Hepatic Encephalopathy 1087
Hepatic Encephalopathy
A S Basile, DOV Pharmaceutical, Inc., Somerset,
NJ, USA
K D Mullen, Case Western Reserve University,
Cleveland, OH, USA
ã 2009 Elsevier Ltd. All rights reserved.
Description
Hepatic encephalopathy (HE) is a complex neuro-
psychiatric syndrome characterized by the global
depression of central nervous system (CNS) activity,
with a gradual deterioration of higher mental and
motor functions (Table 1). The syndrome is asso-
ciated either with acute liver failure, commonly preci-
pitated by drug overdose or viral hepatitis, or with
chronic liver failure, frequently caused by alcoholic
cirrhosis. Liver disease is the fourth largest cause
of death in Americans between 45 and 54 years of
age, and HE (including minimal HE) is associated
with 50–70% of all patients with cirrhosis. Moreover,
HE is more prevalent in nations with higher rates of
liver disease than occur in the United States.
Although HE has been recognized since the begin-
ning of recorded medical history, the precise patho-
genic mechanisms responsible for the syndrome
remain complex and poorly defined. Thus, the mod-
alities for treating HE are still evolving. A profusion of
metabolic abnormalities and gut-derived toxins result
from hepatic failure, resulting in significant alterations
in neurotransmission and CNS energy metabolism,
superimposed upon a characteristic astrocyte patho-
logy (Alzheimer type II degeneration). Thus, it is diffi-
cult to ascribe the neurological and psychiatric
manifestations of HE to the presence of a single agent
or to changes in a particular metabolic pathway. How-
ever, since HE is a metabolic encephalopathy, with few
neuroanatomical abnormalities observed in patients
who die of either acute or chronic liver failure, it has
the potential to be completely reversible.
The neurological manifestations of HE (Table 1) are
determined by two principal components of the under-
lying liver disease: hepatocellular failure and systemic
shunting of portal venous contents (Figure 1). Nor-
mally, potentially neurotoxic substances are absorbed
from the gut and detoxified by the liver. However, in
hepatocellular failure these agents may avoid catabo-
lism by passing through the diseased liver unmetabo-
lized and into the systemic circulation (portal–systemic
shunting). Alternatively, these toxins may bypass
the liver altogether and enter the systemic circula-
tion through portal-venous shunts that are either
surgically constructed, or formed spontaneously as a
result of portal hypertension associated with cirrhosis.
Once these gut-derived substances reach the brain, they
modify CNS function either by altering metabolic
processes such as oxidative metabolism or neuro-
transmitter synthesis, or by interacting directly with
neurotransmitter receptors.
Hyperammonemia and HE
Ammonia is produced systemically by deamination of
amino acids, in the gut wall by the action of gluta-
minase, and by degradation of amines, amino acids,
and urea by gut bacteria. Ammonia diffuses into the
portal circulation, where it would normally be con-
verted to glutamine and urea via the Krebs–Henseleit
cycle. However, this process is impaired in liver fail-
ure, resulting in elevated concentrations of ammonia
in the blood. Ammonia in the blood readily diffuses
across the blood–brain barrier in its uncharged form.
Levels of ammonia in the cerebrospinal fluid (CSF) of
patients and animals with clinically significant mani-
festations of encephalopathy secondary to liver failure
range from 70 to 850 mM, compared to concentrations
<50 mM in normal humans. Brain ammonia concen-
trations may reach as high as 1–5 mM in animal mod-
els of acute liver failure. While total ammonia levels in
the blood are not well correlated with the severity of
HE, brain ammonia uptake, as indicated by glutamine
levels in CSF and by 1H magnetic resonance spectros-
copy, is well correlated with the severity of HE asso-
ciated with cirrhosis.
Acute exposure to elevated levels of ammonia causes
a number of biochemical and electrophysiological
derangements in the CNS, including suppression of
oxidative metabolism, inhibition of Naþ/Kþ-ATPase
activity, inactivation of Cl extrusion pumps, and
decreases in the equilibrium potential of the neuronal
inhibitory postsynaptic potential (IPSP). More recent
investigations indicate a significant impact of ammo-
nia on astrocytic function. In the presence of ammonia,
astrocytes swell (Figure 2), contributing to cerebral
edema in acute hepatic failure, while persistent eleva-
tions of brain ammonia levels, as observed in chronic
hepatic failure, are associated with the development
of Alzheimer type II astrocytosis. In the absence of
a functional hepatic mechanism for converting ammo-
nia to urea, astrocytes remove ammonia by converting
it to glutamine. Exposing astrocytes in vitro to elevated
concentrations of either ammonia or glutamine results
in increased free radical production, possibly by
activation of the mitochondrial permeability transition.
1088 Hepatic Encephalopathy

