REVIEW

Management of Hepatic Encephalopathy in the

Hospital
Michael D. Leise, MD; John J. Poterucha, MD; Patrick S. Kamath, MD;
and W. Ray Kim, MD
Abstract
Hepatic encephalopathy (HE) develops in up to 50% of patients with cirrhosis and is a feature of decompensated cirrhosis. With the goal of reviewing the evidence for treatment and prevention of overt hepatic
encephalopathy, pubmed was searched using search terms hepatic encephalopathy AND treatment, limited to
human studies from January 1, 2003, through December 1, 2013, and supplemented by key references. The
inpatient incidence of HE is approximately 23,000 annually, and management of these patients is common for
internists and subspecialists. Treatment of the hospitalized patient with HE has changed in recent years.
Treatment entails 2 phases: induction and maintenance of remission. Most cases of signicant HE are
precipitated by infection, gastrointestinal bleeding, medications, or other culprits. All patients should be
evaluated for secondary triggers of HE, and treatment should be initiated with a nonabsorbable disaccharide
(ie, lactulose) in most patients. Rifaximin (off label) can be added in patients not responding to lactulose.
Neomycin is a less preferred alternative to rifaximin owing to its adverse effect prole. Other therapies,
including zinc, L-ornithineeL-aspartate, and branched-chain amino acids, can be considered for patients not
responding to disaccharides and nonabsorbable antibiotics. Large portosystemic shunts may be embolized in
patients with medically refractory recurrent or severe HE with otherwise well-compensated cirrhosis. Molecular Adsorbent Recirculating System is now available for patients with severe HE who do not respond to
medical therapy. It is critically important that patients hospitalized with signicant HE continue maintenance
therapy at the time of dismissal to prevent further episodes. Patients with a rst-time episode of HE can be
administered lactulose, and careful instructions should be provided to patients and caregivers about dose
titration to achieve 3 bowel movements daily. Patients with recurrent HE episodes despite lactulose use benet
from the addition of rifaximin, which decreases the frequency of recurrent HE episodes and related hospitalizations. Last, patients and their families should be counseled about the risk of motor vehicle accidents,
which require mandatory reporting to the Department of Motor Vehicles in some states.
2014 Mayo Foundation for Medical Education and Research

epatic encephalopathy (HE) is a significant neuropsychiatric syndrome that

most commonly occurs in decompensated cirrhosis. Clinical features range from
clinically imperceptible symptoms in minimal
HE (MHE), which require neuropsychometric
testing to identify, to a comatose state in the
worst cases.1 The Working Party for Hepatic Encephalopathy established nomenclature for HE
in 1998.2 Type A HE refers to HE secondary to
acute liver failure, type B refers to enteric hyperammonemia (without liver disease), and type C
is associated with chronic liver disease. The
severity of HE is graded using the WestHaven
criteria (grades 1-4), but alternative terminology
has been suggested and has gained some
traction. In the new lexicon, called SONIC (spectrum of neurocognitive impairment in cirrhosis),

Mayo Clin Proc. 2014;89(2):241-253

covert HE (CHE) includes MHE and grade 1 HE

and overt HE (OHE) encompasses grades 2 to 4
HE (Table 1). Episodic HE develops over a short
time frame and can uctuate, whereas persistent
HE impairs day-to-day executive function. Most
patients with episodic OHE (grade 2 or higher)
will require management in the hospital, which
is the focus of this review.
Hepatic encephalopathy eventually occurs in
up to 50% of patients with cirrhosis.3,4 Hepatic
encephalopathy portends a worse survival for patients compared with similar patients without
HE, even after accounting for the Model for
End-Stage Liver Disease (MELD) score.5 The
development of HE merits consideration of liver
transplantation. Whether treatment of HE alters
survival is unknown. Treatment of HE continues
to be a signicant area of investigation. Currently,

Mayo Clin Proc. n February 2014;89(2):241-253 n http://dx.doi.org/10.1016/j.mayocp.2013.11.009

www.mayoclinicproceedings.org n 2014 Mayo Foundation for Medical Education and Research

From the Division of

Gastroenterology and
Hepatology, Mayo Clinic,
Rochester, MN.

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MAYO CLINIC PROCEEDINGS

ARTICLE HIGHLIGHTS
n

Episodic overt hepatic encephalopathy (OHE) is responsible for

an increasing number of hospital admissions and readmissions.
New terminology has been suggested and is gaining traction in
which West Haven grades 0 and 1 are covert HE and grades 2
to 4 are OHE.
Most patients with OHE require hospital-based care during the
induction treatment phase, followed by a maintenance treatment strategy in the outpatient setting.
Lactulose is the mainstay of induction and maintenance
treatment.

