Hepatic encephalopathy in adults: Clinical manifestations and diagnosis

Author:
Peter Ferenci, MD
Section Editor:
Bruce A Runyon, MD
Deputy Editor:
Kristen M Robson, MD, MBA, FACG

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2018. | This topic last updated: Nov 13, 2017.

INTRODUCTION — Hepatic encephalopathy describes a spectrum of potentially reversible

neuropsychiatric abnormalities seen in patients with liver dysfunction and/or portosystemic
shunting. Overt hepatic encephalopathy develops in 30 to 45 percent of patients with
cirrhosis and in 10 to 50 percent of patients with transjugular intrahepatic portal-systemic
shunts [1,2]. The International Society for Hepatic Encephalopathy and Nitrogen
Metabolism consensus defines the onset of disorientation or asterixis (flapping tremor) as
the onset of overt hepatic encephalopathy [3]. Some patients with hepatic encephalopathy
have subtle findings that may only be detected using specialized tests, a condition known
as minimal hepatic encephalopathy [4-6]. Minimal hepatic encephalopathy is seen in up to
80 percent of patients with cirrhosis [7-13].

Hepatic encephalopathy is often easy to detect in patients presenting with overt

neuropsychiatric symptoms. It may be more difficult to detect in patients with chronic liver
diseases who have mild signs of altered brain function, particularly if the underlying cause
of the liver disease may be associated with neurologic manifestations (such as alcoholic
liver disease or Wilson disease).

This topic will review the clinical manifestations and diagnosis of hepatic encephalopathy in
adults. The pathogenesis and treatment of hepatic encephalopathy are discussed
elsewhere. (See "Hepatic encephalopathy: Pathogenesis" and "Hepatic encephalopathy in
adults: Treatment".)

CATEGORIZATION AND GRADING — Hepatic encephalopathy is categorized based on

four factors: the underlying disease, the severity of manifestations, the time course, and
whether precipitating factors are present (figure 1) [14-16].
 ●Underlying disease: A classification scheme based on the underlying disease has
been proposed [14,15]:
•Type A: hepatic encephalopathy occurring in the setting of acute liver failure
•Type B: hepatic encephalopathy occurring in the setting of portal-systemic bypass
with no intrinsic hepatocellular disease
•Type C: hepatic encephalopathy occurring in the setting of cirrhosis with portal
hypertension or systemic shunting
●Severity of manifestations: The severity of hepatic encephalopathy is graded based
on the clinical manifestations (table 1 and figure 2) [16] (see 'Clinical
manifestations' below):
•Minimal: Abnormal results on psychometric or neurophysiological testing without
clinical manifestations (see 'Psychometric tests' below)
•Grade I: Changes in behavior, mild confusion, slurred speech, disordered sleep
•Grade II: Lethargy, moderate confusion
•Grade III: Marked confusion (stupor), incoherent speech, sleeping but arousable
•Grade IV: Coma, unresponsive to pain
Patients with grade I encephalopathy may have mild asterixis, whereas pronounced
asterixis is seen in patients with grade II or III encephalopathy [17]. Asterixis is typically
absent in patients with grade IV encephalopathy, who instead may demonstrate
decorticate or decerebrate posturing.
Patients with minimal or grade I hepatic encephalopathy are described as having
covert hepatic encephalopathy, whereas patients with grade II to IV hepatic
encephalopathy are described as having overt hepatic encephalopathy. The separation
of minimal hepatic encephalopathy from grade I hepatic encephalopathy is important
for clinical studies.
●Time course: The time course for hepatic encephalopathy can be episodic, recurrent
(bouts of hepatic encephalopathy that occur within a time interval of six months or
less), or persistent (a pattern of behavioral alterations that are always present,
interspersed with episodes of overt hepatic encephalopathy).
●Precipitating factors: Episodes of hepatic encephalopathy are described as being
either nonprecipitated or precipitated. If precipitated, the precipitating factors should be
specified (table 2). (See 'Evaluation for precipitating causes' below.)

CLINICAL MANIFESTATIONS — Hepatic encephalopathy is characterized by cognitive

deficits and impaired neuromuscular function (figure 2 and figure 3). Patients with minimal
hepatic encephalopathy have subtle cognitive deficits, often appear to be asymptomatic,
and may only be detected with psychomotor or electrophysiologic testing. Patients with
overt hepatic encephalopathy have signs and symptoms that can be detected clinically,
without the use of psychomotor testing (though psychomotor testing may be helpful in
evaluating patients with mild encephalopathy).

In addition to the clinical manifestations of hepatic encephalopathy, patients frequently have

clinical manifestations of chronic liver disease.

Signs and symptoms — Cognitive findings in patients with hepatic encephalopathy vary

from subtle deficits that are not apparent without specialized testing (minimal hepatic
encephalopathy), to more overt findings, with impairments in attention, reaction time, and
working memory (figure 2 and figure 3) [18]. Patients with severe hepatic encephalopathy
may progress to hepatic coma. Neuromuscular impairments include bradykinesia,
hyperreflexia, rigidity, myoclonus, and asterixis.

Disturbances in the diurnal sleep pattern (insomnia and hypersomnia) are common initial
manifestations of hepatic encephalopathy and typically precede other mental status
changes or neuromuscular symptoms. As hepatic encephalopathy progresses, patients may
develop mood changes (euphoria or depression), disorientation, inappropriate behavior,
somnolence, confusion, and unconsciousness.

Neuromuscular impairment in patients with overt hepatic encephalopathy includes

bradykinesia, asterixis (flapping motions of outstretched, dorsiflexed hands), slurred
speech, ataxia, hyperactive deep tendon reflexes, and nystagmus. Less commonly, patients
develop loss of reflexes, transient decerebrate posturing, and coma.

Focal neurologic deficits may also be present. In a report of 32 patients who had 46
episodes of hepatic encephalopathy, a focal neurologic sign was detected in eight patients
(17 percent of the episodes) [19]. The most common was hemiplegia. None of the patients
with focal neurologic signs had abnormal findings on computed tomography scan or
cerebrospinal fluid examination. Cerebral magnetic resonance imaging was performed in
five of the eight patients and was normal in all five. Similarly, five patients with focal
neurologic signs underwent Doppler ultrasound of the neck and vessels. In all five, the
Doppler imaging was normal. The focal neurologic deficits resolved completely in seven of
eight surviving patients after six months of follow-up.

Patients with hepatic encephalopathy usually have advanced chronic liver disease and thus
have many of the physical stigmata associated with severe hepatic dysfunction. Physical
findings may include muscle wasting, jaundice, ascites, palmar erythema, edema, spider
telangiectasias, and fetor hepaticus. Some of these findings (such as muscle wasting,
spider telangiectasias, and palmar erythema) are usually absent in previously healthy
patients with acute hepatic failure since their development requires a relatively longer period
of hepatic dysfunction. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and
diagnosis", section on 'Clinical manifestations' and "Acute liver failure in adults: Etiology,
clinical manifestations, and diagnosis".)

Laboratory abnormalities — Laboratory abnormalities in patients with hepatic

encephalopathy may include elevated arterial and venous ammonia concentrations. In
addition, patients typically have abnormal liver biochemical and synthetic function tests due
to underlying liver disease. Patients may also have electrolyte disturbances (such as
hyponatremia and hypokalemia) related to hepatic dysfunction and/or diuretic use.
(See 'Ammonia' below and "Cirrhosis in adults: Etiologies, clinical manifestations, and
diagnosis", section on 'Laboratory findings'.)

DIAGNOSIS — The approach to the diagnosis of hepatic encephalopathy includes:

●A history and physical examination to detect the cognitive and neuromuscular

impairments that characterize hepatic encephalopathy
●Exclusion of other causes of mental status changes (see 'Differential
diagnosis' below)
•Serum laboratory testing to rule out metabolic abnormalities
•A computed tomography (CT) scan of the brain if the clinical findings suggest
another cause for the patient's findings may be present (such as a subdural
hematoma from trauma); a CT scan may also demonstrate cerebral edema (found
in 80 percent of patients with acute hepatic encephalopathy) (see "Acute toxic-
metabolic encephalopathy in adults", section on 'Hepatic encephalopathy')
●Evaluation for possible precipitating causes of the hepatic encephalopathy
(see 'Evaluation for precipitating causes' below)

While arterial and venous ammonia concentrations are often elevated in patients with
hepatic encephalopathy, an elevated ammonia level is not required to make the diagnosis.
In addition, elevated ammonia levels may be seen in patients who do not have hepatic
encephalopathy (table 3).

For patients with mild degrees of hepatic encephalopathy (minimal hepatic encephalopathy
or grade I encephalopathy) in whom the diagnosis is unclear, psychometric and
electrophysiologic tests may be helpful. In such patients, our approach is to first to ask
about subtle signs of impaired mental status, and if signs point to the possible presence of
minimal hepatic encephalopathy to perform psychometric testing (typically the number
connection test) (algorithm 1). An alternative but less sensitive test is the Mini-Mental State
Examination (MMSE). (See "Evaluation of cognitive impairment and dementia", section on
'Mini-Mental State Examination'.)
For patients with more severe hepatic encephalopathy (grades III and IV), the Glasgow
Coma Scale may be useful for further stratifying the severity of neurologic impairment
(figure 2) [20]. (See 'Psychometric tests' below and 'Electrophysiologic tests' below
and 'Clinical manifestations' above.)

History and physical examination — The evaluation should start by inquiring about

mental status changes, keeping in mind that in patients with minimal hepatic
encephalopathy the signs may be subtle. Patients should be asked about changes in their
sleep patterns and in cognitive capacity (decreased attention span, impaired short term
memory) leading to difficulties with normal daily activities. Patients should also be asked
about impaired work performance and work- or driving-related accidents. Patients should
also be examined for signs of neuromuscular dysfunction. (See 'Clinical
manifestations' above.)

