alterations of glutamatergic function are implicated in the pathogenesis of central nervous system consequences of acute liver failure.

Neurochemical studies — Total brain glutamate levels are decreased in various models of HE and in patients dying from chronic liver failure [66]. NMR-spectroscopy in hyperammonemic rats and in rats with acute liver failure following liver ischemia confirmed the reduced concentration of glutamate in vivo [67]. This decrease in glutamate is presumably due to glutamine formation during the process of ammonia detoxification. It is not known whether a similar change occurs in neuronal glutamate.

In contrast, extracellular glutamate concentrations are elevated in HE [68,69]. This effect may be due to excessive release of glutamate from neurons depolarized by ammonia or to impaired reuptake by neurons or glial cells [52,70]. Astrocytes may be involved in these derangements since ammonia can impair the ability of these cells to take up glutamate. Reduced capacity of astrocytes to reuptake neuronally-released glutamate and the ensuing compromise in neuron-astrocytic trafficking of glutamate could contribute to the pathogenesis of HE. This effect may result from diminished expression of GLT (glutamate transporter)-1 mRNA [71-73].

Receptor binding studies in some experimental animals with acute liver failure suggested that glutamatergic neurotransmission may be altered in HE [74]. However, this finding has not been found in other models [51].

Glutamate receptors — There are three major subtypes of glutamate receptors, defined according to their coupling to ion channels and their affinity to certain ligands:

N-methyl-D-aspartate (NMDA)

Non-NMDA – amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) and kainate

Metabotropic glutamate receptor

In one study of liver failure induced by ischemia, a selective loss of up to 60 percent of binding sites for the kainate- and AMPA-receptor ligands was observed at coma stages of HE in the cerebral cortex, the hippocampus, the hypothalamus, and cerebellum [75]. NMDA-receptors were within normal limits. In contrast, other models of acute liver failure have noted increased NMDA-displaceable glutamate binding in the cerebral cortex and hippocampus [76,77].

The selective loss of AMPA sites is consistent with the inhibition of AMPA-mediated neuronal depolarization resulting from exposure of hippocampal neurons to millimolar concentrations of ammonia [78]. NMDA sites are uniquely neuronal, whereas kainate and AMPA sites are localized on both neurons and astrocytes. Thus, the selective loss of non-NMDA sites in acute liver failure may reflect astrocytic changes. Because astrocytic glutamate receptors are implicated in potassium and neurotransmitter reuptake, alterations in their density could result in altered neuronal excitability and could contribute to the neurologic dysfunction characteristic of HE in acute liver failure.

Neurobehavioral studies — Memantine is a noncompetitive NMDA-receptor antagonist. In portacaval shunted rats infused with ammonia and rats with acute hepatic failure due to liver ischemia, memantine improved clinical grading, EEG activity, and the increases in CSF glutamate concentrations, intracranial pressure, and brain water content [79]. Memantine had no effect on ammonia concentrations in either model. In another study, different NMDA receptor antagonists, acting on different sites of NMDA receptors, prevented death in mice induced by injection of ammonium acetate [80]. These results suggest that NMDA-receptor activation might be involved in the encephalopathy in these settings [79].

Genetic studies — Certain patients appear to be predisposed to hepatic encephalopathy to a greater degree than others with similarly advanced liver disease. The reasons for these differences in susceptibility are incompletely understood. One study suggested that variation in the glutaminase gene may in part be responsible [81]. Patients who had a variant of the promoter region of the glutaminase gene that was associated with increased enzyme activity appeared to have an increased risk of hepatic encephalopathy.

Catecholamines — Altered concentrations of catecholamines in HE have been linked to altered amino acid metabolism. In chronic liver failure, the plasma and brain concentrations of aromatic amino acids (AAAs; phenylalanine, tryptophan, and tyrosine) are increased, while those of the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine are reduced. Since these amino acids share a common carrier at the blood-brain barrier, decreased BCAA concentrations in the blood may result in increased transport of AAA into the brain [82]. A low molar ratio of plasma BCAA to AAA is a consistent finding in patients with cirrhosis and HE, but also occurs in patients without HE [83,84]. This ratio closely correlates with indices of liver function, with a decreased ratio implying poor hepatocellular function [84]. Thus, it appears unlikely that changes in the plasma concentrations of neutral amino acids contribute to the development of HE.