Rifaximin, when added to lactulose, has been found to prevent

episodes of OHE and hospitalization compared with lactulose
alone.

Rifaximin and neomycin are acceptable adjunctive therapies for

patients with OHE who are not responsive to lactulose or who
have severe OHE, although rifaximin may be preferable owing
to a better adverse effect prole.
Evidence for the use of zinc, L-ornithineeL-aspartate, and
branched-chain amino acids is less compelling, whereas there is
increasing data to suggest a benet of portosystemic shunt
embolization in carefully selected patients.

nonabsorbed disaccharides (eg, lactulose and

lactitol) and nonabsorbable antibiotics (eg,
neomycin and rifaximin) represent the mainstay
of treatment (Table 2).
Hospitalization for episodic OHE, or the
development of OHE during hospitalization, is
common. In the US Nationwide Inpatient Sample, the inpatient incidence of HE ranged from
20,918 (in 2005) to 22,931 (in 2009).6 Up to

80% of OHE episodes are precipitated by an

event such as infection or gastrointestinal
bleeding. Management of the hospitalized patient with episodic OHE, common for internists
and subspecialists, is directed at correcting the
underlying precipitant and providing pharmacologic treatment that reduces ammoniagenesis.
Most patients require maintenance medications at the time of hospital dismissal as secondary prophylaxis for episodic OHE. Data suggest
that many patients do not receive maintenance
medication at or after dismissal. An abstract presented at the American Association of the Study
for Liver Disease annual meeting in 2012 characterized a subset of insurance claims for patients by International Classication of Diseases,
Ninth Revision code for HE (code 572.2) and
compared this to prescriptions lled between
January 1, 2009, and December 31, 2011. For
2009 (n13,623), 2010 (n15,529), and
2011 (n16,328), 89.2%, 87.8%, and 86.4%
of patients with HE had inpatient claims for
HE, respectively, and 60.3%, 62.3%, and
63.9% did not receive ongoing treatment.7,8
Volk et al9 also described a high readmission
rate (69%) in a cohort of patients with decompensated cirrhosis (n402) where one of the
most common reasons for preventable readmission was recurrent HE due to lack of education
on or inappropriate use of lactulose. Thus, more
attention should be focused on ensuring that patients are prescribed and educated about maintenance medication therapy for secondary
prevention of OHE at the time of hospital
dismissal.10 In this review, we summarize the
evidence on the optimal medical treatments
for patients who have been hospitalized for
episodic OHE and suggest treatment algorithms

TABLE 1. Hepatic Encephalopathy Grades

Impairment
Grade

Intellectual

Neuromuscular

0
Normal
MHE Normal examination ndings; subtle changes in work or driving
1
2
3
4

Personality changes, attention decits, irritability, depressed state

Changes in sleep-wake cycle, lethargy, mood and behavioral
changes, cognitive dysfunction
Altered level of consciousness (somnolence), confusion,
disorientation, amnesia
Stupor and coma

Normal
Minor abnormalities of visual perception or on
psychometric or number tests
Tremor and incoordination
Asterixis, ataxic gait, speech abnormalities (slow and
slurred)
Muscular rigidity, nystagmus, clonus, Babinski sign,
hyporeexia
Oculocephalic reex, unresponsiveness to noxious stimuli

SONIC criteria
Normal
Covert
Covert
Overt
Overt
Overt

MHE minimal hepatic encephalopathy; SONIC spectrum of neurocognitive impairment in cirrhosis.

242

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MANAGEMENT OF HEPATIC ENCEPHALOPATHY

TABLE 2. Hepatic Encephalopathy Treatment Options

Drug
Neomycin
Lactulose
Metronidazole
Vancomycin
Rifaximin
MARS

FDA approved

Approval year

Yes
Yes
No
No
Yes
Yes

1970
1976
NA
NA
2010
2013

FDA Food and Drug Administration; MARS Molecular

Adsorbent Recirculating System; NA not applicable.

for induction and maintenance of remission

(secondary prophylaxis). Liver transplantation
for HE is not covered in this review.
The search strategy used for this review
included the search terms hepatic encephalopathy
and treatment in PubMed, with lters of human
and past 10 years. Bibliographies were also manually searched, as were abstracts from recent liver
conferences. Clinical trials were emphasized
when discussing evidence for each modality.
EVIDENCE FOR INDUCTION THERAPIES TO
TREAT EPISODIC OHE
Nonabsorbable Disaccharides
Lactulose (b-galactosidofructose) and lactitol
(b-galactosidosorbitol) reduce ammonia levels
by acidication of the colon with resultant conversion of ammonia to ammonium, shifting the
colonic ora from urease- to noneurease-producing bacterial species, and by their cathartic
effect. Nonabsorbable disaccharides have
demonstrated variable efcacy in clinical trials.
An often-cited meta-analysis performed in
2004 found that nonabsorbable disaccharides
were superior to placebo but did not improve
survival.11 When only high-quality trials were
included in this meta-analysis, nonabsorbable
disaccharides had no effect on HE. To our
knowledge, there have been no trials of nonabsorbable disaccharides vs placebo since these
results. Despite the mixed results, lactulose still
remains the rst-line therapy for acute episodic
OHE. Decades of clinical experience with lactulose speaks to its effectiveness to reverse
episodic OHE in all but the most severe of
cases. The discordance between efcacy in clinical trials and real-life effectiveness is manifold
and includes heterogeneity in the types of HE
(minimal vs overt vs chronic), differences in
the prognostic importance of HE precipitants,
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and subjectivity of HE assessment tools. Clinical guidelines recommend lactulose or lactitol