Laboratory tests — Ammonia is the best characterized neurotoxin that precipitates hepatic

encephalopathy. However, an elevated serum ammonia concentration is not required to
make the diagnosis and is not specific for hepatic encephalopathy. In addition, ammonia
levels are influenced by factors such as how the blood sample is obtained and handled.
Serum ammonia levels should not be used to screen for hepatic encephalopathy in patients
who are asymptomatic or who have mental status changes in the absence of liver disease
or a portal-systemic shunt.

Other routine laboratory tests should be obtained to exclude other causes of mental status
changes (eg, hypoglycemia, uremia, electrolyte disturbances, and intoxication) and to look
for conditions that may have precipitated the hepatic encephalopathy. (See 'Differential
diagnosis' below and 'Evaluation for precipitating causes' below.)

Ammonia — 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. The intact liver clears almost all of the portal vein ammonia, converting it into urea or
glutamine and preventing entry into the systemic circulation. The increase in blood
ammonia levels 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.

Whether to measure of the serum ammonia concentration in patients suspected of having

hepatic encephalopathy remains controversial. While the venous and arterial ammonia
levels correlate with the severity of hepatic encephalopathy, levels are inconsistently
elevated [21,22]. Measuring serum ammonia levels may be useful under certain conditions
(eg, monitoring efficacy of ammonia lowering therapy), but is not required to make the
diagnosis of hepatic encephalopathy or for the long-term follow-up of patients with
advanced liver disease. The accuracy of ammonia determination is influenced by many
factors (such as fist clenching, use of a tourniquet, and whether the sample was placed on
ice). These factors should be considered when interpreting results. Furthermore, ammonia
levels can be elevated in a variety of nonhepatic conditions (table 3).

Venous ammonia concentration is not useful for screening for hepatic encephalopathy since
levels vary [23]. In addition, hepatic encephalopathy is only directly related to ammonia
levels up to about a twofold increase above normal. Any further increase of ammonia
concentration does not contribute to the further evolution of hepatic encephalopathy [24].

As with the venous ammonia concentration, hepatic encephalopathy is only directly related
to arterial ammonia concentration up to about a twofold increase above normal.
Furthermore, the grade of hepatic encephalopathy is more closely related to the partial
pressure of gaseous ammonia (pNH3) than the total arterial ammonia concentration, since
gaseous ammonia readily enters the brain [24]. The pNH3 can be calculated from the total
ammonia and pH [25], though this is rarely done outside of clinical studies. (See "Hepatic
encephalopathy: Pathogenesis".)

Postprandial ammonia levels may be more closely related to minimal hepatic

encephalopathy than fasting levels. Thus, in clinical trials, ammonia is often measured after
a standard meal (or glutamine load) [26]. In one study, induced hyperammonemia was
associated with a significant increase in daytime subjective sleepiness and changes in the
electroencephalogram (EEG) architecture of a subsequent sleep episode in patients with
cirrhosis [27].

Other potential markers — Serum levels of 3-nitrotyrosine may be elevated in patients

with minimal hepatic encephalopathy. One study found that using a cutoff of 14 nM, 3-
nitrotyrosine was 93 percent sensitive and 89 percent specific for detecting minimal hepatic
encephalopathy [28].

Psychometric tests — Commonly performed bedside tests are insufficiently sensitive to

detect subtle changes in mental function. As a result, several psychometric tests have been
evaluated that quantify the impairment of mental function in patients with mild stages of
hepatic encephalopathy [4,29-32]. These tests are more sensitive for the detection of minor
deficits of mental function than conventional clinical assessment or an EEG [29]. Several
psychometric tests have been developed, but none is used routinely in clinical practice. Our
approach is to use the number connection test if signs point to the possible presence of
minimal hepatic encephalopathy.
The use of psychometric tests is limited because many are cumbersome and time
consuming (up to two hours per session), their reliability is decreased by a learning effect
when they are applied repeatedly, and there is poor correlation among the tests [33,34].
Another problem with psychometric tests is that they are nonspecific (ie, any alteration of
brain function will result in abnormal test results). This is a particular problem in patients
with alcoholic liver disease or Wilson disease since both are associated with central
nervous system abnormalities.

Number connection test (Reitan Test) — The most frequently used psychometric test is
the number connection test (NCT or Reitan Test), which is easily administered and
interpreted (figure 4 and figure 5) [30,31,35]. The NCT is a timed connect-the-numbers test.
Patients without hepatic encephalopathy should finish the test in a number of seconds less
than or equal to their age in years. In other words, if a patient is 50 years old, he should be
able to finish the test in ≤50 seconds.

The test traditionally has two parts, but often only the first part of the test (figure 4) is used
because the second part (figure 5) can be confusing and often does not add additional
clinical information.

Psychometric Hepatic Encephalopathy Score (PHES) — In an attempt to improve the

performance of testing for minimal hepatic encephalopathy, a battery of five paper and
pencil tests were combined into a new instrument, the Psychometric Hepatic
Encephalopathy Score (PHES) [36]. The PHES includes a line tracing test, digit symbol
test, serial dotting test, and both parts of the NCT. It examines visual perception,
visuospatial orientation, visual construction, motor speed and accuracy, concentration,
attention, and memory. The test can be performed in 10 to 20 minutes at the bedside.
Possible scores range from -18 to +6 points.

In one study, when a cutoff of ≤-4 points was used, the test had a high sensitivity and
specificity for detecting mild hepatic encephalopathy [36]. A simplified version of the test
consisting only of the digit symbol, serial dotting, and line tracing tests was found to be as
accurate as the full PHES test [37]. However, a study comparing the PHES test with an
EEG in 100 patients with cirrhosis found agreement in detection of minimal hepatic
encephalopathy in only 73 percent of patients [38]. The poor correlation may reflect
differences in how these tests detect various features of minimal hepatic encephalopathy.

The PHES test has been recommended by a panel of international experts for the
neuropsychological assessment of early hepatic encephalopathy, though in practice it is
rarely used [14].
Other psychometric tests — More complex tests continue to be used for clinical studies,
which often include multiple tests that measure different brain functions (such as memory,
motor performance, attention, etc). The interpretation of the tests often requires a trained
psychologist and sophisticated statistical methods [39].

●The Inhibitory Control Test (ICT) is a computerized test of attention and response
inhibition that has been used to characterize attention deficit disorder, schizophrenia,
and traumatic brain injury. The subject is instructed only to respond to two alternating
letters (X/Y) (called "targets") and not to respond when they are not alternating (called
"lures"). Lower lure responses, higher target responses, and shorter lure and target
reaction times indicate good psychometric performance.

A study comparing ICT to a psychometric battery of tests in 136 patients estimated its
sensitivity for minimal hepatic encephalopathy to be 88 percent [40]. Patients with
minimal hepatic encephalopathy had significantly higher ICT lures and lower targets
compared with patients without minimal hepatic encephalopathy. Another study
comparing ICT with other diagnostic standards found that ICT was not useful for
diagnosis of minimal hepatic encephalopathy unless results were adjusted by target
accuracy (a measure reflecting the total number of correct responses from a set of
presented targets, such as specific letters in a string of other letters) [41].
●Computerized testing that measures neurocognitive functions (eg, the Cognitive Drug
Research [CDR] battery) is an alternative to paper and pencil based testing (such at
the PHES). It does not rely as heavily on the motor function of the patient for
completion. The CDR battery was compared with the PHES in 89 patients with
cirrhosis [42]. There was a high correlation between the two assessment methods. The
Model for End-stage Liver Disease score correlated with PHES, whereas venous
ammonia concentrations correlated with the CDR domains of Continuity of Attention
and Quality of Episodic Memory. There were marked deteriorations in the CDR
composite scores representing Accuracy of Working and Episodic Memory after amino
acid challenge to increase blood ammonia concentrations. Both PHES and CDR
returned to the control range after liver transplantation.
●The Stroop task is a test of psychomotor speed and cognitive flexibility that evaluates
the functioning of the anterior attention system and is sensitive for the detection of
cognitive impairment in minimal hepatic encephalopathy [43]. The task has two
components: "off" and "on" states depending on the discordance or concordance of
stimuli. This test is available as an application for smart phones (EncephalApp Stroop)
and can be administered in a few minutes.
●The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
measures a wide range of neurocognitive functions relevant to minimal hepatic
encephalopathy. The test has been used in multiple clinical trials in the United States
 for a variety of neurologic disorders and in patients with advanced cirrhosis [44]. The
RBANS has not yet been compared directly with the PHES, and its responsiveness to
hepatic encephalopathy treatment is unknown.
●Another useful test is the measurement of reaction times to auditory and visual stimuli
[45,46]. The equipment is inexpensive, and the time to perform it is reasonably short. It
can be applied repeatedly since it is not affected by learning effects.
●Other emerging diagnostic strategies concentrate on computerized tests and batteries
such as the Scan test, a three-level-difficulty computerized reaction time test [47],
central nervous system (CNS) vital signs [48], and Immediate Post-concussion
Assessment and Cognitive Testing (ImPACT) [49]. A simple test using a smartphone-
based application may be a useful tool for repeated assessment of minimal hepatic
encephalopathy [43].

Electrophysiologic tests — Electrophysiologic tests to detect minimal hepatic

encephalopathy include EEG monitoring, evoked potentials, and critical flicker frequency
testing. However, none of these tests is widely used.

Electroencephalogram activity — The evolving EEG changes associated with

increasingly severe hepatic encephalopathy consist initially of a bilaterally synchronous
decrease in wave frequency and an increase in wave amplitude, associated with the
disappearance of a readily discernible normal alpha-rhythm (8 to 13 cps). The simplest EEG
assessment of hepatic encephalopathy is grading the degree of abnormality of the
conventional EEG tracing. A more refined assessment can be accomplished with computer-
assisted spectral analysis of the EEG, which permits variables in the EEG (such as the
mean dominant EEG frequency and the power of a particular EEG rhythm) to be quantified.
Minor changes in the dominant EEG frequency occur in mild hepatic encephalopathy.
Spectral EEG analysis may improve the assessment of mild hepatic encephalopathy by
decreasing inter-operator variability and providing reliable parameters correlated with
mental status [50].

