Hepatic Encephalopathy: A Review

Authors: Savan Kabaria,¹ Ishita Dalal,² Kapil Gupta,2,3 Abhishek Bhurwal,² Carlos
D. Minacapelli,2,3 Carolyn Catalano,2,3 *Vinod Rustgi2,3
1. Rutgers Robert Wood Johnson Medical School, Department of Internal Medicine,
New Brunswick, New Jersey, USA
2. Rutgers Robert Wood Johnson Medical School, Department of Medicine, Division
of Gastroenterology and Hepatology, New Brunswick, New Jersey, USA
3. Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson School of
Medicine, New Brunswick, New Jersey, USA
*Correspondence to [email protected]

Disclosure: The authors have declared no conflicts of interest.

Received: 03.02.21

Accepted: 26.03.21

Keywords: Cirrhosis, hepatic encephalopathy, lactulose, liver disease, rifaximin.

Citation: EMJ Hepatol. 2021;9[1]:89-97.

Abstract
Hepatic encephalopathy (HE) is a reversible syndrome observed in patients with liver disease.
The syndrome is characterised by a spectrum of neuropsychiatric abnormalities resulting from
the accumulation of neurotoxic substances in the bloodstream and ultimately in the brain. HE
is a huge burden to patients, caregivers, and the healthcare system. Common treatments for HE,
including rifaximin and lactulose, have been shown to reduce the risk of recurrence, frequency of
hospitalisations, hospital costs, and mortality. New research and therapeutics exist, including faecal
transplants and small-molecule therapies such as branched-chain amino acids. This review article
provides a general overview of the current understanding of HE.

INTRODUCTION and the definition of HE (minimal versus overt).1

Consequently, HE has been reported to occur in
Hepatic encephalopathy (HE) is a complex a wide range (20–80%) of patients with cirrhosis.
neurological process that is seen in advanced The prevalence of overt HE at the time of
liver disease. HE causes significant morbidity cirrhosis diagnosis is approximately 10–14%. This
and mortality and is responsible for considerable rises to 16–21% in patients with decompensated
burden on patients and their caregivers. HE is cirrhosis and approximately 10–50% in patients
treated clinically and can be reversible, especially who have undergone transjugular intrahepatic
in the situation of an acute underlying process. portosystemic shunt (TIPS). Overall, an estimated
This review article will briefly review HE in 30% to 40% of patients with cirrhosis will
its entirety: its epidemiology, manifestations, experience overt HE during their clinical course.1
diagnosis, pathophysiology, and treatment as
well as future research.
CLINICAL MANIFESTATIONS
The incidence and prevalence of HE can be
difficult to assess because of underlying cause, HE can present as a diverse spectrum of
variable severity of the disease manifestations, neurologic, psychiatric, and musculoskeletal