as rst-line therapy.10
Neomycin, Metronidazole, and other
Antibiotics
Neomycin is a poorly absorbed aminoglycoside
used to decrease gut bacteria-derived ammonia,
and it is Food and Drug Administration (FDA)
approved for use in acute (episodic) OHE but
not chronic HE. There are multiple older studies
that explore the efcacy of this agent in HE. One
of the earliest studies, by Atterbury et al12 in
1978, was a randomized controlled trial (RCT)
comparing neomycin-sorbitol with lactulose in
acute (episodic) HE that found no difference between the 2 therapies. One of the most recent
studies, from 1992, compared neomycin, 6 g/d
(n20), with placebo (n19) for episodic HE
in a double-blind randomized trial and found
no statistically signicant difference in treatment
failures (2 per group) or mean  SD time to
resolution of HE in the neomycin arm
(39.1123.04 hours) vs the placebo arm
(49.4721.92 hours).13 In general, the evidence
for neomycin in episodic OHE is weak, and its
use is complicated by the risk of ototoxicity
and nephrotoxicity. Although neomycin is FDA
approved, its decreased efcacy and adverse effects compared with other therapies limit its clinical utility. Other small trials have evaluated
metronidazole and vancomycin and have suggested some benet, but the risk of neurotoxicity
and vancomycin-resistant enterococci colonization, respectively, hamper any enthusiasm about
using these agents as mainstays in the armamentarium for HE.14-19
Rifaximin
The role of rifaximin in the treatment of episodic
OHE is contentious. Rifaximin is not FDA
approved for the treatment of episodic OHE,
only for the secondary prevention of OHE. Older
trials that evaluated rifaximin for episodic HE
used different comparators and generally enrolled
small numbers of patients with acute, chronic, or
unclear acuity of HE. Bucci and Palmieri20
compared rifaximin (1200 mg/d) with xeddose lactitol (30 g/d) in 30 and 28 patients with
moderate to severe HE, respectively. It was not
clear whether these patients had OHE or chronic
HE. End points were HE grade, neuropsychometric test results, and ammonia level at days 3, 6, 9,

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MAYO CLINIC PROCEEDINGS

12, and 15. Overall, there did not seem to be any

clinically important differences between groups at
day 15 across all end points considered, but rifaximin did seem to result in faster improvement
compared with lactitol. An RCT of rifaximin vs
placebo for acute HE (grades 1-3) found improvement in a composite outcome (including mental
status, neuropsychometric test results, electroencephalographic ndings, and ammonia level) at
doses of 1200 and 2400 mg/d.21 A randomized,
double-blind, double-dummy, controlled trial
compared rifaximin, 1200 mg (n50), with lactitol, 60 g/d (n53), and found approximately
80% efcacy in both arms after 5 to 10 days of
treatment. An open-label randomized trial in Koreans compared rifaximin, 1200 mg (n32), with
lactulose, 90 ml/d (n22), in OHE grades 1 to 3
and found no difference in improvement in HE
grades or composite end points.22 Rifaximin
was better tolerated in most studies, as anticipated. Table 3 summarizes data in trials
comparing lactulose/lactitol with rifaximin that
generally reported similar outcomes in both treatment groups. Given the small number of trials
and their methodologic aws, the question of using rifaximin as monotherapy for episodic OHE
remains unanswered.
Rifaximin use for episodic OHE, in addition
to lactulose use, has become increasingly common despite a previous lack of evidence. A recent