Tyrosine-3-hydroxylase is the key enzyme for the synthesis of catecholaminergic neurotransmitters, and high concentrations of phenylalanine in the brain may inhibit the enzyme. In addition, other amines such as tyramine, octopamine, and phenylethanolamine are synthesized from tyrosine by alternative metabolic pathways. These false neurotransmitters may compete with the normal catecholamine neurotransmitters (eg, dopamine) for the same receptor site [82]. However, no experimental or clinical studies investigating the false neurotransmitter hypothesis have been published since the 1990s. In addition, cerebral dopamine concentrations in HE are usually within the normal range in both experimental animals and in humans with HE [85], and depletion of brain dopamine in rats does not result in the induction of coma [86]. Thus, there is no firm evidence that impaired dopaminergic neurotransmission contributes to any appreciable extent to HE.

However, some of the extrapyramidal symptoms in patients with cirrhosis may be due to altered dopaminergic function, which is closely related to accumulation of manganese in basal ganglia [87]. Manganese appears to normalize low striatal levels of dopamine. Thus, manganese accumulation in basal ganglia [88,89] may represent an attempt of the brain to correct dopamine deficiency in liver disease.

Finally, another fairly consistent finding in animal models of acute or chronic liver failure is a reduced norepinephrine (noradrenaline) concentration in the brain. The decreased brain norepinephrine content is due to overactivity of noradrenergic neurotransmission, possibly induced by hyperammonemia [90].

Serotonin — A two to fourfold increase in cerebral concentration of the serotonin metabolite 5-hydroxyindoleacetic acid is the most consistent neurochemical finding in HE [90,91]. In addition, HE is associated with alterations in the number of 5HT1A and 5HT2 receptors [92] and increased activity of both MAOA and MAOB (enzymes catabolizing 5-HT) [93]. These findings suggest an increased serotonin turnover rate in HE, but do not necessarily imply an overactivity of this neurotransmitter system. Although increased neocortical serotonin output has been described in some animal models of HE [94,95], studies using serotonin agonists or antagonists on the evolution of HE in rats with thioacetamide-induced liver failure do not support a pathogenetic role for increased serotoninergic tone in HE [96]; to the contrary, the amount of biologically active serotonin at the synaptic cleft may be reduced [97]. Serotonin transporters are decreased in various brain regions of rats with acute liver failure [98]. The loss of transporter binding sites is accompanied by significant increases of L-tryptophan, serotonin, and 5-HIAA concentrations in extracellular fluid.

Histamine — The binding properties and the regional densities of histamine H1 receptors in the brains of rats with portacaval anastomosis suggested that this neurotransmitter system is also affected in liver failure. Autopsied brain tissue from cirrhotic patients with HE displayed a higher density and a lower affinity of histamine H1 receptors compared with control human frontal cortex [99]. Binding was highest in the parietal and temporal cortices and lowest in caudate-putamen. A selective increase in H1 receptor density was also observed in parietal and insular cortices of patients with HE. The central histaminergic system is implicated in the control of arousal and circadian rhythmicity. A selective up-regulation of brain H1 could contribute to the neuropsychiatric symptoms characteristic of human HE, and may be amenable to treatment with selective histamine H1 receptor antagonists.

Melatonin — Sleep disturbances are common in patients with subclinical HE [100] and may be due to a centrally mediated alteration of circadian rhythm [101]. The 24-hour rhythm of melatonin, which is considered to be the output signal of the biological "clock," is considerably altered in patients with cirrhosis [101]. The onset of the rise in plasma levels of melatonin and the melatonin peak during the night are displaced to later hours. Furthermore, plasma melatonin levels are significantly higher during daylight hours, at a time when melatonin is normally very low or absent. (See "Pharmacotherapy for insomnia in adults", section on 'Melatonin'.)

ALTERATION OF THE BLOOD-BRAIN BARRIER — The brain uptake of various tracer substances is increased in several animal models of acute liver failure [102]. The reason for this nonspecific increase in blood-brain barrier permeability is unknown. Regardless of the mechanism, this change can lead to exposure of the brain to a variety of neurotoxic substances circulating in the blood and may result in brain edema.

Blood-brain permeability was unchanged in a study of patients with chronic liver disease without HE [103]. By contrast, specific changes in blood-brain barrier transport have been demonstrated in patients with HE [104]. Of particular interest are changes of amino acid transport into the brain. Amino acids such as tyrosine, phenylalanine, and tryptophan are precursors of the neurotransmitters dopamine, norepinephrine, and serotonin, while other amino acids, such as glutamate, aspartate, taurine, and glycine, are neurotransmitters themselves. Alterations in specific transport systems seem to be important in chronic HE.