Table 1 Clinical stages of HE

Stage Mental state Neuromuscular state

I Mild confusion, euphoria, depression, decreased attention, slowed analytical Mild incoordination, impaired handwriting
ability, irritability, sleep inversion
II Drowsiness, lethargy, gross deficits in analytical ability, obvious personality Asterixis, ataxia, dysarthria, paratonia, apraxia
changes, inappropriate behavior, intermittent disorientation;
electroencephalogram abnormalities (high-amplitude, low-frequency
waves with nonfocal changes)
III Somnolent but rousable, unable to perform analytical tasks, disorientation Hyperreflexia, muscle spasticity, Babinski’s
with respect to time and/or place, amnesia, rage, slurred speech sign present, seizures (rare)
IVA Coma Thalamic–subcortical spasticity of entire body;
no response to painful stimuli
IVB Deep coma Death imminent

CNS
dysfunction

Astrocyte process
Brain capillary

Tight junction

Carotid
Vesicle

Inferior Simple diffusion

vena ( )
through cell, or
cava across tight
junction
( ) Vesicular transport
Facilitated diffusion
Blood-to-brain
Portacaval transport
Heptocellular
disease shunt
Food protein
Nitrogen GI hemorrhage
Portal load Drugs +
vein
Bacterial action

Intestine

Figure 1 The concept of portal–systemic shunting as it contributes to the development of HE. Nitrogenous substances arising from the
gastrointestinal (GI) system normally are absorbed into the portal venous system and delivered to the liver, where they are extracted and
metabolized. However, in liver disease these substances may pass directly into the systemic circulation or bypass the liver completely via
portal–venous shunts. Once these compounds enter the systemic circulation, they may gain entry to the central nervous system (CNS) by
a variety of mechanisms, including high-capacity active transport or facilitated diffusion, resulting in abnormal brain function. Reprinted
from Basile AS, Jones EA, Skolnick P, et al. (1991) The pathogenesis and treatment of hepatic encephalopathy: Evidence for the
involvement of benzodiazepine receptor ligands. Pharmacological Reviews 43: 27–71, with permission of the American Society for
Pharmacology and Experimental Therapeutics.
 Hepatic Encephalopathy 1089

GABA

GABA-X
Glutamate

GLAST Inhibit uptake

MAPK
Glu Gln Swelling
GS
ROS

PAG
NH3 MPT

Mitochondrion

Astrocyte

Figure 2 Alterations in astrocytic function induced by hyperammonemia. Alzheimer type II astrocytosis and cerebral edema are often
observed in acute liver failure and contribute to the end stages of hepatic encephalopthy. Exposing astrocytes in culture to elevated
concentrations (5 mM) of ammonia (NH3) for 1–3 days causes them to swell. Astrocytes will try to reduce ammonia levels by fixing
ammonia to glutamate (Glu) using glutamine synthase (GS), yielding glutamine (Gln). However, ammonia may be released from
glutamine by mitochondrial phosphate-activated glutaminase (PAG), causing the production of reactive oxygen species (ROS) by the
mitochondria and induction of the mitochondrial permeability transition (MPT). Elevated ROS levels increase the phosphorylation of a
number of mitogen-activated protein kinases (MAPK), such as ERK-1/2, p39MAPK, and JNK-1/2/3. Treating astrocytes with appropriate
MAPK inhibitors or antioxidants will prevent the astrocytic swelling, glutamate uptake inhibition, and decline in glutamate–aspartate
transporter (GLAST) mRNA and protein expression. Suppression of GABA transport (GABA-X), which is reported in experimental
hyperammonemic conditions, may also be influenced by these processes and contribute to some of the manifestations of hepatic
encephalopathy.