RCT (n120) was conducted by Sharma et al23

comparing rifaximin and lactulose with lactulose
and placebo in patients with OHE. Eighty
percent of patients had severe HE, grade 3 or
4, and 70% were Child-Turcotte-Pugh class C,
with the remainder Child-Turcotte-Pugh class
B. Patients in the lactulose and rifaximin group
had a higher proportion of complete reversal of
HE (76% vs 50.8%, P<.004), shorter hospital
stays, and a striking improvement in 10-day
mortality (49.1% vs 23.8%, P<.05). The very
high mortality rate in the lactulose plus placebo
arm raises some concerns about the validity of
this study, which should be repeated in a larger
number of patients at multiple sites. In the
meantime, this is likely the best data that will
be available for some time with which to make
evidence-based treatment decisions.
Zinc
Zinc deciency is common in cirrhosis. In a
recent clinical trial, the zinc deciency prevalence was 96% in patients with a median
MELD score of 12.24 Ammonia is converted to
urea by ornithyl transcarbamylase in the liver
and is combined with glutamate by glutamine
synthetase in the skeletal muscle to form glutamine. Both ammonia-reduction pathways are
impaired by zinc deciency. Treatment with
zinc has been found to enhance the formation

TABLE 3. Disaccharides vs Rifaximin for the Treatment of HE: Summary of Trials

Reference, year

Method

HE type

Bucci and Palmieri,20

1993

N58 DB,
RCT

Festi, 199326

N21
Grade 1 HE
RCT, OL

Massa, 199327

N40 DB,
RCT

Mas 200328

N103
Grade 1-3
DB, RCT
acute HE

Paik et al,22 2005

N54 OL,
RCT

Unknown

Grade 2-3
HE

Grade 1-3

Intervention

Outcome measure

Rifaximin, 1200 mg; MS, asterixis, cancellation

lactulose, 30 g
test, Reitan test, EEG,
ammonia
Rifaximin, 1200 mg; HE symptoms, ammonia,
lactulose, 40 g
serum Na
Rifaximin, 400 mg PSE Index
TID; lactulose
20 g TID
Rifaximin, 1200 mg; PSE Index
lactitol, 60 mg
(titrated)

Rifaximin, 1200 mg; HE index, MS, asterixis,

lactulose, 90 ml
Reitan test

Results
Improvement in MS, ammonia level,
cancellation test, EEG more pronounced,
and faster onset with rifaximin
HE symptom improvement comparable;
faster onset for asterixis, ammonia, Na
in the rifaximin group
MS improvement favored rifaximin, as did
ammonia level (faster drop), Reitan test,
and earlier change in EEG
Comparable overall global improvements in
both groups (z80%), with patients taking
rifaximin demonstrating better HE grade,
ammonia level, and EEG (statistically
signicant) and higher % with complete
HE resolution (53% vs 37%)
Improvements for both, no statistically
signicant difference for any outcome

DB double blind; EEG electroencephalogram; HE hepatic encephalopathy; MS mental status; Na sodium; OL open label; PSE portosystemic encephalopathy; RCT randomized controlled trial; TID 3 times daily.

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MANAGEMENT OF HEPATIC ENCEPHALOPATHY

of urea from ammonia and amino acids.25 Zinc

therapy has been the focus of 4 RCTs, producing
heterogeneous results. Three of these trials are
now 20 years old or more.29-31 The most recent
study, from Takuma et al24 in 2010, randomized patients with cirrhosis and HE grades 1
and 2 refractory to standard treatment to receive
zinc treatment (n39) in addition to lactulose
and branched-chain amino acids (BCAAs) vs
no zinc (n40) with BCAA and lactulose. Patients were followed for 6 months to determine
the effect on quality of life and HE. Hepatic encephalopathy improved in 21 (54%) vs 10
(26%) of patients in the zinc vs no zinc arms,
with 16 zinc-treated patients (41%) improving
to HE grade 0. Other end points, including
ammonia level, psychometric test results, and
quality of life, were met in the zinc treatment
arm. Although this study had some aws,
including lack of blinding and the zinc formulation (contained L-carnosine), it is the only recent
study with reasonable evidence to suggest the
benet of zinc. There is not enough data to
dene the optimal dose of zinc. Zinc is relatively
well tolerated, with rare adverse effects of
dyspepsia and copper deciency (with longterm, high-dose use), and can decrease the effectiveness of ciprooxacin if taken at the same
time (take zinc 2 hours before or 6 hours after
taking ciprooxacin).
L-OrnithineeL-Aspartate
L-ornithineeL-aspartate

(LOLA) is a compound
salt that stimulates ornithine transcarbamolyase
and carbamoyl phosphate synthetase and is a substrate for the formation of urea. Also, LOLA works
by stimulating glutamine synthesis in the skeletal
muscle and, consequently, lowering ammonia.
L-ornithineeL-aspartate has been most thoroughly evaluated in the setting of chronic HE.
Two randomized, placebo-controlled, doubleblind studies were performed in Germany using
intravenous and oral forms of LOLA in patients
with chronic HE, both of which found improvements in the number connection tests,
ammonia values, and HE parameters (mental
state gradation and Portosystemic Encephalopathy Index).32,33 Episodic, recurrent HE was specically excluded from these studies. Few data
exist for the management or prophylaxis of
episodic OHE. One study from Pakistan evaluated LOLA as adjunctive treatment vs placebo
in patients who were allowed to receive standard
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medical treatment (SMT).34 Patients with grade 2