The bispectral index (BIS) monitor is a rapid bedside tool to monitor EEG activity. In a
prospective study, BIS monitoring was useful for grading and monitoring the degree of
involvement of the central nervous system in patients with chronic liver disease and to
classify the degree and progression of hepatic encephalopathy [51].

Evoked potentials — Evoked potentials are externally recorded electrical signals that

reflect synchronous volleys of discharges through neuronal networks in response to various
afferent stimuli. They are categorized as visual, somatosensory, or acoustic, depending on
the type of stimulus [52]. A more sophisticated form of evoked responses is event-related
responses, which require some form of intellectual function. A typical event-related
response is the P300 peak after auditory stimuli. The P300 is extremely sensitive for
detecting subtle changes of brain function and can be used to diagnose minimal hepatic
encephalopathy [53].

Critical flicker frequency — Retinal glial cells are involved in ammonia detoxification by

glutamine synthesis. In patients with liver failure, they exhibit morphological changes similar
to those observed in brain astrocytes, suggesting that retinal gliopathy could serve as a
marker of cerebral gliopathy in patients with hepatic encephalopathy. These observations
provided the rationale for the development of a visual test (the
critical flicker/fusion frequency) for determining whether hepatic encephalopathy is present.
Advantages of the test are that it is objective and it is not affected by the patient's age
or education/literacy level [54-56]. However, a meta-analysis suggests that it is only
moderately sensitive for detecting minimal hepatic encephalopathy. The meta-analysis
included nine studies with 622 patients and found that critical flicker frequency had a
sensitivity for detecting minimal hepatic encephalopathy of 61 percent and a specificity of 79
percent [57].

In an analysis of patients with cirrhosis and controls, critical flicker frequency differentiated
patients with overt hepatic encephalopathy from those without hepatic encephalopathy.
PHES testing, critical flicker frequency, and a combination of PHES and critical flicker
frequency could not reliably distinguish patients with minimal hepatic encephalopathy from
controls or those with overt hepatic encephalopathy [58].

Radiologic imaging — Radiologic imaging is primarily used to exclude other causes of

mental status changes. We typically obtain a noncontrast head CT scan when the clinical
findings suggest that another cause for the patient's mental status changes may be present
(such as a subdural hematoma from trauma).

Computed tomography and magnetic resonance imaging of the brain — A noncontrast

CT scan is indicated in patients with overt hepatic encephalopathy in whom the diagnosis is
uncertain, to exclude other diseases associated with coma or confusion. A CT scan may
also reveal generalized or localized cerebral edema, suggesting a diagnosis of hepatic
encephalopathy.

Magnetic resonance imaging — Magnetic resonance imaging (MRI) is superior to CT for

the diagnosis of brain edema in liver failure, but it is not an established method for
diagnosing hepatic encephalopathy. Changes have been observed on T1-weighted images
with a strong signal in the basal ganglia in patients with hepatic encephalopathy, possibly
due to manganese accumulation [59]. However, these changes are neither sensitive nor
specific indicators of hepatic encephalopathy [60,61].
Magnetic resonance spectroscopy and positron emission tomography — In vivo
magnetic resonance spectroscopy (MRS) is a noninvasive method that is being studied but
is not yet in routine clinical use. It permits serial measurement of various neurometabolites
in the brain using a variety of isotopes, such as (1)H, (32)P, and (12)C. Proton (1H) MRS
assesses regional brain concentrations of choline, creatine (Cr), glutamine/glutamate (Glx),
myoinositol, and N-acetyl aspartate, depending on the spectral sequence used. (1H) MRS
has tremendous potential for the future, particularly for documenting treatment effects [62].

Patients with hepatic encephalopathy should display an increase in Glx resonance since
ammonia is detoxified in astrocytes to glutamine by glutamine synthetase. Several studies
have assessed changes in Glx/Cr in patients with different stages of hepatic
encephalopathy [63-66]. Some have shown significant direct correlation between the
severity of hepatic encephalopathy and Glx/Cr [63,64], whereas others have not [65,66]. In
other studies, findings on MRI and MRS correlated with abnormalities in the basal ganglia
and presence of Parkinsonian signs in patients with cirrhosis [67].

Another pertinent observation is that the increase in brain glutamine during hepatic
encephalopathy (represented in MRS by increased Glx) increases intracellular osmolality.
To maintain osmotic equilibrium, the astrocytes lose osmolytes such as myoinositol (mI).
The mI/Cr ratio is significantly reduced in patients with hepatic encephalopathy, suggesting
that an imbalance in the astrocytic osmotic equilibrium may contribute to the pathogenesis
of hepatic encephalopathy [65,66]. (See "Hepatic encephalopathy: Pathogenesis".)

Microstructural white matter changes in the brain can be detected using voxel-based
diffusion tensor imaging analysis during MRS. The test is based upon calculating indices for
an apparent diffusion coefficient (ADC) and fractional anisotropy (FA). One study showed
widespread brain regions with increased brain mean diffusion values, indicating enhanced
water content and decreased FA in patients with hepatic encephalopathy [68]. The brain
mean ADC and FA values from selected regions correlated with the neuropsychological
scores.

The variability among the results of proton MRS studies may be due to differences in the
patient populations studied (eg, sample size, severity of hepatic encephalopathy, age, and
cause of liver failure), differences in techniques, and the methods used in the diagnosis of
hepatic encephalopathy.

Another method, T1 mapping with partial inversion recovery (TAPIR), has been used to
obtain a series of T1-weighted images to produce T1 maps. In one report using this
technique, imaging of 15 control subjects and 11 patients was performed on a 1.5T MRI
scanner [69]. The measurement time per patient with this technique, including adjustments,
was approximately five minutes. T1 changes in the brains of patients with hepatic
encephalopathy were determined quantitatively with TAPIR in short, clinically relevant
measurement times. Significant correlations between the change in T1 and hepatic
encephalopathy severity were shown in the globus pallidus, the caudate nucleus, and the
posterior limb of the internal capsule.

Cerebral glucose metabolism is considered to be a marker for brain function and thus
should correlate with cerebral ammonia metabolism in patients with hepatic
encephalopathy. A study evaluated this hypothesis by correlating plasma and cerebral
ammonia metabolism with the results of (13)N-ammonia and (18)F-fluorodeoxyglucose
positron emission tomography in 21 patients with cirrhosis and no hepatic encephalopathy
or grade I hepatic encephalopathy [70]. A correlation between MRS with plasma and
cerebral ammonia metabolism could be demonstrated only in white matter. By contrast,
MRS alterations correlated with glucose utilization in several brain regions. These data
suggest that cerebral ammonia metabolism is important but not the only causal factor
related to development of hepatic encephalopathy.

Evaluation for precipitating causes — There are several conditions that may precipitate
an episode of hepatic encephalopathy in patients with liver disease or a portal-systemic
shunt (table 2). These include [18,71-74]:

●Gastrointestinal bleeding
●Infection (including spontaneous bacterial peritonitis and urinary tract infections)
●Hypokalemia and/or metabolic alkalosis
●Renal failure
●Hypovolemia
●Hypoxia
●Sedatives or tranquilizers
●Hypoglycemia
●Constipation
●Rarely, hepatocellular carcinoma and/or vascular occlusion (hepatic vein or portal
vein thrombosis)

Patients with hepatic encephalopathy should be evaluated for potential precipitating causes.
This evaluation should include:

●A history to determine if the patient has been exposed to any medications or toxins
(including alcohol)
●Physical examination to look for signs of gastrointestinal bleeding or hypovolemia
(see "Approach to acute upper gastrointestinal bleeding in adults", section on 'Bleeding
 manifestations' and "Etiology, clinical manifestations, and diagnosis of volume
depletion in adults", section on 'Clinical manifestations')
●A search for sources of infection with blood and urine cultures, as well as
paracentesis for patients with ascites (see "Spontaneous bacterial peritonitis in adults:
Diagnosis")
●Routine serum chemistries to look for metabolic and electrolyte abnormalities
●Serum alpha-fetoprotein (see "Clinical features and diagnosis of primary
hepatocellular carcinoma")

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of patients presenting with

mental status changes is long (table 4). While hepatic encephalopathy should be
considered in patients with acute or chronic liver disease or a portal-systemic shunt,
particularly those with a history of hepatic encephalopathy, other causes for the patient's
confusion should be considered, such as a subdural hematoma, renal failure, or mental
status changes associated with the patient's underlying liver disease (eg, Wilson disease).

A general approach to the evaluation of patients with delirium and confusional status is
discussed elsewhere. (See "Diagnosis of delirium and confusional states".)

CAPACITY TO DRIVE — A concern in patients with minimal hepatic encephalopathy is

whether they are at increased risk for driving accidents since declines in cognitive function
in other populations (such as those with dementia) have been associated with such a risk
[75]. Studies evaluating this question have reached disparate conclusions. The majority
suggest that patients with minimal hepatic encephalopathy are at increased risk for
accidents [4,76-80], though a pilot study of stable individuals with cirrhosis found that while
66 percent of the subjects had minimal hepatic encephalopathy, they did not exhibit major
impairments in their fitness to drive [81].