The resulting increase in oxidative stress causes
phosphorylation of extracellular signal-regulated
kinase-1/2 (ERK-1/2), p38 mitogen-activated protein
kinase (p38MAPK), and c-Jun N-terminal kinase-1/2/3
(JNK-1/2/3). Ammonia-induced astrocytic swelling,
which can be blocked in vitro by antioxidants and
MAPK inhibitors, may have a number of secondary
effects on neuronal function and neurotransmitter
levels, as detailed in following sections.
Other Neurotoxins
Hyperammonemia plays a significant role in the patho-
genesis of HE, but other conditions/agents are pres-
ent in hepatic failure/portal–systemic shunting that
can alter CNS function. Early work attempting to
identify and characterize the potential neurotoxins
involved in HE focused on the following classes of
agents: mercaptans, fatty acids, imbalances in the
ratio of branched-chain to aromatic amino acids,
and catecholamines/false neurotransmitters. The rel-
evance of these agents to the pathogenesis of HE
is now mostly historical. Mercaptans, phenol, and
medium-chain-length fatty acids are present in ele-
vated concentrations in patients with liver disease.
However, the neurotoxic concentrations of these
substances are 8–15 times higher than the levels
commonly observed in patients with HE. While it
has been proposed that the toxicity of these agents is
enhanced in the presence of ammonia, the concept of
‘synergistic neurotoxicity’ clearly applies to the
effects of all of the metabolic abnormalities and
toxic compounds that arise in liver failure, and is
not unique to these agents.
CNS levels of aromatic amino acids (e.g., tryptophan,
phenylalanine, and tyrosine) are increased between
70% and 300% in patients with cirrhosis. These
amino acids are precursors to several monoaminergic
neurotransmitters, including serotonin (Table 2). The
rate of serotonin turnover in discrete brain regions
1090 Hepatic Encephalopathy
Table 2 CNS levels of selected neurotransmitters in HEa
Neurotransmitter Control
Dopamineb 2698 ng g1 caudate
Noradrenalineb 92 ng g1 caudate
Serotoninc 0.281 ng mg1 protein
Glutamated 9.54 mmol g1 brain
g-Aminobutyric acid 1.46 mmol g1 braind
0.38 mmol l1 plasmae
Benzodiazepine receptor ligandsf 78 ng DZ equiv g1 brain
a
Values represent mean concentrations per unit of brain obtained during autopsy, or plasma from patients with acute or chronic liver
failure, with or without HE, or from patients with diseases other than liver failure (controls). DZ equiv., diazepam equivalents. *, **, P < 0.05,
0.01 vs. control, respectively.
b
Levels measured in samples of frontal cortex (Cuilleret et al., 1980).
c
Levels measured in samples of caudate nucleus (Bergeron et al., 1989).
d
Levels measured in samples of prefrontal cortex (Lavoie et al., 1987).
e
Median values of GABA levels measured in plasma samples from controls and patients with acute liver failure, stage IV HE (Levy and
Losowsky, 1989).
f
Levels measured in samples of frontal cortex from patients with acute liver failure (Basile et al., 1991).
increases in liver failure, possibly as a result of increased
concentrations of tryptophan associated with liver fail-
ure. However, serotonin may play only a minor role in
the development of HE (possibly in the development of
sleep inversion), since there is no correlation between
the severity of HE and the concentration of serotonin or
its metabolites. Alternatively, it has been proposed that
the elevations in CNS tyrosine and phenylalanine con-
centrations could enhance the synthesis of ‘false’ neuro-
transmitters, such as octopamine or tyramine, which
may serve to deplete catecholamine neurotransmitters.
However, the levels of the false neurotransmitter octo-
pamine decrease in the brains of patients with HE, while
noradrenaline and dopamine levels are generally
unchanged or increased (Table 2).
Magnetic resonance imaging (MRI) of some cir-
rhotic patients reveals hyperintense T1 signals in the
globus pallidus, suggestive of manganese accumula-
tion. Subsequent analysis of necropsy samples from
cirrhotics indicated a 128% increase in manganese
levels. Manganese is neurotoxic and causes Alzheimer
type II astrocytic changes. However, the degree of
pallidal hyperintensity resulting from liver failure
does not, in itself, appear to be associated with the
severity of HE.
Enhancement of GABAergic
Neurotransmission and HE
g-Aminobutyric acid (GABA) is the primary inhibi-
tory neurotransmitter in the CNS, and overactivation
of this pathway results in behavioral changes consistent
with the primary manifestations of HE, specifically
motor dysfunction, cognitive deficits, and altered
consciousness. No consistent changes in the GABAA
Liver failure Liver failure with HE
2852 4774
94 154
1.397
7.59**
1.21
3.37**
405*
receptor complex are observed in animal models of HE
or in humans with liver failure. While plasma GABA
levels are reportedly increased in liver failure (Table 2),
they may not impact basal levels of free GABA in the
CNS. Nonetheless, there is evidence that synaptic con-
centrations of GABA may be increased, possibly as a
result of ammonia-induced decreases in glial reuptake
(Figures 2 and 3) or alterations in release parameters.
GABAergic neurotransmission may also be
enhanced by the presence of endogenous, positive
modulators of the GABAA receptor, including ago-
nists of the benzodiazepine-binding site on the
GABAA receptor complex and neurosteroids. Benzo-
diazepine binding site agonists are increased in sev-
eral animal models of the syndrome and in humans
suffering from HE due to either acute or chronic liver
failure (Table 2, Figure 3). Tissues and body fluids
from humans and animals with HE, who were other-
wise never exposed to 1,4-substituted benzodiaze-
pines, contain numerous benzodiazepine binding
site ligands, as determined by radiometric techni-
ques. Only two of these were chemically and
immunochemically identified as 1,4-benzodiazepines.
However, these compounds comprised less than 20%
of the total concentration of benzodiazepine binding
site ligands present in HE in both animal models and
humans (Table 2, Figure 3). The identification and
source of the remaining benzodiazepine binding-site
ligands is unclear, but metabolites of hemoglobin,
including hemin and protoporphyrin IX, are possible
candidates.
Alterations in astrocytic function induced by
ammonia may increase the production of neuroster-
oids such as allopregnanolone, a potent inhibitor of
neuronal activity acting through the GABAA receptor.
 Hepatic Encephalopathy 1091

