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Introduction
Continuing Medical Education online
Hepatic encephalopathy (He) is a serious neuro
This activity has been planned and implemented in accordance psychiatric complication of both acute and chronic
with the Essential Areas and policies of the Accreditation Council liver disease.1 this disease encompasses a broad range
for Continuing Medical Education through the joint sponsorship of
Medscape, LLC and Nature Publishing Group. Medscape, LLC is
of neuropsychiatric abnormalities of varying severity:
accredited by the ACCME to provide continuing medical education affected patients exhibit alterations in psychomotor,
for physicians. intellectual, cognitive, emotional, behavioral and fine
Medscape, LLC designates this educational activity for a maximum motor functions. He can be classified as either overt
of 1.0 aMa pra Category 1 CreditstM. Physicians should only claim or minimal. overt He (oHe) is a syndrome of neuro
credit commensurate with the extent of their participation in the
activity. All other clinicians completing this activity will be issued
logical and neuropsychiatric abnormalities that can be
a certificate of participation. To participate in this journal CME detected by bedside clinical tests. By contrast, patients
activity: (1) review the learning objectives and author disclosures; with minimal He (mHe) present with normal mental
(2) study the education content; (3) take the post-test and/or and neurological status upon clinical examination but
complete the evaluation at http://www.medscapecme.com/journal/
nrgastro; and (4) view/print certificate.
specific psychometric tests yield abnormal results. a
classification system for He disorders was devised
learning objectives by the working Party at the 1998 world Congress of
Upon completion of this activity, participants should be able to:
Gastroenterology in vienna, austria (Figure 1).1 this
1 Describe the types and patterns of hepatic encephalopathy
(HE) and risk factors for the development of both minimal classification has helped to standardize the nomenclature
and overt HE. used in He diagnosis and research worldwide, and has
2 Construct an appropriate diagnostic assessment for been used throughout this article.
patients with suspected HE that addresses a valid
Historically, the role of ammonia accumulation has
differential diagnosis.
3 Develop treatment strategies for HE that incorporate dominated explanations of the pathogenesis of He. over
pharmacologic and nonpharmacologic therapies. the past decade, however, evidence has emerged for a role Division of
of other concurrent factors (such as inflammation and Gastroenterology,
MetroHealth Medical
hyponatremia) in the development of He.26 some degree Center, Case Western
of cerebral edema occurs in all patients with He, includ Reserve University,
2500 MetroHealth
ing those with mHe, and astrocyte swelling is thought Drive, Cleveland,
Competing interests to have a key role in the disease. the precise molecular OH 44109, USA
K. D. Mullen declares an association with the following mechanisms that cause these changes in the brain of (r. prakash,
K. D. Mullen).
companies: Ocera Therapeutics and Salix Pharmaceuticals. See patients with He are, however, yet to be elucidated.
the article online for full details of the relationship. R. Prakash
the burden of disease for cirrhosis is increasing, espe Correspondence to:
and the Chief Editor N. Wood declare no competing interests. K. D. Mullen
The CME questions author D. Lie has served as a nonproduct cially with regard to the rise in the number of patients kevin.mullen@
speaker for Topics in Health for Merck Speaker Services. with hepatitis C or nonalcoholic steatohepatitis. For this case.edu
ammonia in vitro (equivalent to the levels of ammonia in cells to secrete the cytokines il1 and il6.43 tnF also
the brain observed during acute liver failure and thereby, compromises the endothelial bloodbrain barrier and
type a He) results in glutamate release.3133 this release il1 affects the integrity of the glial side of the blood
is thought to contribute to increased neuronal activity brain barrier. 44,45 Both tnF and il6 enhance fluid
because glutamate is an excitatory neurotransmitter phase permeability of isolated brain endothelial cells
and is believed to be responsible for the clinical changes in vitro, and tnF also increases the diffusion of ammonia
observed in patients with type a He, including agitation, into astrocytes.46
confusion, seizures and coma.
lowgrade cerebral edema and a predominantly neuro neurosteroids
inhibitory state (that is, slowing of mental processes) is in patients with He, expression of the 18 kDa trans
pathognomonic of type C He, which is associated with locator protein (also known as the peripheraltype
chronic liver disease (Figure 1).3436 in astrocytes, pro benzodiazepine receptor) is thought to be upregulated
longed exposure to increased concentrations of ammonia in microglial cells that are activated by inflammation.