HE or above had improvement in HE grade on
SMT LOLA (79%) vs SMT placebo (55%),
which was signicant (P.019). In other countries, LOLA is used as adjuvant therapy, but this
medicine is not available in the United States.
Branched-Chain Amino Acids
The plasma amino acid prole in patients with
cirrhosis is altered, with a decrease in BCAAs
and an increase in aromatic amino acids. The
BCAAs are a source of glutamate, which helps
to metabolize ammonia in skeletal muscle. The
benets of BCAAs in liver disease have been
investigated for several decades. Supplementation with BCAAs may improve albumin
synthesis, decrease insulin resistance, decrease
hepatocellular carcinoma, and improve immune
function.35 Two RCTs found that BCAAs
improved important composite end points of
death/hospitalization metrics in one study and
hepatic failure, variceal bleeding, hepatocellular
carcinoma, and mortality in a second study.36,37
Branched-chain amino acids have been studied
in HE as well, to a lesser degree. An early study
indicated that BCAAs were effective for latent
(minimal) HE.38 More recently, BCAAs were
administered to 58 patients with 1 previous
episode of OHE and compared with 58 patients
receiving maltodextrin.39 There was no signicant difference in the frequency of recurrent
HE. However, there was substantial loss to
follow-up in this trial, so results must be interpreted cautiously. Currently, the European Society for Clinical Nutrition and Metabolism
recommends the use of 1.2 g/kg per day of protein for compensated cirrhosis and 1.5 g/kg per
day for decompensated cirrhosis. This recommendation was based on the results of an RCT
of a normal protein diet (1.2 g/kg per day) vs a
restricted diet reporting no effect on the outcome
of episodic HE but increased muscle breakdown
in the low-protein-diet group.40 In addition, the
European Society for Clinical Nutrition and
Metabolism provides a grade A recommendation
for the use of standard protein supplementation
in patients with HE grade 2 or less and BCAA
preparations for HE grades 3 and 4.41
Percutaneous Embolization of Large
Portosystemic Shunts
Two large retrospective series have been published reporting the efcacy and safety of

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embolization of large portosystemic shunts in

medically refractory HE. In a European multicenter cohort study (n37), 59% of patients
were free of HE within 100 days and 48% were
HE free an average of 2 years after embolization.42
There was 1 hepatic capsular hemorrhage, otherwise there were no other major periprocedural
complications. Long-term safety seemed good,
with no increase in variceal bleeding events. In
the largest US series (n15), 90% of patients
with cirrhosis improved 2 months after the procedure.43 One patient developed an infected hepatic
cyst 2 weeks after the procedure, otherwise there
were no signicant complications attributed to
the procedure. The median MELD score in both
studies was 13. Logistic regression performed in
the European study suggested that patients with
MELD score greater than 11 were at risk for HE
recurrence after shunt embolization.
Molecular Adsorbent Recirculating System
Molecular Adsorbent Recirculating System
(MARS) was introduced in 1999 and is based
on the concept of albumin dialysis. This system
was designed to remove protein- and albuminbound toxins, such as bilirubin, bile acids,
nitrous oxide, and endogenous benzodiazepines
(among others), and it also removes none
protein-bound ammonia that accumulates in
liver failure. More than 45,000 MARS treatments
have been administered to approximately 15,000
patients. Although the effect of MARS on survival
for patients with liver failure remains in question,
3 studies44-46 have reported improvements in
HE. The most recent and the largest trial (RELIEF
Trial) enrolled 189 patients with acute-onchronic liver failure and evaluated MARS plus
SMT vs SMT alone on the primary end points
of 28- and 90-day liver transplantationefree survival.44 Survival end points were not met, but
safety was demonstrated. There was a higher
proportion of patients with MELD scores greater
than 20 (78.9% vs 69.7%, P.16) and spontaneous bacterial peritonitis (14.4% vs 6.7%,
P.94) at baseline in the MARS treatment group.
The proportion of patients with HE grade 3 or 4
improvement to HE grade 0 or 1 was higher in
MARS-treated patients (15 of 24; 62.5%)
compared with SMT (13 of 34; 38.2%), which
trended toward signicance (P.07).44 In
another study designed specically to evaluate
the effect of MARS on HE, 70 patients with grade
3 (56%) and grade 4 (44%) HE were randomized
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Mayo Clin Proc.