Plasma GABA Ammonia BZR agonists

CNS

D Astrocytic
function

BBB permeability (FHF)

Neurosteroid
GABA uptake
synthesis

GABA concentrations
in synaptic cleft

GABAA receptor
activation

Neuronal depression

Hepatic encephalopathy
Figure 3 GABAergic neurotransmission is enhanced in hepatic failure through a variety of mechanisms. g-Aminobutyric acid (GABA),
benzodiazepine receptor (BZR) agonists, and particularly ammonia, originating from outside of the brain (top tier), make their way into the
central nervous system (CNS) either through diffusion or via a permeabilized blood–brain barrier (BBB). Elevations in CNS ammonia
levels alter astrocytic function, which may lead to swelling and permeabilization of the BBB and fulminant hepatic failure (FHF), often
observed in acute liver failure. Astrocytes in a hyperammonemic state also show a reduction in GABA uptake. The increased access of
plasma GABA to the CNS, combined with decreased GABA uptake by astrocytes and evidence of enhanced GABA release, increases the
availability of GABA at the synapse. In addition, the presence of positive modulators of the GABAA receptor, such as neurosteroid and
benzodiazepine receptor agonists, as well as ammonia itself, yields a net increase in GABAergic neurotransmission. These changes, in
combination with the suppression of oxidative metabolism of neurons by elevated ammonia levels, cause neuronal depression, which is
expressed as the core manifestation of HE (see Table 1).