induces a number of changes. astrocyte swelling is, in increased expression of this receptor results in increased
part, compensated for by release of the osmolytes myo mitochondrial synthesis of neuroactive steroids, which
inositol and taurine from inside the cell.34 this homeo are also known as neurosteroids.47
static mechanism results in depletion of intracellular evidence suggests that neurosteroids are involved in the
myoinositol stores; low intracellular myoinositol levels pathogenesis of He.48 these compounds are synthesized
are associated with an increased risk of sudden deteriora in the central and peripheral nervous system, either from
tion of He. 37 the activity of glutamate receptors in cholesterol or from steroid precursors (metabolites of
the postsynaptic plate are downregulated and gluta steroid hormones produced in the gonads and adrenals).
mate transporters on the astrocyte cell membrane are in the brain, neurosteroids are mainly produced by myeli
inactivated.38 over time, some of these cells change in nating glial cells (such as astrocytes).49 neurosteroid
shape and form and become alzheimer type ii astro synthesis occurs in the mitochondrial endoplasmic
cytes, as observed in both in vitro studies and in human reticulum of astroglial cells. translocator proteins are
autopsy specimens.39,40 situated on the mitochondrial membrane in astrocytes
and regulate neurosteroid synthesis.50,51 ammonia and
inflammation manganese, which accumulate in patients with liver
ammonia dysmetabolism cannot singlehandedly failure, are thought to enhance neurosteroid synthe
explain all the neurological changes that are seen in sis by activating these translocator proteins.6 Findings
patients with He.41 sepsis is a wellknown precipitating from brain autopsies have shown an increased density of
factor for decompensation of liver disease in a previously expression of this protein in patients with cirrhosis.52,53 in
stable patient with cirrhosis (a process now termed acute addition, Cagnin et al.47 demonstrated increased densi
onchronic liver failure). shawcross et al.3 studied the ties of translocated protein expression in the brains of
effect of induced hyperammonemia in a group of patients patients with mHe by using a specific ligand that binds
with cirrhosis who were admitted to hospital with sys to this protein in Pet imaging studies.47 neurosteroids
temic inflammatory response syndrome (sirs).3 Patients are positive allosteric modulators of the GaBaa receptor;
with sirs who were given an oral amino acid solution they increase influx of chloride ions and thereby enhance
to induce hyperammonemia achieved worse psycho GaBaergic tone. these effects are responsible for some
metric test results. However, once sirs (and the infec clinical sequelae in patients with type C He.54
tion) had been successfully treated, and patients levels of
the inflammatory markers tumor necrosis factor (tnF), oxidative and nitrosative stress
interleukin (il)1 and il6 had returned to normal, their enhanced production of reactive nitrogen species
psychometric test results did not deteriorate after hyper (rns) and reactive oxygen species (ros) occurs in cul
ammonemia was induced.3 similar results were obtained tured astrocytes (isolated from rats) that are exposed to
when a large population of patients with cirrhosis under ammonia, inflammatory cytokines, hyponatremia or
went blood tests (to measure levels of ammonia and benzodiazepines.5,55 this process is dependent on levels of
inflammatory markers) and psychometric assessment.2 calcium and occurs through Nmethyldaspartate recep
the presence and severity of mHe were independent of tor pathways.56 Hilgier et al.57 demonstrated overstimula
both serum levels of ammonia and the severity of liver tion of Nmethyldaspartate receptors in the rat brain
disease; however, serum levels of inflammatory markers after intravenous administration of ammonium chlo
(such as Creactive protein, white blood cell count, il6) ride. acute swelling of astrocytes has also been observed
were much higher in patients with mHe than in patients when these cells are exposed to ros or rns in vitro.58 in
without mHe.2 2006, albrecht and norenberg proposed a trojan horse
the peripheral immune system communicates with hypothesis to account for the toxic effect of glutamine in
the brain in response to infection and inflammation. astrocytes.59 these researchers suggested that glutamine
astrocytes and microgial cells release cytokines in formed in the cytoplasm enters the mitochondrial matrix
response to injury or inflammation. 42 Findings from and is cleaved to release ammonia while still inside the
studies in rats have indicated that the rise in blood levels mitochondria. this intramitochondrial ammonia is then
of tnF that occurs during inflammation stimulates glial thought to mediate release of ros and rns through
Rule out other causes Identify precipitating cause of hepatic Initiate empiric treatment
of encephalopathy encephalopathy for hepatic encephalopathy
Figure 2 | Management of patients with hepatic encephalopathy (HE). A tripartite strategy is useful in the management of
patients with HE. Other potential causes of encephalopathy, such as CNS sepsis, cerebral edema and hypoxia, must be
excluded and the precipitating cause of HE identified before a firm diagnosis of HE can be made. in patients with cirrhosis,
factors such as sepsis, drugs and dietary protein overload can precipitate HE. When HE is suspected, simultaneous,
empiric treatment for HE should be initiated to improve the patients symptoms. Any improvement in HE symptoms after
initiation of therapy indicates that the diagnosis of HE is correct. A lack of improvement indicates that another explanation
for the symptoms should be sought. *Predominantly observed in patients with acute liver failure.