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 symptoms. In many cases, patients are unaware The most commonly occurring type is Type
of the symptoms, but family members or close C in which patients frequently show signs of
friends may notice changes and voice their liver failure, such as jaundice, ascites, spider
concerns.2 In the early stages, patients may only telangiectasias, and palmar erythema, among
report subtle symptoms, such as disturbances other manifestations.10
in their sleep–wake cycles.3 As symptoms
progress, patients may develop personality The severity of HE is generally classified using the
changes such as apathy, irritability, and West Haven Criteria (WHC) and the International
disinhibition. If left unrecognised, symptoms Society for Hepatic Encephalopathy (ISHEN)
worsen and patients can present with cognitive criteria (Table 1).6 Alternate grading systems,
impairments such as disorientation, memory such as HE Scoring Algorithm (HESA), were
impairment, slurred speech, confusion, and developed to provide more reliable grading
eventually coma.4,5 Along with neurologic and of HE severity by combining both subjective
psychiatric symptoms, HE can also affect the and objective data.11 Clinical HE Staging
musculoskeletal system. Patients with minimal Scale (CHESS) is another scoring system that
HE may show minor issues with coordination, consists of nine clinical items and linearly
such as changes in their handwriting.6 determines severity using simple terms and
questions.12 Various criteria to define the severity
The most widely recognised symptom of HE of HE are depicted in Table 1.
is asterixis. However, asterixis is not isolated
to HE. It can also be seen in other causes of The third and fourth axes allow patients to
encephalopathy, such as uraemia.7 Asterixis be further classified according to the time
presents as a flapping tremor that occurs course and precipitating factors.6 Timing is
because of negative myoclonus resulting in loss further sub-classified into episodic, recurrent,
of postural tone.7 It is elicited when patients or persistent. To classify as recurrent, episodes
hyperextend their wrists but can also be of HE occur within intervals of less than 6
observed in the patient’s feet, legs, arms, tongue, months, whereas persistent HE involves altered
and eyelids.6 If it continues to progress, patients behaviour that is always present in the setting of
can develop hyperreflexia, clonus, and rigidity.6 recurrent HE. Examples of precipitating factors
They can also present with cirrhosis-related include infections, gastrointestinal bleeding,
Parkinsonism symptoms, with extrapyramidal over-diuresis, electrolyte abnormalities, and
symptoms including masked facies, rigidity, constipation. Treating precipitating factors can
bradykinesia, slowed speech, and tremors.7,8 resolve HE in 90% of all patients.6
These symptoms are seen in approximately 4%
of patients, suggesting they are more prevalent DIAGNOSIS
than previously thought.8 In patients with TIPS,
HE usually becomes clinically apparent 2–3 There is no standardised serologic testing or
weeks after TIPS insertion.9 imaging modality to accurately diagnose HE
and assess its severity. Ammonia is classically
CLASSIFICATION associated with HE; however, increased blood
ammonia level alone does not help with the
According to national guidelines, HE is classified diagnosis or prognosis of HE. Elevation of
using four main axes: the underlying cause, the ammonia in combination with the clinical
severity of the disease manifestation, the time picture of HE can be more useful, as isolated
course of the disease, and the existence of increased ammonia level can be seen in other
precipitating factors.6 medical conditions.13
The first criterion is based on the underlying
cause of HE. Type A is HE seen in acute liver
failure, Type B in the portal-systemic bypass
setting with no intrinsic hepatocellular disease,
and Type C is in the setting of cirrhosis with
portal hypertension or systemic shunting.

90 HEPATOLOGY • August 2021 EMJ

 Table 1: Various criteria to define severity of hepatic encephalopathy.

WHC Grade ISHEN HESA CHESS Clinical Features

Unimpaired No encephalopathy at
all, no history of HE
Minimal Covert Grade 0 0–1 Alterations in
psychomotor speed/
executive functions.
No evidence of clinical
mental status change.
Grade I Grade I 0–3 Anxiety, attention
span deficit, impaired
simple mathematic
skills, altered sleep
pattern, unaware of
deficits
Grade II Overt Grade II 1–6 Lethargy, not oriented
to time, personality
changes, bizarre
behaviour, dyspraxia,
asterixis
Grade III Grade III 3–6 Somnolence, semi-
stupor, responsive to
stimulus, increasing
confusion and
disorientation
Grade IV Grade IV 9 Coma

The data are reported as mean±SD or median (and interquartile range) as appropriate.
HRS: hepatorenal syndrome; MAP: mean arterial pressure: NA, not available.

Current national guidelines suggest the use of Imaging modalities such as CT and MRI scans
an electroencephalogram and complementary of the brain are generally non-specific for HE;
neurophysiological tests to diagnose however, sequential scans may be a useful marker
HE in the absence of other neurological for acute brain volume change.14 PET is not
process.6 Sensitivity and specificity of an widely used because of cost and limitations of
electroencephalogram depend on both modality availability; however, PET does provide valuable
of data analysis and severity of HE and vary insight into the pathogenesis of HE in regard
from 57–100% and 41–88%, respectively.14 to calculating blood flow, glucose metabolism,
Neurophysiological tests include psychometric and ammonia metabolism, which may have
testing of attention as well as working memory prognostic value.14
and psychomotor speed. Visuospatial ability may
also be necessary to identify subtle mental status PATHOPHYSIOLOGY
changes.15,16 Specific examples of these tests and
time required to perform them are depicted in The pathophysiology of HE is vital in
Table 2.14,17 While these tests can be beneficial, understanding its management. The most well-
they are limited because they do not account for understood pathophysiological mechanism and
results secondary to the patient’s age or baseline correlate of HE is the neurotoxicity of ammonia in
education status. They are also limited by time the brain, either due to increased production or
and lack of adequately trained professionals.17 impaired excretion.18

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 Table 2: Diagnostic and screening methods of hepatic encephalopathy.