to receive MARS SMT vs SMT alone.45 The

primary end point was met whereby a higher
proportion of patients had a 2-grade improvement in HE in the MARS arm (mean, 34%) vs
the SMT arm (19%), with a P.044 and more
rapid improvement (P.045).45 The MARS
was also well tolerated in this trial. In the smallest
study, MARS had a statistically signicant effect
on improvement of HE in 9 patients with alcoholic hepatitis and HE (without SMT) and
decreased circulating aromatic phenolic amino
acids.46 The FDA has approved the use of
MARS for HE related to decompensation of
chronic liver disease. Exclusion criteria in the 2
largest trials included active hemorrhage, active
infections, severe cardiopulmonary disease, renal
replacement therapy, and hemodynamic instability, which will decrease the applicability of
MARS. Also, MARS may reduce the bioavailability of certain antibiotics.47 Cost is also a major
concern with this modality. Nevertheless, MARS
seems to be a viable option for patients with severe HE unresponsive to SMT.
EVIDENCE FOR SECONDARY
PROPHYLACTIC/MAINTENANCE
STRATEGIES FOR HE
Lactulose
The results of 2 recent trials provided solid evidence for the practice of secondary prevention
with lactulose alone or lactulose and rifaximin.
Sharma et al48 performed an open-label study
randomizing 140 patients to receive placebo or
daily lactulose after recovery from an episode
of OHE. After dropouts and protocol violations,
19.7% of lactulose-treated patients (12 of 61)
experienced recurrent OHE vs 46.9% (30 of
64) in the placebo arm (P.001) over median
follow-up of 14 months. In a similarly designed
trial by Agrawal et al,49 patients recovered from
OHE received lactulose (n80), probiotics
(n77), or no therapy (n78). Patients in the
probiotic arm received 3 capsules per day containing 112.5 billion viable lyophilized bacteria
per capsule containing 4 strains of Lactobacillus,
3 strains of Bidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus.
The intention-to-treat results demonstrated a
signicantly lower rate of OHE for lactulose
(37.5%) and probiotics (45.4%) compared
with no treatment (64.1%). Ideally, these results
should be reproduced in studies in other

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MANAGEMENT OF HEPATIC ENCEPHALOPATHY

countries/centers. The role of probiotics as

stand-alone maintenance treatment is also interesting and deserving of further investigation.
Rifaximin
In 2010, Bass et al50 published results from an
RCT of rifaximin (n140) vs placebo (n159)
for the secondary prevention of episodic OHE
in adult patients with 2 or more previous episodes of unprecipitated HE who were in remission at the time of enrollment. The MELD score
was required to be 25 or less for participants.
More than 90% of patients in both arms were
taking lactulose. Patients experienced a reduction in breakthrough HE in the rifaximin group
(31 of 140) compared with the placebo group
(73 of 159), with a hazard ratio of 0.42 (95%
Cl, 0.28-0.64; P<.001). The authors also reported a 50% reduction in hospitalizations for
the rifaximin group (19 of 140) compared
with the placebo group (36 of 159). Adverse
events were similar between the rifaximin and
placebo groups. Based on data from this phase
3 study, rifaximin was approved by the FDA
for the secondary prevention of OHE. It is
important to reiterate that this trial did not
address rifaximin use for episodic HE. A trial
to evaluate the safety and efcacy of rifaximin
in patients with cirrhosis with MELD scores of
25 or greater is under way (ClinicalTrials.gov
Identier: NCT01846663). Another ongoing
trial is examining rifaximin plus lactulose vs
rifaximin alone for secondary prevention
(ClinicalTrials.gov Identier: NCT01842581).
Patients with advanced MELD scores or
Child-Turcotte-Pugh class B/C cirrhosis require
secondary prophylaxis after recovery from spontaneous or precipitated episodic HE. Patients
with Child-Turcotte-Pugh class A cirrhosis who
are otherwise well compensated but develop isolated OHE in the setting of infection or gastrointestinal bleeding represent a more challenging
decision. Some of these patients may not need
or benet from long-term maintenance treatment
with lactulose, but data to drive patient selection
for this strategy is not readily available. Decisions
about secondary prophylaxis for these patients
are made on a case-by-case basis, with no guidelines for best care. Ideally, these types of patients
would receive neuropsychometric testing for
CHE within a few weeks after leaving the hospital.
However, neuropsychometric testing for CHE is
not practical for most patients, and a simple
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clinical tool to detect CHE is badly needed. Patients with 1 previous precipitated (ie, gastrointestinal bleeding) OHE event, otherwise well
compensated (Child-Turcotte-Pugh class A),
and with lingering CHE as identied by specialized testing might warrant ongoing maintenance
treatment with lactulose. However, this potential
strategy requires further investigation before
incorporating into standard clinical practice.
APPROACH TO INDUCTION AND
MAINTENANCE TREATMENT OF HE
Approach to Induction and Maintenance
Treatment for the First Episode of Episodic
OHE, West Haven Grades 1 and 2
The rst step in the management of episodic OHE
is evaluation for the typical precipitants of OHE,
including gastrointestinal bleeding, infections,
new medications (such as opioids or benzodiazepines), constipation, diarrhea, dehydration, alkalosis or hypokalemia, and hypoxemia (Figure 1).
Up to 80% of patients may have a precipitant.
When a precipitant is found, management of
the precipitant along with concomitant lactulose
therapy is recommended. For those not responding to initial treatment, it is important to reevaluate the diagnosis of OHE, review the possibility of
other precipitants, and ensure that the patient is
having 3 to 4 stools per day while taking lactulose.
For example, a head computed tomographic (CT)
scan may be necessary in a patient who has a new
focal neurologic defect on reexamination. If the
diagnosis of OHE is correct, no other precipitants
are found, and bowel movements are adequate,
then neomycin or rifaximin could be added to lactulose therapy. Neomycin is FDA approved for
this indication, but there are obvious concerns
regarding nephrotoxicity, ototoxicity, and, to
some degree, efcacy. Rifaximin use in this setting
is off label. However, with the recent RCT reporting improved HE outcomes and a mortality
benet in patients taking lactulose with rifaximin,
we recommend using rifaximin preferentially. Patients who recover from a rst episode of OHE
generally require lactulose maintenance therapy,
especially if Child-Turcotte-Pugh class B/C.
Approach to Induction and Maintenance
Treatment for Recurrent (2 Episodes)
Episodic OHE
The management of recurrent OHE requires a
careful evaluation for precipitating factors