calciumdependent pathways.59 evidence indicating a indicates that further treatment options should be
close association and interplay between astrocyte swell considered (as discussed below).
ing and ros is now growing. 5 apart from astrocyte
swelling, ros are also involved in nitration of tyrosine Differential diagnosis and underlying causes
residues in intracellular proteins.55,58 tyrosine nitration several conditions have similar symptoms to He
affects transastrocytic substrate transport and selec (Figure 2) and exclusion of these causes of encephalo
tive degradation of the permeability of the bloodbrain pathy is imperative for the correct management of
barrier, which ultimately promotes astrocyte swelling patients with He. if patients show evidence of changes
and cerebral edema.29 in mental status, exclusion of subdural hematoma is vital
as patients with cirrhosis have coagulopathies and an
Manganese increased risk of falls.67 Cirrhosis is associated with
manganese is a neurotoxin that preferentially accumu an increased risk of sepsis, sepsisrelated organ failure
lates in the basal ganglia. manganese deposition has and death.68 medicationinduced adverse effects are
been detected by mri in the basal ganglia of patients very common in patients with cirrhosis, as the liver is
with cirrhosis and in rats with an extensive portacaval the site of firstpass metabolism for most drugs and
shunt 6163 and has been shown to resolve with normaliza this organ is dysfunctional in these patients. as well as
tion of liver function.64,65 manganese is thought to induce excluding conditions that can mimic He, diagnosis of
changes in astrocytes of the basal ganglia that promote this disease involves the identification of potential pre
the formation of alzheimer type ii astrocytes. this cipitating causes. these two processes are a key aspect
neurotoxin is also involved in stimulation of translocator of the management of patients with suspected He. most
proteins on astrocytes, which further enhances neuro patients with chronic liver disease have at least one (and
steroid synthesis and GaBaergic tone. 8 Preferential often multiple, coexisting) simultaneous precipitating
deposition of manganese in the basal ganglia might factors capable of inducing an episode of He.
explain the Parkinsonian symptoms (such as tremors) many different assessments, including brain imaging
seen in some patients with He.66 and neuropsychometric tests, can be used to diagnose He
(table 1). oHe is conventionally graded by clinical scales
Diagnosis such as the west Haven criteria.69 mHe, by contrast, can
the approach to He comprises exclusion of other causes only be diagnosed by specific neuropsychometric tests.1
of encephalopathy, identification of the precipitating a wide spectrum of neurological and neuropsychological
cause and a trial of empiric treatment for He (Figure 2). abnormalities exists in patients with cirrhosis, which
a rapid response to this empiric treatment confirms a stretches from no He at one end to severe He and coma
diagnosis of He, whereas lack of response within 72 h at the other.70
Clinical scales for grading he introduced objective scales for the assessment of the indivi
a number of scales have been devised for the diagnosis of dual components of the criteria in patients with He.73,74
He; the first of its kind was proposed by Parsonsmith and Further studies are needed to determine whether this
colleagues in 1957.71 For patients with moderate to severe version of the west Haven criteria should be implemented
He, the Glasgow Coma scale can also be employed.72 for general use in patients with suspected He.
Box 1 | The psychometric hepatic encephalopathy score this test assesses two different cognitive domains that
are affected in patients with mHeresponse inhibition
The psychometric hepatic encephalopathy score includes the following battery
and attention.81,82 the principle of this test is based on
of tests: Number Connection Test A, measures concentration, mental tracking
and visuomotor speed; Number Connection Test B, measures concentration,
targets and lures. Patients are shown a series of different
mental tracking and visuomotor speed (but with greater complexity than test A); alphabet sequences that flash on the computer screen one
Digit Symbol Test, measures psychomotor and visuomotor speed; Line Tracing after another, and are expected to respond when X is fol
Test, measures visuomotor and visuospatial components (for both speed and lowed by Y and vice versaa socalled target. However,
accuracy); Serial Dotting Test, measures psychomotor speed. impairment of patients are told not to respond to a lurewhen X fol
>2 SD in two or more tests (of at least four tests) in this battery is necessary for lowed by X or Y is followed by Y. a lure response
a diagnosis of minimal hepatic encephalopathy. greater than five (out of 40 attempts) detects mHe with
high sensitivity.81,82 this test has been validated against
functioning, attention, processing speed and response conventional standard psychometric tests and, in a trial
inhibition. over time, these tests have proven to be sensi of probiotic therapy for He, has shown close correlations
tive to the changes associated with mHe. However, these with other He scores and improvements in test results
tests are not without their limitations (table 1). in patients who responded to therapy.82 However, most
studies that used the inhibitory control test have been
PHES published by a single group of investigators and have
the psychometric He score (PHes) is a battery of neuro been conducted only in either wisconsin or virginia,
psychometric tests that was specifically designed to usa. nonetheless, this test shows promise and might
diagnose the subtle cognitive changes that characterize ultimately be approved for the diagnosis of mHe.