ALTERED BRAIN ENERGY METABOLISM — Undisturbed energy supply and energy metabolism is a prerequisite for normal brain function. Glucose is the most important cerebral energy fuel and hypoglycemia can occur in the terminal stages of liver failure due to impaired hepatic gluconeogenesis. However, the administration of glucose is not sufficient to normalize brain function in HE.

Several studies have addressed cerebral glucose utilization in HE. A report which evaluated regional cerebral glucose metabolism in rats with a portacaval shunt found a 5 to 34 percent decrease in cerebral glucose utilization in the 38 brain areas examined [37].

The depression in cerebral glucose metabolism is due in part to hyperammonemia. This effect seems to begin with increased synthesis of glutamine [105,106]. Ammonia itself is without effect at concentrations less than 1 micromol/mL if it is not converted into glutamine. A study evaluating the impact of ammonia on cerebral metabolism relied on measurement of the oxygen metabolism rate (CMRO(2)) by (15)O-oxygen positron emission tomography (PET) and of cerebral blood flow (CBF) by (15)O-water PET [107]. There were no differences between patients with cirrhosis without HE and healthy subjects, but both measures were significantly reduced in patients with cirrhosis with HE throughout the brain. CMRO(2) and CBF correlated negatively with arterial ammonia concentration. These observations suggested that the primary event in the pathogenesis of HE was the inhibition of cerebral energy metabolism by increased blood ammonia. Hyperammonemia may also reduce brain ATP levels, indicating a marked impairment of brain energy metabolism [108]. However, this abnormality was found only in patients with severe disease who had already developed multi-organ failure and may therefore be unrelated to the evolution of HE.

Impaired hemichannel-mediated lactate transport between astrocytes and neurons may provide evidence that a neuronal energy deficit is involved in the pathogenesis of HE [109,110]. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels, allowing transfer molecules across the plasma membrane. Hemichannels may function as a conduit of lactate transport across the membrane, and hemichannel-mediated release of lactate is altered in animal models of HE.

ALTERED GLYMPHATIC CLEARANCE — The glymphatic system refers to a brain-wide glial dependent perivascular network that functions to remove interstitial metabolic waste products. In bile duct ligated rats, altered glymphatic clearance was detected in discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus), which aligned with cognitive and behavioral deficits. Reduced aquaporin-4 (AQP4) expression was observed in the olfactory bulb and prefrontal cortex in hepatic encephalopathy [111,112].

SYSTEMIC RESPONSE TO INFECTIONS AND NEUROINFLAMMATION — Infection is a well-known precipitant of hepatic encephalopathy, but the mechanisms involved are incompletely understood [4,113,114]. Patients with cirrhosis are known to be functionally immunosuppressed and prone to develop infections [115]. Whether infections themselves or the inflammatory response exacerbate HE is unclear.

The systemic inflammatory response syndrome (SIRS) results from the release and circulation of proinflammatory cytokines and mediators. Sepsis-associated encephalopathy is characterized by changes in mental status and motor activity, ranging from delirium to coma [116]. Up to one-third of patients with sepsis have a reduced level of consciousness, which is an independent prognostic factor for increased mortality. Possible causes of brain dysfunction include alterations in cerebral blood flow, brain metabolites, and the release of inflammatory mediators; importantly, these processes occur without the direct infection of brain tissue [117].

During an episode of sepsis, cytokines (15 to 20 kDa) cannot diffuse across the blood-brain barrier and are therefore unable to have a direct effect. Nevertheless, the peripheral immune system can lead to the production of proinflammatory cytokines (both in the periphery and in the brain). These proinflammatory cytokines can signal the brain to elicit a response. Brain signaling may occur through direct transport of the cytokine across the blood-brain barrier [118].

The circumventricular organs (which are positioned around the margin of the brain's ventricular system) express components of innate and adaptive immune systems and are located close to neuroendocrine nuclei. Activated endothelial cells, microglial cells, and astrocytes produce repertoire variety of cytokines in response to inflammation and release of various mediators into the brain, resulting in the intracerebral synthesis of NO and prostanoids. Cytokines also influence the permeability of the blood-brain barrier [119].