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(Figure 2). In addition, one must scrutinize the

baseline maintenance medication regimen for
these individuals. Inappropriate lactulose dose
titration to achieve 3 stools per day and
noncompliance are common. Patient education
or reeducation is an important part of the management of this scenario. If symptoms such as
bloating and excessive diarrhea occur, even
while taking small doses of lactulose, rifaximin
or neomycin should be substituted for lactulose. Breakthrough OHE while receiving an
appropriate lactulose regimen calls for the addition of rifaximin (off label) or neomycin,
although rifaximin is preferred. In more challenging patients who develop recurrent episodic
OHE while appropriately using lactulose and
rifaximin, the provider should consider looking
for a large intra-abdominal portosystemic shunt

with contrast-enhanced CT. In the trial of secondary prevention with lactulose by Sharma
et al, the frequency of large spontaneous shunts
was 23% (32 of 140)49 but may be present in up
to 70% of patients with persistent HE.51 The
risk of CT contrast nephropathy needs to be
considered in these patients, who often have
falsely normal creatinine levels with tenuous
renal function; magnetic resonance angiography is an alternative for patients with a
glomerular ltration rate greater than 30 mL/
min per body surface area. For wellcompensated patients with Child-TurcottePugh class A cirrhosis or low MELD scores
(arbitrarily dened as <12-15), percutaneous
shunt embolization should be considered,
which can result in remission from recurrent
OHE in 59% to 90% of patients. Recurrent

HE grade 1-2
first episode

Precipitants
Infections
Gastrointestinal bleeding
Medications
Dehydration
Electrolyte abnormality
Hypoglycemia
Very high protein intake

Identify and treat

precipitant

Start lactulose

Improvement?
Yes

No

Continue lactulose
for acute treatment
and maintenance
of remission

Reevaluate diagnosis and cause

Ensure stool output
Diagnosis correct, no other
precipitants, adequate stools
Add rifaximina (preferred)
or neomycin
Resolution

Worsening HE

Continue lactulose for

maintenance of remission

See HE grade 3-4

algorithm

FIGURE 1. Management of a rst episode of hepatic encephalopathy (HE), grade 1 or 2. aRifaximin is not
Food and Drug Administration approved for overt HE.

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MANAGEMENT OF HEPATIC ENCEPHALOPATHY

OHE after shunt embolization is more likely

with MELD scores greater than 11. If a shunt
is not found or a high MELD score precludes
embolization, then additional treatments, such
as zinc, LOLA (where available), and BCAA
feeding, should be considered. It is reasonable
to check zinc levels in patients with HE to
help guide dosing, using a 220-mg dose of
zinc sulfate (contains 50 mg of elemental zinc)
once daily in those with normal zinc levels.
Once resolution of episodic OHE is achieved,
all patients with recurrent OHE need to be
maintained on lactulose, rifaximin, or both,
depending on their initial therapy. For example,
a patient with breakthrough OHE while taking
lactulose will need a maintenance regimen of
lactulose and rifaximin.