mHe in patients with cirrhosis (table 1 and Box 1).76,77
normative data for comparison were initially obtained CDR computerized assessment system
in Germany, followed by italy and spain.73,76,78 abnormal the eponymous computerized assessment system from
test results are strongly correlated with changes found on Cognitive Drug research ltd (CDr), Goringonthames,
functional brain neuroimaging scans. the working Party uK, was devised specifically for neuropsychiatric profil
of the 1998 world Congress of Gastroenterology, vienna, ing of patients with cirrhosis and mHe.83 this battery
austria, endorsed this test as the official gold standard consists of seven tests that comprise over 50 parallel
for the diagnosis of mHe. notably, apart from the PHes, forms of each task and comprehensively measure power
no other psychometric tests for He have been validated by of attention, continuity of attention, quality of episodic
comparisons with normative data. this lack of validation memory, quality of continuous memory and speed of
remains an important area for further research in the field memory. this test has shown good correlation with the
of mHe. the PHes has failed to gain popularity in the goldstandard PHes test and is popular in the uK.83
usa, however, owing to the lack of usspecific normative
data and limited availability of the testing system. electrophysiological assessments
Critical flicker frequency test
RBANS the critical flicker frequency test was validated for
the repeatable Battery for the assessment of neurological the assessment of patients with He in 200284 and for the
status (rBans) was issued to diagnose neurocognitive assessment of patients with He who were undergoing
disorders such as dementia, traumatic brain injury, stroke, transjugular intrahepatic portosystemic shunt (tiPs)
multiple sclerosis and bipolar disorder in the usa. a placement in 2009.85 the principle of this test is based on
subset of the rBans tests is used in the usa instead the fact that retinal glial cells in patients with He undergo
of the PHes. this modified version of the rBans was similar changes (that is, swelling) to those seen in cerebral
designed to focus specifically on the cognitive changes glial cells, termed hepatic retinopathy. the test involves
that occur in patients with oHe.77 the modified rBans showing the patient light pulses, initially at a frequency of
test has now been used in multiple studies in the usa 60 Hz, which is gradually reduced in 0.1 Hz decrements,
and has proven to be effective in screening patients for once per second. the critical flicker frequency represents
mHe.79,80 like the PHes, the rBans is a paper and pencil the frequency at which discrete light pulses are first per
test that takes about 2025 min to administer. in addition ceived. the test results are not influenced by sex, occupa
to the domains assessed in the PHes, the rBans test tion or education level, and are only slightly dependent on
scores patients visual, verbal and working memory. age. Furthermore, the test results correlate positively with
those of paper and pencil neuropsychometric tests.84,85
Computerized psychometric tests moreover, a critical flicker frequency of below 39 Hz diag
a number of computerized psychometric tests have been noses mHe with high sensitivity and specificity. this tool
developed in the past 5 years that, once approved by a has been widely used to assess He in therapeutic trials.
large consensus group, have the potential to revolutionize
the assessment of patients with He. Electroencephalography
electroencephalography is an excellent tool for diag
Inhibitory control test nosing He in the research setting. He is associated with
the inhibitory control test seems to be the most popular a decreased mean frequency of electrical activity in
of the currently available computerized tests for He. the brain, and the diagnostic sensitivity for He of this
Box 2 | Options for long-term treatment of hepatic encephalopathy predominantly vegetarian diet include abdominal bloat
Lactulose (oral dose of 1530 ml twice daily)8891 ing and flatulence. to reduce these effects and increase a
patients protein intake vegetable protein can be combined
Rifaximin (oral dose of 550 mg twice daily)94
with dairy products, such as milk and cheese.