Deciding when and how to evaluate the driving capacity of patients with cirrhosis is
complex. Psychometric tests alone do not appear to be useful for assessing driving fitness.
Several factors have to be considered [80]:

●The available data suggest that most patients with cirrhosis do not have minimal
hepatic encephalopathy at any given time and do not have impaired driving capacity
when measured under real life conditions.
●Optimal means to identify patients at risk for driving remain unclear.
●Legislation regarding reporting of individuals with impaired driving capacity varies by
state in the United States, and by country elsewhere. Thus, it may not be possible to
restrict driving based on the results of specific testing in all regions.
●How often patients should be reassessed for driving capacity is unclear.
The legal ramifications related to driving and hepatic encephalopathy remain poorly defined
[82]. Until further data are available, we use the following approach [83]:

●It may be reasonable to restrict driving in patients with persistent hepatic

encephalopathy associated with cirrhosis, particularly in those in whom their clinical
course, physical examination, and reports from relatives suggest that they may be at
increased risk of accidents.
●Neuropsychiatric testing to detect minimal hepatic encephalopathy is reasonable in
centers where it is available, particularly in patients at increased risk, such as those
with advanced cirrhosis (Child-Pugh Class B or C), large portal-systemic shunts (eg,
transjugular intrahepatic portal-systemic shunt or surgery), alcoholic liver disease, or
prior episodes of hepatic encephalopathy. However, the cost-effectiveness of this
approach is unknown. Another option would be to have such patients undergo a driving
test conducted by a trained examiner, but how such driving tests should be performed
has not been standardized.
●A graded approach (such as restricting driving to short distances during daytime
hours) may be adequate for patients with only mild neuropsychiatric impairment and
good driving reports from relatives.
●Reassessment of patients at risk for progressive liver disease should be made on an
individual basis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines

from selected countries and regions around the world are provided separately.
(See "Society guideline links: Cirrhosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

●Hepatic encephalopathy describes the spectrum of potentially reversible

neuropsychiatric abnormalities seen in patients with liver dysfunction.
(See 'Introduction' above.)
●Hepatic encephalopathy is characterized by cognitive deficits and impaired
neuromuscular function (figure 2 and figure 3). Cognitive findings in patients with
hepatic encephalopathy vary from subtle deficits that are not apparent without
specialized testing (minimal hepatic encephalopathy) to more overt findings, with
impairments in attention, reaction time, and working memory. Patients with severe
hepatic encephalopathy may progress to hepatic coma. Neuromuscular impairments
include bradykinesia, hyperreflexia, rigidity, myoclonus, and asterixis. Disturbances in
the diurnal sleep pattern (insomnia and hypersomnia) are common initial
manifestations of hepatic encephalopathy and typically precede other mental status
changes or neuromuscular symptoms. (See 'Clinical manifestations' above
and 'Categorization and grading' above.)
●The approach to the diagnosis of hepatic encephalopathy includes (algorithm 1)
(see 'Diagnosis' above):
•Ahistory and physical examination to detect the cognitive and neuromuscular
impairments that characterize hepatic encephalopathy.
•Psychometric testing if minimal hepatic encephalopathy is suspected.
•Exclusion of other causes of mental status changes: Serum laboratory testing to
rule out metabolic abnormalities, a computed tomography scan of the brain if the
clinical findings suggest another cause for the patient's findings may be present
(such as a subdural hematoma from trauma).
●While arterial and venous ammonia concentrations are often elevated in patients with
hepatic encephalopathy, an elevated ammonia level is not required to make the
diagnosis. In addition, elevated ammonia levels may be seen in patients who do not
have hepatic encephalopathy (table 3).
●Patients with hepatic encephalopathy should be evaluated for potential precipitating
causes (table 2). This evaluation should include (see 'Evaluation for precipitating
causes' above):
•A history to determine if the patients have been exposed to any medications or
toxins (including alcohol)
•Physical examination to look for signs of gastrointestinal bleeding or hypovolemia
•Asearch for sources of infection with blood and urine cultures, as well as
paracentesis for patients with ascites
•Routine serum chemistries to look for metabolic and electrolyte abnormalities
•Serum alpha-fetoprotein
Hepatic encephalopathy: Pathogenesis
Author:
Peter Ferenci, MD
Section Editor:
Bruce A Runyon, MD
Deputy Editor:
Kristen M Robson, MD, MBA, FACG

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2018. | This topic last updated: Dec 11, 2017.

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 alcoholics, intravenous drug users, 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: 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 brain to
blood 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 agonists 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 "Physiology and available
preparations of 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.

SYSTEMIC RESPONSE TO INFECTIONS AND NEUROINFLAMMATION — Infection is a

well-known precipitant of hepatic encephalopathy, but the mechanisms involved are
incompletely understood [4,111]. Patients with cirrhosis are known to be functionally
immunosuppressed and prone to develop infections [112]. 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 [113]. 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 [114].
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 [115].

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 [116].

In patients with cirrhosis, SIRS may exacerbate the symptoms of HE, both in patients with
minimal and overt HE [117,118]. 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 [119].

Another potential factor inciting an inflammatory response is bacterial translocation of

organisms from the gut, which results in chronic endotoxemia [119]. Bacterial translocation
may activate proinflammatory cytokines/chemokines and neutrophils through Toll-like and
chemokine receptors [120]. 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 [119,121,122]. Some
reports suggest that hyperammonemia may cause neuroinflammation [122]. In vitro
ammonia impairs neutrophil chemotaxis, phagocytosis, degranulation, and stimulated
oxidative burst, resulting in swelling of certain cells, including neutrophils and possibly
astrocytes [123]. 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 [124]. 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 [123].
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 [30,123,125]. 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 [126]. 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 [127]. 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 [128].

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 [129]. 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 [130].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●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
Hepatic encephalopathy in adults: Treatment
Author:
Peter Ferenci, MD
Section Editor:
Bruce A Runyon, MD
Deputy Editor:
Kristen M Robson, MD, MBA, FACG

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Feb 2018. | This topic last updated: Aug 17, 2017.

INTRODUCTION — Hepatic encephalopathy or portal-systemic encephalopathy represents

a reversible impairment of neuropsychiatric function associated with impaired hepatic
function. Despite the frequency of the condition, we lack a clear understanding of its
pathogenesis. Nevertheless, decades of experience have suggested that an increase in
ammonia concentration is implicated and that 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.
(See "Hepatic encephalopathy: Pathogenesis".)

Currently available therapies for hepatic encephalopathy are based on these hypotheses
(table 1). Some treatments are based on clinical observations, some on extrapolation of
experimental data obtained in animal models of hepatic encephalopathy, and a smaller
number on randomized trials. However, there are a number of problems that interfere with
the interpretation of data from these studies:

●A common problem is the variety of clinical conditions that are summarized under the
term "hepatic encephalopathy." The clinical features of hepatic encephalopathy include
a wide range of neuropsychiatric symptoms ranging from minor, not readily discernible
signs of altered brain function (minimal hepatic encephalopathy), to overt
psychiatric and/or neurologic symptoms, to deep coma. As a result, the methods to
quantify treatment effects and endpoints are highly variable. (See "Hepatic
encephalopathy in adults: Clinical manifestations and diagnosis".)
●It is not known if data regarding treatment in patients with overt hepatic
encephalopathy can be extrapolated to minimal hepatic encephalopathy and vice
versa. However, many studies included patients both with overt and minimal hepatic
encephalopathy.
 ●Another important variable is the treatment of control groups. Very few studies use a
placebo; in most cases, the new drug was compared with "standard treatment" (which
by itself may be highly effective) or specifically to lactulose.
●The sample size of most published studies was small.

This topic will review the management of hepatic encephalopathy in patients with chronic
liver disease. The pathogenesis, clinical manifestations, and diagnosis of hepatic
encephalopathy and the approach to patients with hepatic encephalopathy in the setting of
acute liver failure are discussed elsewhere. (See "Hepatic encephalopathy:
Pathogenesis" and "Hepatic encephalopathy in adults: Clinical manifestations and
diagnosis" and "Acute liver failure in adults: Management and prognosis", section on
'Hepatic encephalopathy'.)

The management of hepatic encephalopathy has also been addressed in a 2014 joint
guideline from the American Association for the Study of Liver Diseases and the European
Association for the Study of Liver Diseases. The discussion that follows is consistent with
this guideline [1].

MANAGEMENT OVERVIEW

Overt hepatic encephalopathy — Patients with overt hepatic encephalopathy have

clinically apparent impairments in cognitive and neuromuscular function. Treatment includes
determining the appropriate setting for care, correcting any predisposing conditions, and
lowering blood ammonia levels with medications such as lactulose, lactitol, or rifaximin.
Restricting dietary protein is not recommended for the majority of patients.

The severity of overt hepatic encephalopathy is graded from I to IV based on the clinical
manifestations (table 2 and figure 1). (See "Hepatic encephalopathy in adults: Clinical
manifestations and diagnosis", section on 'Clinical manifestations'.):

●Grade I: Changes in behavior, mild confusion, slurred speech, disordered sleep

●Grade II: Lethargy, moderate confusion
●Grade III: Marked confusion (stupor), incoherent speech, sleeping but arousable
●Grade IV: Coma, unresponsive to pain

Treatment will vary depending on the severity of a patient's hepatic encephalopathy. An

elevated serum ammonia level in the absence of clinical signs of hepatic encephalopathy is
not an indication for treatment. (See "Hepatic encephalopathy in adults: Clinical
manifestations and diagnosis", section on 'Ammonia'.)
Patient triage — Patients with mild hepatic encephalopathy (grade I) may be managed as
outpatients, provided caregivers are available to look for signs of worsening hepatic
encephalopathy and to bring the patient to the hospital if needed. Whether to admit a
patient with grade II encephalopathy to the hospital will depend on the degree of lethargy
and confusion. If there is any concern that a patient may not be able to adhere to treatment
or if caregivers are not available who can monitor the patient, the patient should be admitted
to the hospital for care. Patients with more severe hepatic encephalopathy (grades III to IV)
require hospital admission for treatment, typically to an intensive care unit. In addition,
consideration should be given to intubating such patients for airway protection.
(See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis", section on
'Categorization and grading'.)

General supportive care — General supportive care for patients with hepatic

encephalopathy includes providing appropriate nutritional support, avoiding dehydration and
electrolyte abnormalities, and providing a safe environment. Precautions to prevent falls
should be instituted for patients who are disoriented.