The peripheral-type benzodiazepine receptor (PBR),
located on glial mitochondria, plays a role in neuro-
steroid synthesis. The density of PBRs is increased in
animal models of HE, and in postmortem samples
from humans with hepatic failure, but interestingly
is not observed using positron emission tomography
(PET) imaging in patients with HE. Nonetheless, allo-
pregnanolone has been measured in postmortem sam-
ples of brain from patients with HE in concentrations
sufficient to enhance GABA-gated chloride currents,
which may serve to depress neuronal activity.
Evidence also indicates that ammonia can enhance
GABAergic neurotransmission through direct actions
at the GABAA receptor. An electrophysiological study
using isolated cortical neurons indicated that the
maximal level of GABA-activated current is enhanced
by pathophysiologically relevant concentrations of
ammonia, as is the potency of GABA. Subsequent
investigations of the effects of ammonia on radioligand
binding to sites on the GABAA receptor confirmed and
extended these observations. Pathophysiologically rel-
evant concentrations of ammonia selectively increased
the density of agonist (flunitrazepam) ligand binding
to the GABA-binding site of the GABAA receptor com-
plex, with no effect on antagonist (flumazenil) ligand
binding. Further, ammonia increased the affinity of
agonist binding to the benzodiazepine-binding site on
the GABAA receptor complex, without altering antag-
onist binding. The latter effect was further enhanced
(threefold) in the presence of GABA. It appears that
the ability of ammonia to modulate ligand binding to
the GABAA receptors (a heterooligomeric complex
composed of members from five families of subunits)
depends on the presence of the b subunit, as ammonia
can enhance [3H]flunitrazepam binding to recombi-
nant GABAA receptors composed of a1b2g2 subunits
(the pharmacology of which most resembles that of the
native GABAA receptor) but has no effect on binding
1092 Hepatic Encephalopathy
to a1g2 constructs. Taken together, the numerous
neurochemical changes present in hepatic failure may
enhance GABAergic neurotransmission, leading to the
motoric and behavioral changes characteristic of HE.
Suppression of Glutamatergic
Neurotransmission and HE
Contrasting with GABA, glutamate is the primary
excitatory neurotransmitter. Accumulating evidence
suggests that there are alterations in glutamatergic
neurotransmission in acute liver failure. Total brain
glutamate levels are decreased under hyperammone-
mic conditions, including liver failure, consistent with
the conversion of glutamate to glutamine by astro-
cytes in order to reduce ammonia levels. Basal extra-
cellular glutamate levels increase in models of acute
hepatic failure, but not in the portal–systemic shunted
rat model of chronic hepatic failure. In the latter model,
stimulated release of glutamate is variably increased.
Glial glutamate transporter (GLT-1 and/or GLAST)
expression is transiently decreased in portal–systemic
shunted rats and is more consistently decreased in rats
with acute liver failure. Glutamate uptake by astrocytes
in vitro is also reduced in the presence of ammonia.
Thus, there is evidence for increased extracellular
glutamate levels in acute liver failure, resulting from
either increased release or decreased reuptake. There is
no consistent evidence of a change in N-methyl-D-
aspartate (NMDA) receptor density in animal models
of acute liver failure.
The specific contribution(s) of the alterations in glu-
tamatergic neurotransmission to the manifestations of
HE is unclear. It has been proposed that increased
glutamate levels may contribute to glial swelling and
cerebral edema, but there is no correlation between the
onset of glutamate elevations and increased intracranial
pressure. Similarly, changes in glutamate levels may
contribute to the sleep-inversion, extrapyramidal disor-
ders and to the cognitive deficits observed in HE, par-
ticularly when associated with chronic liver failure.
However, the evidence for alterations in extracellular
glutamate levels in animal models of chronic liver
failure is variable, and the role of glutamatergic neuro-
transmission in the aforementioned behavioral changes
is weak. Nonetheless, the significance of glutamatergic
neurotransmission to CNS function is so great as to
warrant continued investigation of its role in HE.
Therapy
Therapeutic strategies for allaying the manifestations
of HE may focus on the target organ, the CNS, and the
gut. Current, standard therapeutic regimens are dir-
ected at reducing ammonia production and absorption
from the gut. Restricting oral protein consumption in
order to reduce a source of ammonia was a primary
treatment for decades, but is now discouraged because
it aggravates lean body wasting in cirrhosis. Another
approach to reducing gut ammonia production from
dietary sources is to prescribe less encephalopatho-
genic, vegetable-based protein diets. Nonabsorbable
antibiotics and cathartics (lactulose and lactitol) have
also been used to reduce ammonia production and
absorption. In addition to its antibiotic actions, neo-
mycin may reduce ammonia production by inhibiting
intestinal glutaminase. Bacterial overgrowth in the
small intestine and other disturbances of the micro-
ecology of indigenous gut flora are common in cirrho-
sis, and may impact toxin/ammonia production. The
ammonia-lowering actions of lactulose/lactitol may
be due in part to their effects on gut flora. However,
despite their widespread use, controlled trials have
indicated that lactulose/lactitol and neomycin therapies
are not superior to placebo in the treatment of HE. The
utility of these agents in the treatment of HE is cur-
rently being reassessed using randomized, placebo-
controlled trials. Similarly, the efficacy of modulating
intestinal flora, such as through the administration of
Enterobacter faecium SF 68, in treating HE is receiving
renewed interest.
Another mode of therapy is to enhance the excre-
tion of waste nitrogen from the body in patients
with liver failure. Sodium benzoate, phenylacetate,
and L-ornithine-L-aspartate (LOLA) promote this
process through a variety of mechanisms. LOLA
may improve HE by lowering ammonia levels and
suppressing ammonia-induced neurotoxicity by
stimulating urea cycle function. Moreover, LOLA is
more effective than placebo in clinical trials.
Other therapies for HE shown to be effective in
placebo-controlled trials include acarbose and the
centrally acting benzodiazepine receptor antagonist,
flumazenil. There are a number of anecdotal reports
of the efficacy of flumazenil in treating patients
suffering from HE. It has been claimed that the rever-
sal of coma by flumazenil in these reports reflects the
abuse of benzodiazepines by patients with liver dis-
ease. However, these claims do not take into account
that endogenous benzodiazepine receptor ligands
have been found in multiple animal models of HE.
Moreover, a number of placebo-controlled trials of
the efficacy of flumazenil in controlled patient popu-
lations have been conducted. Typically, low doses
(1–5 mg) of flumazenil reverse HE in 30% of patients
within 0.5–5 min of administration. In a meta-analy-
sis of 12 randomized trials, eight with cross-over
design, flumazenil was associated with a significant
improvement of HE (30%) compared to placebo
(7%), particularly in a subpopulation of patients