Zinc repletion (zinc sulfate and zinc acetate, oral dose of 600 mg)105,106
Bromocriptine (oral dose of 1560 mg daily)107 long-term management
Sodium benzoate (oral dose 5 g twice daily)108 Outpatient management of HE
l-ornithine l-aspartate (oral dose of 6 g three times daily)109,110 after an episode of He has resolved, patients with cirrho
vegetable-based protein diet sis tend to remain on empiric therapy for an indefinite
BCAA-enriched diet period of time or until they undergo liver transplanta
tion. the goals of therapy at this stage are to prevent
Abbreviation: BCAA, branched-chain amino acid. recurrent episodes of He and to ensure a reasonable
quality of life.100
neomycin was one of the first antibiotics to be investi lactulose and rifaximin are popular choices for
gated as a potential treatment for He. this drug mainly ongoing therapy in patients who have experienced an
works by inhibiting mucosal glutaminase in the intes episode of He (Box 2). adherence of patients to lactu
tine, which reduces ammonia production in the gut.69 lose therapy on a longterm basis is limited by its gastro
neomycin inhibits ammoniagenic coliform bacteria intestinal adverse effects. Patients must also be educated
that produce urease (an enzyme that converts urea into with regard to the need to monitor the consistency of
ammonia) and are prevalent in the gut. the main adverse their bowel movements and use appropriate dose titra
effects of neomycin sulfate administration include oto tion when being treated with lactulose. rifaximin, by
toxic and nephrotoxic effects and intestinal malabsorp contrast, has emerged as an effective treatment strategy
tion. the use of this antibiotic has declined over the past to prevent recurrence of He in a multicenter study pub
few years, owing to the availability of safer antibiotics lished in 2010.94 Patients who had previously experienced
such as rifaximin. at least two episodes of He and were in remission were
randomly assigned to receive either rifaximin or placebo
nutritional interventions and were followed up for 6 months. more than 90% of
skeletal muscle metabolizes ammonia in patients with participants in this study were treated with lactulose in
chronic liver disease.1921 loss of lean body mass depletes addition to rifaximin or placebo. the patients in the rifax
this ammonia sink and increases the ammonia load to imin group maintained their remission from He more
the brain, thereby worsening He. a strong consensus, effectively than did patients in the placebo group, and
therefore, exists that patients with cirrhosis should rifaximin was associated with improved tolerability
receive a highprotein diet. the european society for and decreased adverse effects compared with placebo.94
Parenteral and enteral nutrition recommended, in 2006, rifaximin is, therefore, likely to dominate treatment
that patients with cirrhosis must eat at least 1.2 g/kg of strategy for He in the future.
protein daily.95,96 they also recommended that the diet
of patients with cirrhosis should be supplemented with Persistent HE
branchedchain amino acids (BCaas) and vegetable orthotopic liver transplantation is the ultimate solu
protein once He has developed. tion for patients affected by He. However, He has lost
ground as an indication for liver transplantation in the
Branched-chain amino acids era of the model for endstage liver Disease (melD)
BCaas have been studied extensively and a recent score. stewart et al.101 reported that the severity of He
metaanalysis has shown that patients with cirrhosis before liver transplantation is inversely correlated with
who receive BCaas are more likely to recover from He the duration of survival after transplantation, and that
than those who do not receive this supplement.97 BCaas the prognosis of patients who undergo transplantation for
improve levels of serum albumin, increase progression He is worse than that indicated by their melD score.101
free survival and reduce both the number of hospitaliza a crucial issue, therefore, is that the workup of a patient
tions and the length of hospital stays in patients with who is eligible for liver transplantation should be initiated
cirrhosis.9799 these amino acids can be administered at the earliest opportunity after an acute episode of He.
orally as well as intravenously; however, their use can be surgical portosystemic shunting or tiPs placement
limited by poor availability and high costs. worsens He because ammonia in the gut circulation can
then bypass firstpass metabolism in the liver and go
Vegetable-based protein directly to the brain.102 symptoms of He that result from
vegetablebased protein is better tolerated by patients portosystemic shunting are amenable to shunt closure
with cirrhosis than meatbased protein. vegetablebased or a reduction in stent diameter, but these procedures
protein foods have a high fiber content, which increases are indicated only if the patient is not a candidate for
intestinal transit time and colonic motility and enhances transplantation. alternative treatments for the under
intestinal nitrogen clearance.99 vegetable protein also lying condition that prompted shunt placement (that is,
reduces colonic pH, which prevents ammonia from recurrent variceal bleeding or refractory ascites) should
being absorbed in the gut. the adverse effects of a be considered to prevent the development of He.
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