Patients hospitalized with hepatic encephalopathy may be agitated. Agitation often resolves
with treatment of the hepatic encephalopathy; however, patients may represent a hazard to
themselves and their caregivers until treatment takes effect. Management may include
judicious use of restraints, which may be a safer option than pharmacologic treatment, since
patients with advanced liver disease and hepatic encephalopathy may be particularly
vulnerable to oversedation with medications. Should medications be required, haloperidol is
a safer option than benzodiazepines based mainly on clinical experience and some limited
data [2]. Patients with advanced cirrhosis may be particularly sensitive to benzodiazepines
because of an increased concentration of benzodiazepine receptor ligands in the brain.
(See 'Flumazenil' below.)

Protein restriction and nutritional support — Nutritional support should include

maintaining an energy intake of 35 to 40 kcal/kg/day, with a protein intake of 1.2 to
1.5 g/kg/day. Patients with cirrhosis are often malnourished and protein restrictions are
associated with increased mortality, so patients with hepatic encephalopathy should
generally not have their protein intake restricted [3-5]. Patients with mild to moderate
hepatic encephalopathy can typically take nutrition orally. Patients with severe hepatic
encephalopathy usually do not receive oral nutrition. As soon as they improve, a standard
diet can be given. Patients should be instructed to eat small meals throughout the day with
a late-night snack of complex carbohydrates because fasting results in the production of
glucose from amino acids, with resultant ammonia production [6]. (See "Nutritional
assessment in chronic liver disease", section on 'Cirrhosis'.)
In patients whose symptoms worsen with protein intake, substitution of proteins from fish,
milk, or meat with vegetable proteins may improve nitrogen balance and mental status [7].
Another alternative for patients intolerant to protein is the addition of branched-chain amino
acids (BCAA) to a low protein diet. BCAA supplementation is indicated only in severely
protein-intolerant patients. As a general rule, only patients who have had a transjugular
intrahepatic portosystemic shunt or surgical portosystemic shunt have hepatic
encephalopathy severe enough to warrant use of vegetable protein or protein restriction
with BCAA supplementation. (See 'Branched-chain amino acids' below.)

Acute therapy — The initial management of acute hepatic encephalopathy in patients with

chronic liver disease involves two steps:

●Identification and correction of precipitating causes

●Measures to lower the blood ammonia concentration

Correction of precipitating causes — The first step in the treatment of hepatic

encephalopathy is the identification and correction of precipitating causes. Treatment of
precipitating causes combined with standard therapy is typically associated with a prompt
improvement in the hepatic encephalopathy.

Careful evaluation should be performed to determine if any of the following are present
(table 3) (see "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis",
section on 'Evaluation for precipitating causes'):

●Gastrointestinal bleeding
●Infection (including spontaneous bacterial peritonitis and urinary tract infections)
●Hypokalemia and/or metabolic alkalosis
●Renal failure
●Hypovolemia
●Hypoxia
●Sedative or tranquilizer use
●Hypoglycemia
●Constipation
●Rarely, hepatocellular carcinoma and/or vascular occlusion (hepatic vein or portal
vein thrombosis)

When possible, these precipitating causes should be treated.

Lower blood ammonia — The second step in the treatment of hepatic encephalopathy is

initiation of measures to lower blood ammonia concentrations (whether or not the values are
frankly elevated) with medications such as lactulose, lactitol, or rifaximin. Polyethylene
glycol is also being studied for the treatment of acute hepatic encephalopathy and appears
to be effective [8]. It is important to note that an elevated serum ammonia level in the
absence of clinical signs of hepatic encephalopathy is not an indication for ammonia-
lowering therapy. (See "Hepatic encephalopathy in adults: Clinical manifestations and
diagnosis", section on 'Ammonia'.)

Correction of hypokalemia is also an essential component of therapy since hypokalemia

increases renal ammonia production. However, dietary protein restriction is generally not
recommended. (See 'Commonly used treatments' below and 'Protein restriction and
nutritional support' above.)

Drug therapy is the mainstay of treatment to lower the blood ammonia concentration. Our
approach to drug therapy is as follows:

●We suggest initiating drug therapy for acute hepatic encephalopathy with lactulose or
lactitol (available in some countries outside of the United States). Lactulose and lactitol
act through a variety of mechanisms that lead to decreased absorption of ammonia
from the gastrointestinal tract. The dose of lactulose (30 to 45 mL [20 to 30 g] given
two to four times per day) should be titrated to achieve two to three soft stools per day.
An equivalent dose of lactitol is approximately 67 to 100 grams lactitol powder, diluted
in 100 mL of water. Lactulose or lactitol enemas can be given if the patient cannot take
lactulose orally. (See 'Lactulose and lactitol' below.)
Ornithine-aspartate, which stimulates the metabolism of ammonia, is an alternative for
the treatment of hepatic encephalopathy, but it is not available in the United States.
(See 'L-ornithine-L-aspartate' below.)
●For patients who have not improved within 48 hours or who cannot take lactulose or
lactitol, we suggest treatment with rifaximin. The dose of rifaximin is 400 mg orally
three times daily or 550 mg orally two times daily. As a general rule, antibiotics are
added to, rather than substituted for, lactulose or lactitol. (See 'Oral antibiotics' below.)
Neomycin has been used as a second-line therapy in patients who have not responded
to disaccharides, but it has not been shown to be efficacious in randomized trials and is
associated with ototoxicity and nephrotoxicity. We reserve neomycin for patients who
are unable to take rifaximin. Various doses have been used, but we generally use 500
mg three times a day or 1 gram twice daily. Other antibiotics that can be used
include vancomycin and metronidazole.
Other alternatives for patients who are refractory to conventional therapy include L-
ornithine-L aspartate and branched-chain amino acids. (See 'L-ornithine-L-
aspartate' below and 'Branched-chain amino acids' below.)
Chronic therapy — In patients with recurrent encephalopathy, we suggest continual
administration of lactulose or lactitol. The dose of lactulose (30 to 45 mL [20 to 30 g] two to
four times per day) or lactitol (67 to 100 g of lactitol powder diluted in 100 mL water) should
be titrated to achieve two to three soft stools per day. If needed (eg, if hepatic
encephalopathy is not adequately treated or recurs despite lactulose or
lactitol), rifaximin can be added to the regimen. (See 'Lactulose and lactitol' below and 'Oral
antibiotics' below.)

As with the acute treatment of hepatic encephalopathy, patients receiving chronic therapy
should generally not have their protein intake restricted. (See 'Protein restriction and
nutritional support' above.)

If the precipitating factors that were responsible for the recurrent hepatic encephalopathy
are controlled or if liver function or nutritional status improves, prophylactic therapy may be
discontinued.

Minimal hepatic encephalopathy — Compared with patients who have cirrhosis but do

not have minimal hepatic encephalopathy (MHE), patients with MHE appear be at increased
risk for developing overt hepatic encephalopathy, requiring hospitalization, requiring liver
transplantation, or dying [9]. However, data are limited on the value of treatment in these
patients [10].

Patients with MHE may benefit from treatment with lactulose or lactitol, but the decision to
treat should be individualized based on the results of psychometric testing and the degree
to which the encephalopathy has an impact on quality of life [1]. We typically reserve
treatment with lactulose or lactitol for patients with minimal hepatic encephalopathy who
have impaired quality of life attributable to the minimal hepatic encephalopathy. An elevated
serum ammonia level in the absence of clinical signs of hepatic encephalopathy is not an
indication for treatment. (See "Hepatic encephalopathy in adults: Clinical manifestations and
diagnosis", section on 'Diagnosis' and 'Use in minimal hepatic encephalopathy' below.)

Nutritional support — Patients with cirrhosis and minimal hepatic encephalopathy (MHE)

are advised to implement oral nutritional therapy. In a trial that compared a daily diet of 30
to 35 kcal/kg and 1.0 to 1.5 g vegetable protein/kg with no dietary intervention in 120
cirrhotic patients with MHE, the rate of reversal of MHE was greater in those receiving
nutritional therapy (71 versus 23 percent) [11]. In addition, overt hepatic encephalopathy
developed in fewer patients in the nutritional therapy group (10 versus 22 percent). MHE
was diagnosed using the psychometric hepatic encephalopathy score, which is discussed
separately. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis",
section on 'Psychometric Hepatic Encephalopathy Score (PHES)'.)
Nutritional support for patients with cirrhosis is discussed separately. (See "Nutritional
assessment in chronic liver disease", section on 'Cirrhosis'.)

SPECIFIC TREATMENTS

Commonly used treatments — Commonly used treatments for hepatic encephalopathy

aim to reduce ammonia production and absorption. This is accomplished by correcting
hypokalemia, giving synthetic disaccharides (such as lactulose) and/or antibiotics, and
favoring colonization with non-urease-producing bacteria.

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. A
healthy liver clears almost all of the portal vein ammonia, converting it into glutamine and
preventing its entry into the systemic circulation. Elevations of ammonia are detected in 60
to 80 percent of patients with hepatic encephalopathy, and therapy aimed at reduction of
the circulating ammonia level usually results in resolution of the encephalopathy. However,
an elevated serum ammonia level in the absence of clinical signs of hepatic encephalopathy
is not an indication for treatment. (See "Hepatic encephalopathy in adults: Clinical
manifestations and diagnosis", section on 'Ammonia' and "Hepatic encephalopathy:
Pathogenesis".)

Correct hypokalemia — Correction of hypokalemia, if present, is an essential component

of therapy for hepatic encephalopathy, since hypokalemia increases renal ammonia
production. The often concurrent metabolic alkalosis may contribute to hepatic
encephalopathy by promoting ammonia entry into the brain by favoring the conversion of
ammonium (NH4+), a charged particle that cannot cross the blood-brain barrier, into
ammonia (NH3), a neutral particle that can [12]. (See "Hypokalemia-induced renal
dysfunction", section on 'Increased ammonia production'.)

Lactulose and lactitol — Lactulose and lactitol are synthetic disaccharides that are a

mainstay of therapy of overt hepatic encephalopathy, albeit there is limited evidence from
well-designed randomized trials showing their efficacy. The available data suggest that
approximately 70 to 80 percent of patients with hepatic encephalopathy improve on
lactulose treatment [13-15]. Lactulose is widely available, but lactitol is not available in some
countries (including the United States).