Tests Equipment required Tested domains Time required (min)

PHES Paper and pencil test Psychomotor speed, visual 20
perception, visuospatial
orientation, visuomotor
ability, and attention
RBANS Paper and pencil test Psychomotor speed, 30
anterograde memory, and
working memory
Computer-aided test Computer test Working memory, vigilance, 15
Scan test and attention
CDR assessment battery Computer test Reaction time, memory, and 15
recognition
ICT Computer test Response inhibition, working 15
memory, vigilance, and
attention
EncephalApp Requires smartphone with Psychomotor speed and 10
Stroop App application (EncephalApp cognitive alertness
Stroop Application)
CFF Light pulse with portable Visual discrimination 10
machine (e.g., Hepatonorm and general arousal.
Analyzer*) CFF is meant to detect
neuropsychological
abnormalities that can range
from visual signal processing
to cognitive functions

* Accelab GmbH, Kusterdingen, Germany.

CDR: Cognitive Drug Research; CFF: Critical Flicker Frequency; ICT: Inhibitory Control Test; PHES: Psychometric
Hepatic Encephalopathy Score; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status.

The two main sites of ammonia production are the reduced capability of the liver to detoxify
the small/large intestine (50%) and the kidneys ammonia, secondary to hepatocellular damage
(40%). In the gastrointestinal system, ammonia or shunting, ammonia levels increase within
is produced by degradation of dietary protein the systemic circulation. The kidneys also
to ammonia from urease-producing bacteria as contribute to decreased ammonia excretion
well as breakdown of glutamine by enterocyte due to acid–base and potassium imbalance,
glutaminase. Within the kidneys, the proximal increased protein intake, and dysregulation of
tubular cells generate ammonia from glutamine glucocorticoid hormones.19 Skeletal muscle also
and create bicarbonate as a by-product. The plays a role in ammonia detoxification through
production of ammonia at these sites can be glutamine synthase, which converts ammonia to
altered through various mechanisms including glutamine. Consequently, sarcopenia, a common
gastrointestinal bleeding, hypovolaemic states, complication of cirrhosis, can be an adverse
over-diuresis, hypokalaemia, acidosis, and factor in HE.20
excessive protein intake.18
Dysfunction of the neurons can result from
The liver is the major site of ammonia catabolism elevations in ammonia in the systemic circulation.
using the urea cycle (Krebs–Henseleit cycle), Astrocytes, via astrocytic glutamine synthetase,
which converts ammonia into water-soluble convert ammonia and glutamate into glutamine,
urea. The generated urea is subsequently which causes increased cerebral volume by
excreted via the intestine and the urine. Due to osmosis. Consequently, a rapid rise in ammonia