with low-grade encephalopathy. While no follow-up
therapy was employed in these studies, long-term
suppression of HE has been reported with chronic
oral administration of flumazenil (25 mg). Develop-
ment of a long-acting, orally available form of a benzo-
diazepine antagonist should enhance the use of this
therapy for HE.
Finally, can the evidence implicating ammonia in
the enhancement of GABAergic neurotransmission
be used to develop therapeutic modalities for treating
HE? An agent that can reverse ammonia’s enhance-
ment of GABA and benzodiazepine receptor function
with minimal convulsant activity would be desirable.
Such an agent may be an antagonist of the neuroster-
oid-binding site on the GABAA receptor complex,
such as pregnenolone. As previously noted, ammonia
enhances the binding of [3H]flunitrazepam. Perfor-
ming these assays in the presence of pregnenolone
sulfate completely abolished the ability of ammonia
to enhance the binding of [3H]flunitrazepam. Similar
effects were seen on ligand binding to the GABA site
on the GABAA receptor complex. These preliminary
observations suggest a potential use for neurosteroid
antagonists in reversing some of the psychomotor
symptoms of HE. Interestingly, present therapeutic
protocols aimed at reducing ammonia levels by restrict-
ing dietary intake and modifying colonies of enteric
bacteria may also reduce the synthesis or uptake of
benzodiazepine receptor ligands or their precursors.
Conclusion
In summary, multiple factors contribute to the patho-
genesis of HE, including agents that impair oxidative
metabolism or neurotransmitter synthesis in the CNS,
or which interact directly with neurotransmitter recep-
tors. The principal effect of this is to suppress neuronal
activity, in part by enhancing GABAergic neuro-
transmission. The renewed emphasis on the role of
abnormal CNS function in the manifestations of
HE suggests that future therapeutic modalities for this
disorder will focus upon the brain as well as the gut.
See also: GABAA Receptors: Developmental Roles;
Gamma-Aminobutyric Acid (GABA); Glutamatergic and
Gabaergic Systems; Neural Stem Cells and CNS
Diseases; Neurotoxins; Neurotoxins and their
Neurotoxicology.
Further Reading
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