The dose of medication should be titrated to achieve two to three soft stools per day.
Typically, lactulose is given as 30 to 45 mL [20 to 30 g] two to four times per day. An
equivalent dose of lactitol is approximately 67 to 100 grams lactitol powder diluted in 100
mL of water. Treatment is usually well tolerated, and the principal side effects include
abdominal cramping, diarrhea, and flatulence. Lactulose and lactitol may also be given as
enemas in patients who are unable to take them orally (1 to 3 L of a 20 percent solution).

Mechanism of action — Treatment with lactulose or lactitol is based on the absence of a

specific disaccharidase on the microvillus membrane of enterocytes in the human small
bowel, thereby permitting entry of the disaccharides into the colon. In the colon, lactulose
(beta-galactosidofructose) and lactitol (beta-galactosidosorbitol) are catabolized by the
bacterial flora to short chain fatty acids (eg, lactic acid and acetic acid), which lower the
colonic pH to approximately 5. The reduction in pH favors the formation of the
nonabsorbable NH4+ from NH3, trapping NH4+ in the colon and thus reducing plasma
ammonia concentrations.

Other effects that may contribute to the clinical effectiveness of lactulose and lactitol include
[13]:

●Increased incorporation of ammonia by bacteria for synthesis of nitrogenous

compounds.
●Modification of colonic flora, resulting in displacement of urease-producing bacteria
with non-urease-producing Lactobacillus [16].
●Cathartic effects of a hyperosmolar load in the colon that improves gastrointestinal
transit, allowing less time for ammonia absorption.
●Increased fecal nitrogen excretion (up to fourfold) due to the increase in stool volume
[17].
●Reduced formation of potentially toxic short-chain fatty acids (eg, propionate,
butyrate, valerate) [18].

Efficacy — A systematic review found that the use of lactulose or lactitol was more
effective than placebo in improving hepatic encephalopathy (relative risk of no improvement
0.6, 95% CI 0.5 to 0.8) but did not improve survival [19]. However, the benefit on
encephalopathy no longer reached statistical significance when the analysis was confined
to studies with the highest methodologic quality. The authors also found that antibiotics
appeared to be more effective than lactulose or lactitol. (See 'Oral antibiotics' below.)

At least two meta-analyses suggest that lactitol is at least as effective as lactulose, is more
palatable, and may have fewer side effects [20-22]. In patients with lactase deficiency, non-
digested lactose has most of the same effects as the synthetic disaccharides and is much
less expensive [23].

Lactulose has also been studied for the prevention of recurrent hepatic encephalopathy. In
a randomized trial with 140 patients who had recovered from hepatic encephalopathy,
patients assigned to lactulose (30 to 60 mL in two to three divided doses so that patients
passed two to three soft stools per day) had significantly fewer episodes of recurrent overt
hepatic encephalopathy than patients who received placebo during 14 months of follow-up
(20 versus 47 percent) [24]. However, there were no significant differences in deaths or
rates of readmission for causes other than hepatic encephalopathy.

Disaccharide enemas are also effective for removing ammoniagenic substrates from the
colon. A randomized trial that included 20 patients with hepatic encephalopathy suggested
that 1 to 3 L of a 20 percent lactose or lactitol solution given as an enema was more
effective than tap water enemas [25]. A possible explanation for this finding is that colonic
acidification rather than bowel cleansing was the therapeutic mechanism.

It is unclear whether the route of administration of nonabsorbable disaccharides affects their

efficacy. However, the convenience of oral administration generally makes it the preferred
route.

Use in minimal hepatic encephalopathy — Most trials of disaccharides included patients

with overt hepatic encephalopathy. However, the use of nonabsorbable disaccharides may
also benefit patients with minimal hepatic encephalopathy [10,26]. One trial that showed this
included 61 patients with minimal hepatic encephalopathy [27]. Treatment
with lactulose was associated with improvement in health-related quality of life and cognitive
function. However, other trials have failed to show a benefit of treating patients with minimal
hepatic encephalopathy. As a result, whether treatment should be routine in patients with
minimal hepatic encephalopathy is unclear. (See 'Minimal hepatic encephalopathy' above.)

Oral antibiotics — Nonabsorbable antibiotics are also effective for treating hepatic

encephalopathy. Rifaximin is currently used most often. The dose of rifaximin is 550 mg
orally twice daily or 400 mg orally three times daily. As a general rule, antibiotics are added
to rather than substituted for lactulose or lactitol. However, antibiotics all cause alterations in
gut flora and some are substantially more costly than nonabsorbable disaccharides. As a
result, they may be best suited for patients who cannot tolerate or do not respond
sufficiently to disaccharides. (See 'Lower blood ammonia' above.)

A meta-analysis of five randomized trials of rifaximin for hepatic encephalopathy found that

it had similar efficacy to nonabsorbable disaccharides for acute and chronic hepatic
encephalopathy, but was perhaps somewhat better tolerated [28]. A randomized trial
published after the meta-analysis found that during six months of follow-up, rifaximin was
more effective than a placebo in preventing recurrent episodes of hepatic encephalopathy in
patients with cirrhosis who had a documented history of recurrent hepatic encephalopathy
and were in remission at the start of the trial [29]. Eighty-two patients in the placebo group
of the phase 3 trial joined a 24-month open-label maintenance (OLM) study [30]. Thirty-nine
of the patients (48 percent) had experienced an episode of hepatic encephalopathy during
the original randomized trial compared with 14 patients (17 percent, p<0.0001) during the
OLM study. Other randomized trials found that rifaximin improved quality of life [31,32] and
performance on a simulated driving test in patients with minimal hepatic encephalopathy
[33].

Another randomized trial compared the combination of rifaximin and lactulose with lactulose

alone in 120 patients hospitalized with overt hepatic encephalopathy [34]. Patients were
followed until they were discharged from the hospital or died. Patients who received
rifaximin and lactulose were more likely than those who received lactulose alone to have
complete resolution of their hepatic encephalopathy (76 versus 44 percent) and lower
mortality (24 versus 49 percent). A meta-analysis of 19 trials showed that rifaximin has a
beneficial effect on hepatic encephalopathy and may reduce mortality [35].

Neomycin had been used for many years to treat hepatic encephalopathy, but studies
reached variable conclusions regarding its efficacy, and there is concern over its
association with ototoxicity and nephrotoxicity if used long-term. An early study found
neomycin to be as effective as lactulose in 33 patients [14], and a subsequent randomized
trial that compared neomycin with rifaximin in 49 patients with cirrhosis found that both
treatments were similarly effective at reducing the neuropsychiatric signs of hepatic
encephalopathy and blood ammonia levels [36]. On the other hand, a randomized trial of 39
patients comparing neomycin at a dose of 6 g per day with placebo reported no difference
in outcomes between the two treatment groups [37].

Other antibiotics, such as metronidazole and oral vancomycin, were effective for treating

hepatic encephalopathy in limited clinical trials and are not associated with the same
toxicities as neomycin [38,39]. However, metronidazole is associated with neurotoxicity and
there are concerns about bacterial resistance in patients receiving vancomycin. As a result,
neither is used commonly.

L-ornithine-L-aspartate — Oral L-ornithine-L-aspartate (LOLA) is frequently given to

patients with hepatic encephalopathy outside of the United States [40]. Treatment with L-
ornithine-L-aspartate has shown benefit compared with placebo, although trials comparing
LOLA with standard therapy (ie, lactulose or lactitol) are needed [40-43]. LOLA improves
health-related quality and is well tolerated [44].

In a meta-analysis of four trials, patients with overt hepatic encephalopathy who received L-
ornithine-L-aspartate were more likely to improve clinically compared with those receiving
placebo (OR 3.71, 95% CI 1.98-6.98) [42].
In trial of 40 patients who underwent transjugular intrahepatic portosystemic shunt
placement, prophylactic use of LOLA infusion was safe and effective in reducing post-
prandial increases in venous ammonia concentration [45]. (See "Transjugular intrahepatic
portosystemic shunts: Complications", section on 'Portosystemic encephalopathy'.)

L-ornithine-L-aspartate does not appear to be effective for patients with hepatic

encephalopathy in the setting of acute liver failure [46]. (See "Acute liver failure in adults:
Management and prognosis", section on 'Hepatic encephalopathy'.)

L-ornithine-L-aspartate lowers plasma ammonia concentrations by enhancing the

metabolism of ammonia to glutamine. Ammonia is removed from the body by formation of
urea in periportal hepatocytes and/or by synthesis of glutamine from glutamate in
perivenous hepatocytes. In patients with cirrhosis, the activities of carbamyl phosphate
synthetase and of glutamine synthetase (the key enzymes for urea and glutamine
synthesis) are impaired and the glutaminase flux is increased in a compensatory fashion,
resulting in hyperammonemia. Ornithine serves both as an activator of carbamyl phosphate
synthetase and ornithine-carbamyl transferase in periportal hepatocytes and as a substrate
for ureagenesis. Ornithine (via alpha-ketoglutarate) and aspartate increase ammonia
removal by these cells via stimulation of glutamine synthesis.

Branched-chain amino acids — It has been suggested that increases in the ratio of
plasma aromatic amino acids (AAA) to branched-chain amino acids (BCAA) as a
consequence of hepatic insufficiency could contribute to encephalopathy. The altered ratio
could then increase brain levels of aromatic amino acid precursors for monoamine
neurotransmitters and contribute to altered neuronal excitability. As a result, a number of
studies have evaluated the effects of the provision of BCAA, given either intravenously or
orally. The efficacy of BCAAs was examined in a meta-analysis of 16 trials with 827
participants with hepatic encephalopathy [47]. Patients in the control groups
received placebo/no intervention (2 trials), dietary interventions (10 trials), lactulose (2
trials), or neomycin (2 trials). Treatment with BCAAs did not result in a benefit with regard to
mortality (relative risk [RR] 0.8, 95% CI 0.7-1.1), but it did have a beneficial effect on hepatic
encephalopathy (defined as improvement in the manifestations of hepatic encephalopathy;
RR 0.7, 95% CI 0.6-0.9).