92 HEPATOLOGY • August 2021 EMJ

 can place the patient at risk of brain oedema, anaerobic Gram-negative and Gram-positive
as often evidenced on MRI.21 Additionally, bacteria.29,33 Rifaximin has been found to reduce
glutamine is converted to ammonia in the hospital admissions and frequency of recurrent
mitochondria of the astrocytes, which can also episodes.27,34 In the past, neomycin, vancomycin,
lead to direct oxidative damage.22 and metronidazole have also been used to treat
HE but have fallen out of favour.29,35,36
Another well-described pathophysiological
mechanism is alterations in the gut flora that Faecal microbiota transplant (FMT) is a
play a vital role in HE. It is theorised that promising treatment for refractory overt HE.
decreased bile acid production allows urease- Enteric bacteria play an important role in the
producing bacteria to proliferate and overtake pathophysiology of HE as described previously.
protective bacteria (i.e., Lachnospiraceae).18,23 The goal of FMT is to manipulate the gut
Multiple studies have stressed the importance microbiome in an attempt to reverse intestinal
of the microbiota in the development of dysbiosis. Two trials exploring the use of FMT
HE.18,24,25 Several molecules other than ammonia, in HE found improvement after pre-treatment
particularly altered neurotransmitters, may also with antibiotics.29,37,38
participate in the development of HE. These
can include glutamine, histamine, serotonin, Protein restriction is not recommended as
γ-aminobutyric acid, and manganese.18 Further normal protein intake levels do not exacerbate
investigation is required to identify additional or cause HE. Protein restriction may actually
targets of HE pathophysiology for prompt be deleterious in patients who are already
diagnosis and treatment. sarcopenic.27 Other pharmacologic treatments
that have efficacy in treating HE are L-ornithine
Manifestation of HE is often exacerbated in L-aspartate and branched-chain amino acids.
patients with prior TIPS because of creation of a L-ornithine L-aspartate works to improve HE
shunt, allowing portal blood flow to bypass the by upregulation of two enzymes, carbamoyl
liver parenchyma. Consequently, ammonia is not phosphate synthetase and glutamine synthetase,
broken down or excreted and ultimately crosses which are enzymes for urea and glutamine
the blood–brain barrier, with varying effect on synthesis; these are impaired in cirrhosis.39
cognitive function.26 Branched-chain amino acids are theorised to
assist with HE through increased detoxification
TREATMENT of ammonia in the skeletal muscle. Common
treatments for HE are summarised in Table 3.
The first-line pharmacologic therapy for HE is
laxative. The initial goal of therapy is to prevent PROGNOSIS
ammonia absorption through non-absorbable
disaccharides (i.e., lactulose). They are potent The development of subclinical or overt HE in a
laxatives and additionally help alter the intestinal patient with liver pathology has been considered
microbiome to non-urease-producing bacteria one of the adverse markers of decompensation
that reduce ammonia production.27,28 Lactulose and carries significant morbidity and more. HE
also lowers the pH of the colon, causing was incorporated into early prognostic tools,
conversion of ammonia to the ammonium ion, including the Child–Turcotte–Pugh score, based
which is not readily absorbable in the colon.29,30 on clinical experience at the time. The prognosis
Disaccharide enemas and polyethylene glycol related to HE varies significantly depending on
have also been proven to be useful for removing the decompensation status of the underlying
excess ammonia from the colon.29,31 Use of liver cirrhosis.6,40
prophylactic therapy to prevent post-TIPS HE
was not shown to be beneficial.6,32 Subclinical HE has been shown to be present in
as many as 80% of patients with cirrhosis in the
Antimicrobials are used to treat HE by targeting USA. It may adversely impact activities of daily
culprit gut flora and thereby leading to living, such as driving, which can further affect
decreased ammonia production. The most patients’ socioeconomic status.41
commonly used antimicrobial is rifaximin, a
synthetic antibiotic that targets aerobic and

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 Table 3: Common agents used in the treatment of hepatic encephalopathy.

Therapy Mechanism Benefits Comments

Lactulose Osmotic laxative Improved cognitive function Cost effective
Acidification of the colon Most extensively studied Mainstay of HE treatment
↓ urease-producing bacteria ↓ progression to overt HE Result in dehydration if
↓ ammonia production/ severe diarrhoea
absorption
Rifaximin ↓ urease-producing bacteria Improved cognitive function Modulates gut flora
↓ ammonia production ↓ HE-related hospitalisations Expensive
BCAA Promotes synthesis of Improves recurrent HE No effect on overall
glutamine from ammonia in mortality
the skeletal muscle
LOLA Ammonia scavenging ↓ progression to overt HE Further studies required to
↑ production of urea in prove efficacy
hepatocytes, activating
glutamine synthase in
hepatocytes and skeletal
muscle
Glycerol phenylbutyrate ↑ excretion of glutamine ↑ time to HE recurrence No benefit for patients on
rifaximin
Zinc If deficient, reduced urea Improvement in cognitive No evidence on other
cycle utilisation of ammonia tests outcomes
FMT Manipulate gut microbiome Improvement in HE Currently under
recurrence investigation
Used for recurrent HE

BCAA: branched-chain amino acid; FMT: faecal microbiota transplant; HE: hepatic encephalopathy;
LOLA: L-ornithine L-aspartate.

It may adversely impact activities of daily variceal bleeding or ascites, which suggests that
living such as driving; this can further affect HE may potentially hold more prognostic value
patients’ socioeconomic status.42,43 Patients than other events of decompensation.48
with subclinical HE also have a higher likelihood
The duration of HE, with episodes lasting
of developing overt HE within a period of 2
longer than 48 hours, is important and has
weeks to 2 years after the initial diagnosis.44,45
been correlated with lower survival rates.49
Further, subclinical HE has been independently
Higher mortality has also been shown in
associated with increased mortality and the
patients hospitalised with HE and follow-up
need for liver transplantation, irrespective of
periods including 28, 90, and 365 days after
the Model for End-Stage Liver Disease (MELD)
hospitalisation.50,51 The presence of overt HE is
score.46 Therefore, the diagnosis of subclinical HE
also of prognostic importance in patients with
is important in prognosticating the development
cirrhosis after placement of TIPS. Compared to
of overt HE as well as overall prognosis.
a single episode of HE, early recurrent overt HE
The development of overt HE is one of the events has been found to have three times the increased
that defines a decompensated phase of cirrhosis. mortality after adjusting for the MELD score,
The development of the first episode of overt ascites, albumin, indication for TIPS, and age.52
HE is independently associated with shorter
life expectancies. The cumulative survival of FUTURE RESEARCH
patients who developed overt HE has been found
to be <50% in 1 year and <25% at 3 years.47,48 There are still controversies related to the
Development of HE has been shown to have classification of HE and the role of ammonia
a worse 1-year mortality outcome than either measurement in the management of patients