In patients with cirrhosis, SIRS may exacerbate the symptoms of HE, both in patients with minimal and overt HE [120,121]. The presence and severity of minimal HE in patients with cirrhosis are independent of the severity of liver disease and plasma ammonia concentration, but markers of systemic inflammation are significantly higher in those with minimal HE compared with those without [33]. In one report, increasing grades of HE were associated with SIRS and neutrophilia, but not arterial ammonia concentration [122].

Another potential factor inciting an inflammatory response is bacterial translocation of organisms from the gut, which results in chronic endotoxemia [122]. Bacterial translocation may activate proinflammatory cytokines/chemokines and neutrophils through Toll-like and chemokine receptors [123]. In support of this hypothesis are studies in rats with endotoxin-induced chronic neuroinflammation or with portocaval shunts [3]. Learning and memory deficits were reversed by the glutamatergic antagonist memantine and by the nonsteroidal anti-inflammatory drug ibuprofen [3].

Experimental evidence points to a synergistic relationship of inflammation and infection with ammonia, both at the level of the brain and at the level of neutrophils [122,124,125]. Some reports suggest that hyperammonemia may cause neuroinflammation [125]. In vitro ammonia impairs neutrophil chemotaxis, phagocytosis, degranulation, and stimulated oxidative burst, resulting in swelling of certain cells, including neutrophils and possibly astrocytes [126]. Impaired phagocytosis may augment the impaired immune response to bacterial antigens. A similar reduction in phagocytosis following induction of hyponatremia, which is a well-known stimulus for cell swelling, supports neutrophil swelling as a potential mechanism to explain this neutrophil dysfunction [127]. Similar observations have been made in patients with liver disease. The effects of hyponatremia and ammonia were additive, causing more pronounced neutrophil swelling and phagocytic dysfunction [126].

These observations potentially have therapeutic implications. Potential therapeutic strategies might include antibiotics, the use of granulocyte colony-stimulating factor, antagonist of proinflammatory cytokines or their receptors, antioxidants, nonsteroidal anti-inflammatory drugs, and hypothermia [30,126,128]. Modulation of intestinal microbiota by probiotics is an emerging strategy to reduce the bacterial translocation of LPS and other bacterial activators of TLRs. (See "Hepatic encephalopathy in adults: Treatment".)

BACTERIAL OVERGROWTH — Small bowel bacterial overgrowth has been hypothesized to contribute to minimal hepatic encephalopathy [129]. However, more studies are needed to clarify the validity and implications of the association.

Gut bacterial microbiome analysis is a valuable new approach to study the pathogenesis of various diseases. The gut microbiome was studied by multitag pyrosequencing of stool of patients with cirrhosis and age-matched controls. Patients with cirrhosis had significantly fewer autochthonous and more pathogenic genera than controls [130]. This was especially true for patients with HE. Patients with cirrhosis had more Enterobacteriaceae, Alcaligenaceae, and Fusobacteriaceae and fewer Ruminococcaceae and Lachnospiraceae than controls. In the patients with cirrhosis, Alcaligenaceae and Porphyromonadaceae were positively associated with cognitive impairment. Fusobacteriaceae, Veillonellaceae, and Enterobacteriaceae were positively associated with markers of inflammation, and Ruminococcaceae was negatively associated. Lactulose withdrawal did not change the microbiome significantly [131].

Altered gut microbiota resulting from decreased autochthonous or commensal taxa has been found in stool and colonic mucosa in patients with cirrhosis, which is in turn linked with disease severity and systemic inflammation [132]. Dysbiosis, represented by reduction in autochthonous bacteria, is present in both saliva and stool in patients with cirrhosis, compared with controls; thus, investigating microbiota in saliva may be used in clinical practice [133].

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Basics topic (see "Patient education: Hepatic encephalopathy (The Basics)")

SUMMARY AND RECOMMENDATIONS

The various hypotheses of the pathogenesis of hepatic encephalopathy (HE) are not mutually exclusive. It seems likely that many of the described abnormalities may be present at the same time and may ultimately be responsible for the development of HE. The synergistic action of ammonia with other toxins may account for many of the abnormalities occurring in liver failure, such as the changes in blood-to-brain transport of neurotransmitter precursors, the metabolism of amino acid neurotransmitters, and cerebral glucose oxidation. These changes may lead to activation of inhibitory (gamma-aminobutyric acid, serotonin) and impairment of excitatory (glutamate, catecholamines) neurotransmitter systems, resulting in enhanced neural inhibition. Sepsis, neuroinflammation, and alterations in gut flora appear to be additional factors in the development of altered brain function in advanced liver disease.

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