●BCAA infusions – Several randomized trials have evaluated the use of parenteral

nutrition with modified amino acid solutions with a high content of BCAA and a low
content of AAA [48,49]. A meta-analysis suggested that mental recovery was
consistently more rapid in patients who received BCAA [49]. Three studies suggested
lower mortality in BCAA-treated patients, while two others suggested that BCAA-
treatment increased mortality. The studies included in this meta-analysis differed with
 respect to the amino acid solutions used, the study protocols, patient selection, and the
duration of treatment, and therefore cannot be compared directly. In addition, all
studies were of relatively short duration. We do not presently consider infusions of
modified amino acid solutions or BCAA as standard treatment of patients with hepatic
encephalopathy.
●Oral BCAA supplements – The benefit of oral BCAA is unclear. Significant
improvement in chronic hepatic encephalopathy has been described in some trials. As
an example, a randomized trial with 64 patients found that a low-protein diet
supplemented with oral BCAA was more likely to improve mental performance at three
months than supplementation with casein (80 versus 35 percent) [50]. In addition,
some patients who did not improve on casein rapidly improved when switched to
BCAA. Another trial evaluated 37 hospitalized patients with cirrhosis who were protein-
intolerant [51]. The addition of BCAA to the diet enabled the daily protein intake to be
increased to up to 80 g without worsening cerebral function; by comparison, many
control patients (receiving casein as a protein source) deteriorated after increasing
dietary protein intake. No benefit of BCAA supplementation was observed in protein-
tolerant patients. A subsequent randomized trial of 116 patients who had a prior
episode of hepatic encephalopathy found no benefit of BCAA on recurrent
encephalopathy, although supplementation appeared to improve minimal hepatic
encephalopathy and muscle mass [52]. Based on these results, we believe that dietary
BCAA supplementation is indicated only in severely protein-intolerant patients.
(See 'Protein restriction and nutritional support' above.)

Modification of colonic flora (prebiotics and probiotics) — Probiotics are formulations

of microorganisms that have beneficial properties for the host. (See "Probiotics for
gastrointestinal diseases", section on 'Mechanisms of benefit'.). Prebiotics are substances
that promote the growth of such organisms. Prebiotic and probiotic therapy appear to lower
blood ammonia concentrations, possibly by favoring colonization with acid-resistant, non-
urease producing bacteria [53]. The most commonly used prebiotic for the treatment of
hepatic encephalopathy is lactulose, though it also acts by altering the colonic pH,
improving gastrointestinal transit and increasing fecal nitrogen excretion. Fermentable fiber
is another prebiotic that may promote the growth of beneficial bacteria. (See 'Mechanism of
action' above.)

Most commercial probiotic products have been derived from food sources, especially
cultured milk products. The list of such microorganisms continues to grow and includes
strains of lactic acid bacilli (eg, Lactobacillus and Bifidobacterium), a nonpathogenic strain
of Escherichia coli (eg, E. coli Nissle 1917), Clostridium butyricum, Streptococcus salivarius,
and Saccharomyces boulardii (a nonpathogenic strain of yeast). The most efficacious
species for hepatic encephalopathy appear to be Lactobacilli and Bifidobacteria [40].
Alteration of gut flora (either with prebiotics or with probiotics) has been associated with
improvement in hepatic encephalopathy. A meta-analysis of 21 trials that included 1420
participants showed improved recovery compared with placebo or no treatment, but failed to
show a benefit in clinically significant outcomes when probiotics were compared
with lactulose [54]. However, probiotic groups had reduced plasma ammonia concentrations
compared with the placebo/no intervention groups, but not when compared with lactulose
groups. Additional studies are needed before probiotics can routinely be recommended for
the treatment or prevention of hepatic encephalopathy.

Probiotics may prevent recurrent encephalopathy. Prevention of recurrent hepatic

encephalopathy was investigated in an unblinded randomized trial. Two hundred and thirty-
five patients who had recovered from hepatic encephalopathy were assigned to
receive lactulose, VSL#3 (containing four species of lactobacilli and three of bifidobacteria
and Streptococcus thermophilus) or no therapy [55]. Recurrent hepatic encephalopathy
occurred in fewer patients who received lactulose or probiotics compared with no treatment
(27 and 34 percent, respectively, versus 57 percent). The difference in recurrence rates
between those who received lactulose and those who received probiotics was not
statistically significant.

Treatments that require more study — Several additional treatments for hepatic

encephalopathy appear to be effective, but additional trials are needed before they can be
routinely recommended.

Polyethylene glycol — Polyethylene glycol (PEG) solution is a cathartic that may help treat
hepatic encephalopathy by increasing excretion of ammonia in the stool. PEG was
compared with lactulose in a trial that included patients with cirrhosis who were admitted to
the hospital with hepatic encephalopathy [8]. Patients were randomly assigned to receive
four liters of PEG over four hours or lactulose (three or more doses of 20 to 30 g over 24
hours). After 24 hours, patients who received PEG had more improvement in their hepatic
encephalopathy scoring algorithm (HESA) score compared with those who received
lactulose (from a mean of 2.3 to 0.9 compared with 2.3 to 1.6). In addition, the median time
to resolution of the hepatic encephalopathy was shorter with PEG (one versus two days).

Acarbose — Acarbose (an inhibitor of alpha glycosidase that is approved for treatment of

diabetes mellitus) inhibits the upper gastrointestinal enzymes (alpha-glucosidases) that
convert carbohydrates into monosaccharides. It also promotes the proliferation of intestinal
saccharolytic bacterial flora, while reducing proteolytic flora that produce mercaptans,
benzodiazepine-like substances, and ammonia. This reduction in proteolytic flora
theoretically could improve hepatic encephalopathy. This hypothesis appeared to be
confirmed by a randomized crossover trial involving 107 patients with cirrhosis, diabetes
mellitus, and grade I-II hepatic encephalopathy [56]. Treatment was associated with a
significant reduction in blood ammonia levels and improvement in encephalopathy.
(See "Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus".)

Sodium benzoate — Sodium benzoate reduces ammonia levels by reacting with glycine to

form hippurate, which is renally excreted. For each mole of benzoate used, one mole of
waste nitrogen is excreted into the urine.

A randomized trial of 74 patients with acute hepatic encephalopathy found that treatment
with sodium benzoate (5 gm twice daily) resulted in similar improvements in
encephalopathy as lactulose [57]. The cost of lactulose was 30 times that of sodium
benzoate. While this study is encouraging, we would not recommend sodium benzoate as
first-line therapy until the results are confirmed in additional randomized trials, given the
much broader experience with lactulose.

Flumazenil — While some patients with hepatic encephalopathy have short-term benefit

from the benzodiazepine receptor antagonist flumazenil, it cannot be recommended as
routine therapy. Flumazenil may be helpful, however, in patients who have received
benzodiazepines. (See "Benzodiazepine poisoning and withdrawal".)

In a meta-analysis of nine trials including 824 patients with hepatic encephalopathy, more
patients treated with flumazenil improved compared with patients given placebo (RR of
failure to improve 0.75, 95% CI 0.71-0.80); however, follow-up duration was less than one
day in most trials [58]. Although patients may respond to flumazenil within a few minutes
after intravenous administration, the effect is transient and the majority of patients
deteriorate within two to four hours [59-63]. In a meta-analysis of 11 trials including 842
patients, flumazenil had no effect on all-cause mortality [58].

The gamma-aminobutyric acid (GABA)-receptor complex appears to be a contributor to

neuronal inhibition in hepatic encephalopathy. This complex, in the postsynaptic membrane,
is the principal inhibitory network in the central nervous system. It consists of a GABA-
binding site, a chloride channel, and barbiturate and benzodiazepine receptor sites.
GABAergic transmission may interact with ammonia in the pathogenesis of hepatic
encephalopathy [64]. Increases in transmission could be caused by increases in ligands for
any of the three receptors. Since there is evidence for an increase in benzodiazepine
receptor ligands in patients with hepatic encephalopathy, the effects of benzodiazepine
receptor antagonists, such as flumazenil, have been studied [65,66]. (See "Hepatic
encephalopathy: Pathogenesis".)

Zinc — Zinc has been suggested as having potential value in some patients with chronic or
recurrent hepatic encephalopathy, but little evidence exists to document its effectiveness.
Zinc deficiency is common in patients with cirrhosis and in those with hepatic
encephalopathy [67]. Zinc is contained in vesicles in the presynaptic terminals of some
classes of neurons, the majority of which are a subclass of the glutamatergic neurons [68].
Stimulated zinc release may modulate ion channel function and neurotransmission [69].
Zinc may also enhance the hepatic conversion of amino acids into urea [70].

Little information is available on the clinical effects of zinc supplementation in overt hepatic
encephalopathy. A patient has been described who exhibited a relationship between zinc
deficiency and severe recurrent hepatic encephalopathy [71]. The study included a period in
which zinc deficiency was artificially induced by oral histidine. An episode of overt
encephalopathy occurred that was identical to earlier episodes and responded to oral zinc.
Long-term zinc supplementation significantly improved severe recurrent hepatic
encephalopathy that had been refractory to protein restriction, lactulose, and neomycin.

However, this anecdotal report has not been confirmed in larger studies. As an example,
short-term zinc supplementation had no clinically significant effect in 15 patients with
chronic hepatic encephalopathy studied in a randomized crossover trial [72]. As a result, we
do not recommend zinc supplementation for treatment of hepatic encephalopathy.

Melatonin — One of the most frequently described symptoms of subclinical forms of

hepatic encephalopathy is sleep disturbances or, more generally, alterations in
the sleep/wake cycle. The alterations in the sleep/wake cycle may be disabling for some
patients. Unsatisfactory sleep is also characteristic of patients with cirrhosis who do not
have encephalopathy (48 percent of patients in one study [73]).