94 HEPATOLOGY • August 2021 EMJ

 with HE.53 Multiple tools are in development improvement in symptoms of HE as assessed
to accurately diagnose HE that are not yet by neuropsychological testing and cognitive
validated. The challenge is to keep the clinical abilities, with parallel reductions in serum and
diagnostic test simple for the patients while brain ammonia levels.60
providing high accuracy in diagnosing HE. For
example, naming the maximum number of animals The use of liver support systems, such as the
displayed in 1 minute has been shown to directly Molecular Adsorbent Recirculating System
correlate with the grade of encephalopathy.54 (MARS®; Gambro Lundia AB, Lund, Sweden) and
A pilot study utilising biomolecular testing has Prometheus® device (Fresenius Medical Care,
demonstrated the potential use of exhaled Bad Homburg, Germany), have shown some
volatile organic compounds to detect HE.55 With promise in the acute setting. They function by
further improvements in MR and PET technology, removing circulating toxins that accumulate in
research may help personalise prophylactic and
the blood due to liver dysfunction. Both devices
therapeutic approaches for patients with HE.53
have been well tolerated by patients with liver
The classification of HE in the setting of acute-
on-chronic liver failure (ACLF) also remains failure and pilot studies suggest improvement
undefined. However, HE in patients with ACLF in survival rates in some groups of patients with
has distinct clinical features, prognosis, and liver failure.61 These devices might have particular
pathophysiology compared to the conventional utility as bridges to transplantation; however,
forms represented in Types A, B, and C. Further they might not be appropriate in all patients
investigations into the classification of HE in given the requirement for central venous access
patients with ACLF and the role of modulating and the non-uniform treatment protocols.62
ammonia in this patient population need to
be conducted.50,56 Despite several promising avenues of treatment
of HE, studies remain in the early phase and
Ultimately, liver transplantation remains the await proof. Future research should understand
most effective treatment available for cirrhosis
the impact of comorbidities on outcomes,
and HE; however, it is not always an available
biomolecular diagnostic strategies, targeting
option. Unfortunately, permanent cognitive
systematic, and neuroinflammation and provide
impairment from pre-transplant HE may persist
even after this step. clear endpoints for clinical trials.

There are a few promising treatments for HE

CONCLUSION
that are still experimental. Probiotics are being
evaluated for efficacy in treatment of HE, given
The clinical presentation of HE may be highly
the role of microbiota; however, the data that
suggests any benefit have been of low quality variable and may range from defects in cognition,
with no evidence of mortality improvement.29 personality, and intellect, to an altered state of
Minocycline, which reduces microglial cell consciousness and impaired neuromuscular
activation, has been shown to potentially reduce function with asterixis and hyperreflexia.
brain oedema and plasma and cerebrospinal
The heterogeneous manifestations of HE vary
fluid ammonia levels.57 Alternative potential
treatments include indomethacin, ibuprofen, not only between patients but also longitudinally
and phosphodiesterase inhibitors, which restore for an individual patient. By categorising HE's
the function of the glutamate–nitric oxide–cyclic severity accurately and efficiently, valuable
guanine monophosphate pathway in the cerebral prognostic information and current clinical status
cortex in experimental models.29 Benzodiazepine can be ascertained.
inverse agonists, such as Ro15-4513, have also
been shown to be effective in treating HE in In conclusion, HE remains one of the most
animal models of liver failure.58 Flumazenil critical prognosticators of worsening cirrhosis,
improved clinical symptoms of HE, albeit contributing to and correlating with the mortality
temporarily, in a double-blind crossover clinical and morbidity of patients with cirrhosis. Advances
trial, possibly by decreasing γ-aminobutyric in therapeutics are underway to improve clinical
acidergic tone.59 Acetyl-L-carnitine has shown outcomes in patients with HE.

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