The abnormalities in sleep may be due in part to alterations in the 24-hour rhythm of the
hormone melatonin, which is considered to be the output signal of the biological "clock." In
one series of patients with cirrhosis, the onset of the rise in plasma concentrations of
melatonin and occurrence of the melatonin peak during the night were delayed by hours
[74]. Furthermore, plasma melatonin levels in patients with cirrhosis were significantly
higher during daylight hours, a time when melatonin is normally very low or absent.
(See "Physiology and available preparations of melatonin".)

These findings support the hypothesis that an alteration of circadian rhythmicity of

melatonin is responsible for the disruption in the sleep/wake cycle frequently seen in
cirrhosis. Melatonin can influence its own rhythm when administered at defined time points
during the day, shifting the curve forward or backward [75]. Some authorities have tried
orally administered melatonin in patients with cirrhosis who have an
altered sleep/wake cycle. However, our clinical experience with this drug has not revealed a
benefit in patients with cirrhosis. (See "Physiology and available preparations of
melatonin".)
Experimental treatments — A number of experimental approaches are being evaluated in
animal models for the treatment of hepatic encephalopathy. Few have received any testing
in clinical trials.

●L-Carnitine – Carnitine is a metabolite in the degradation pathway of the essential

amino acid lysine and is synthesized by oxidation of E-amino-trimethyl-lysine. It serves
as a carrier for short chain fatty acids across the mitochondrial membrane. Data in
portacaval-shunted rats suggest that L-carnitine is protective against ammonia
neurotoxicity [76,77]. (See "Carnitine metabolism in renal disease and dialysis", section
on 'Role of carnitine in intermediary metabolism'.)
The available clinical data are insufficient to assess the role of L-carnitine in human
disease. In patients with cirrhosis who were subjected to a rectal ammonia overload
test, intravenous L-carnitine improved psychometric tests significantly after 30 minutes,
whereas circulating ammonia levels were not influenced [78]. However, the increase in
plasma ammonia after rectal ammonia overload was significantly lower in treated
patients with evidence of portal hypertension than in patients without evidence of portal
hypertension.
Treatment with acetyl-L-carnitine has been tested in a randomized trial of patients with
minimal hepatic encephalopathy. The trial included 67 patients who were assigned to
receive acetyl-L-carnitine or placebo [79]. Patients treated with acetyl-L-carnitine had
more improvement in energy levels, general functioning, and well-being than those
who received placebo.
●Glutamatergic antagonists – There is good evidence that the glutamatergic
neurotransmitter system is involved in the pathogenesis of hepatic encephalopathy.
The N-methyl-D-aspartate (NMDA) receptor is one of three known central glutamate
receptors. NMDA overactivity has been observed in two different experimental rat
models of encephalopathy. The administration of the NMDA receptor
antagonist memantine resulted in a significant improvement in clinical grading and less
slowing of electroencephalogram activity, smaller increases in cerebral spinal fluid
glutamate concentrations, and lower intracranial pressure and brain water content than
in untreated control rats [80]. (See "Hepatic encephalopathy: Pathogenesis", section on
'Glutamatergic neurotransmission'.)
●Serotonin antagonists – Accumulated neurochemical data in different animal
models of fulminant hepatic failure and in humans with hepatic encephalopathy
suggest that serotoninergic tone is increased in the brain in hepatic encephalopathy.
The nonselective serotonin receptor antagonist methysergide had no effect in control
rats, but it increased motor activity in rats with stage II to III hepatic encephalopathy in
a dose-dependent manner; by contrast, the 5-HT2 receptor antagonist seganserin had
no effect [81]. (See "Hepatic encephalopathy: Pathogenesis", section on 'Serotonin'.)
 ●Opioid antagonists – Plasma levels of methionine (Met)-enkephalin and beta-
endorphin are elevated in patients and in experimental animals suffering from liver
failure. Administration of (+/-)-naltrexone, but not (+)-naloxone, significantly increased
the motor activity of rats with stage III hepatic encephalopathy [82].
●Embolization of large spontaneous portosystemic shunts – Large spontaneous
portosystemic shunts may contribute to hepatic encephalopathy. In a retrospective
study of 37 patients with large spontaneous portosystemic shunts who were treated
with embolization, 22 (59 percent) were free of hepatic encephalopathy within 100 days
of the procedure, and 18 (49 percent) remained hepatic encephalopathy-free over a
mean follow-up of 697 days [83]. There did not appear to be an increase in de novo
development or worsening of varices, portal hypertensive gastropathy, or ascites.

PROGNOSIS AFTER RECOVERY — Patients with overt hepatic encephalopathy may

have persistent and cumulative neurologic deficits despite an apparent normalization of
mental status after treatment [84,85]. In a study that summarized the results of two cohorts
of patients with cirrhosis, for example, overt hepatic encephalopathy was associated with
persistent deficits in working memory, response inhibition, and learning when assessed by
psychometric testing [84]. The number of episodes of overt hepatic encephalopathy
correlated with the severity of residual impairment.

CAPACITY TO DRIVE — Issues related to driving in patients with hepatic encephalopathy

are discussed separately. (See "Hepatic encephalopathy in adults: Clinical manifestations
and diagnosis", section on 'Capacity to drive'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines

from selected countries and regions around the world are provided separately.
(See "Society guideline links: Cirrhosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
 ●Basics topic (see "Patient education: Hepatic encephalopathy (The Basics)")

SUMMARY AND RECOMMENDATIONS

Overt hepatic encephalopathy

●Patients with overt hepatic encephalopathy have clinically apparent impairments in

cognitive and neuromuscular function. Treatment includes determining the appropriate
setting for care, correcting any predisposing conditions, and lowering ammonia
production and absorption with medications such as lactulose, lactitol, or rifaximin.
Restricting dietary protein is not recommended for the majority of patients. (See 'Overt
hepatic encephalopathy' above.)
●Patients with mild hepatic encephalopathy (grade I) may be managed as outpatients,
provided caregivers are available to look for signs of worsening hepatic
encephalopathy and to bring the patient to the hospital if needed. Whether to admit a
patient with grade II encephalopathy to the hospital will depend on the degree of
lethargy and confusion. If there is any concern that a patient may not be able to adhere
to treatment or if caregivers are not available who can monitor the patient, the patient
should be admitted to the hospital for care. Patients with more severe hepatic
encephalopathy (grades III to IV) require hospital admission for treatment, typically to
an intensive care unit. In addition, consideration should be given to intubating such
patients for airway protection. (See 'Patient triage' above and "Hepatic encephalopathy
in adults: Clinical manifestations and diagnosis", section on 'Categorization and
grading'.)
●General supportive care for patients with hepatic encephalopathy includes avoiding
dehydration and electrolyte abnormalities, providing nutritional support, and providing a
safe environment. Patients should not have their protein intake restricted unless they
are severely protein-intolerant. Patients should be instructed to eat small meals
throughout the day with a late-night snack of complex carbohydrates. Precautions to
prevent falls should be instituted for patients who are disoriented. (See 'General
supportive care' above and 'Protein restriction and nutritional support' above.)
●The initial management of acute hepatic encephalopathy in patients with chronic liver
disease involves two steps. (See 'Acute therapy' above.):
•Identificationand correction of precipitating causes (table 3) (see 'Correction of
precipitating causes' above)
•Measures to lower the blood ammonia concentration
●For patients with acute, overt hepatic encephalopathy, we suggest initial treatment
with lactulose or lactitol (where available) rather than a nonabsorbable antibiotic
(Grade 2B). This recommendation is based primarily on cost; for patients for whom
cost is not an important consideration, initial treatment with rifaximin is a reasonable
 alternative. The dose of lactulose (30 to 45 mL [20 to 30 g] two to four times per day)
should be titrated to achieve two to three soft stools per day. An equivalent dose of
lactitol is approximately 67 to 100 grams lactitol powder, diluted in 100 mL of water.
Lactulose or lactitol enemas can be given if the patient cannot take lactulose orally.
(See 'Lactulose and lactitol' above and 'Oral antibiotics' above.)
●For patients who have not improved within 48 hours of starting lactulose or lactitol or
who cannot take lactulose or lactitol, we suggest rifaximin rather than an alternative
nonabsorbable oral antibiotic (Grade 2C). The dose of rifaximin is 400 mg orally three
times daily or 550 mg orally two times daily. As a general rule, antibiotics are added to,
rather than substituted for, lactulose or lactitol. (See 'Oral antibiotics' above.)
Neomycin has been used as a second-line therapy in patients who have not responded
to disaccharides, but it has not been shown to be efficacious in randomized trials and is
associated with ototoxicity and nephrotoxicity. We reserve neomycin for patients who
are unable to take rifaximin.
L-ornithine-L-aspartate, which stimulates the metabolism of ammonia, is an alternative
for the treatment of hepatic encephalopathy in countries where it is available. (See 'L-
ornithine-L-aspartate' above.)
Oral branched-chain amino acids can also be used as an alternative or additional
agent for treating patients who do not respond to lactulose, lactitol, or rifaximin and
who are severely protein-intolerant.
●In patients with recurrent encephalopathy, we suggest daily administration
of lactulose or lactitol rather than waiting for episodes of overt hepatic encephalopathy
to develop to initiate treatment (Grade 2B). Rifaximin can be added to lactulose or
lactitol if needed. (See 'Chronic therapy' above.)

Minimal hepatic encephalopathy

●Patients with minimal hepatic encephalopathy have signs and symptoms that are not
clinically apparent, but can be detected with psychometric testing. (See "Hepatic
encephalopathy in adults: Clinical manifestations and diagnosis", section on 'Clinical
manifestations'.)
●Whether to treat patients with minimal hepatic encephalopathy is unclear. For patients
with minimal hepatic encephalopathy that is impacting quality of life, we suggest
treating with lactulose or lactitol rather than not treating (Grade 2C). We do not give
treatment to patients with minimal hepatic encephalopathy who do not have impaired
quality of life attributable to the minimal hepatic encephalopathy. (See 'Minimal hepatic
encephalopathy' above.)