Management of Severe HE (West Haven

Criteria Grade 3 or 4)
Grade 3 or 4 HE is a serious condition that requires intensive care unit monitoring (Figure 3).
Patients who cannot protect their airway owing
to decreased consciousness require endotracheal
intubation and mechanical ventilation. After a
thorough evaluation for precipitants, patients
should be given lactulose via nasogastric (NG)
tube. Lactulose at 15 to 30 cc can be given every
1 to 2 hours via NG tube until 3 stools are
achieved. If NG or orogastric access is not available, then 300 cc of lactulose can be given in 1 L
of water as an enema (300 cc of lactulose [10 g/15
mL] in 700 cc of sterile water). This can be
repeated as necessary, although care should be
taken to avoid excessively loose or voluminous

HE grade 1-2 (spontaneous or precipitated)

recurrent (2)

Identify and treat precipitant

Breakthrough HE
on lactulose &
rifaximin

Breakthrough HE
with appropriate
lactulose use

Add rifaximina
(preferred) or
neomycin

Reevaluate
diagnosis and cause
Confirm compliance
No resolution

No shunt

+ shunt

Add zinc
LOLAwhere available
BCAA (limited evidence)

Lactulose
intolerance/
adverse
events

Lactulose
noncompliance
or inappropriate
dose titration

Stop
lactulose
Start
rifaximin

Education on
lactulose use

Breakthrough HE
on rifaximin
monotherapy

Add
lactulose

Resolution

Continue
lactulose + nonabsorbable
abx maintenance

Evaluate for PS shunt

if not previously
performed

Breakthrough HE
with inappropriate
lactulose use

Consider shunt
embolization for
MELD score <12

All patients who recover from

recurrent episodes of OHE
require maintenance therapy
with lactulose and/or rifaximin.
Drug choice will depend on initial
therapy patients were on at time
of breakthrough OHE

FIGURE 2. Management of recurrent episodes of hepatic encephalopathy (HE), grade 1 or 2. aRifaximin is not
Food and Drug Administration approved for overt HE (OHE). abx antibiotic; BCAA branched-chain amino
acid; LOLA L-ornithineeL-aspartate; MELD Model for End-Stage Liver Disease; PS portosystemic.
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MAYO CLINIC PROCEEDINGS

HE grade 3-4

Identify and treat precipitant

Start lactulose NG tube or enema

No improvement
(24 h)

Improvement
Continue lactulose
Add rifaximin for
maintenance of remission

Reevaluate diagnosis
and precipitant
Ensure adequate stooling
Diagnosis correct,
no other precipitants,
adequate stools

For dx uncertainty
consider:
Head CT
EEG

Add rifaximina (preferred)

or neomycin
No improvement

+ shunt

MELD score <12-15 evaluate

for large portosystemic shunt
No shunt

All patients who recover

from severe OHE should
receive maintenance
therapy with lactulose and/or
rifaximin unless otherwise
contraindicated

Shunt embolization

Add zinc
LOLA where available
BCAA
No improvement
MARS

FIGURE 3. Management of a severe episode of hepatic encephalopathy (HE), grade 3 or 4.aRifaximin is

not Food and Drug Administration approved for overt HE (OHE). BCAA branched-chain amino acid;
CT computed tomography; dx diagnostic; EEG electroencephalogram; LOLA L-ornithineeLaspartate; MARS Molecular Adsorbent Recirculating System; MELD Model for End-Stage Liver
Disease; NG nasogastric tube.

stool. We recommend down-titration or temporary interruption of lactulose administration in

that circumstance. Rifaximin should be administered with lactulose in patients with grade 3 or 4
HE. Those who are diagnosed as having OHE, in
whom precipitating factors have been sought
and addressed, and who do not respond to lactulose and nonabsorbable antibiotics should be
reevaluated to make sure that the diagnosis is accurate. If the diagnosis is in question, a head CT
scan and an EEG may be helpful to rule out the
possibility of a central nervous system bleeding
event or nonconvulsive status epilepticus,
respectively. If the diagnosis of OHE is accurate,
then the patients should be evaluated for a large
portosystemic shunt. A large shunt should be
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Mayo Clin Proc.

treated in the presence of refractory HE and relatively low MELD scores (<12-15). Most initial
medication nonresponders will not have a large
shunt and can be treated with BCAAs, zinc,
and, where available, LOLA. Last, for patients
not responsive to the aforementioned approach,
MARS should be considered. Patients recovering
from severe HE should be kept on a maintenance
program of lactulose and rifaximin.
DRIVING INSTRUCTIONS FOR PATIENTS
LEAVING THE HOSPITAL
Minimal HE is a risk factor for motor vehicle accidents (MVAs). Although the term CHE (which
encompasses MHE) has replaced the term MHE,
we will use the term MHE in this section as this

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MANAGEMENT OF HEPATIC ENCEPHALOPATHY

was the terminology used in the cited literature.

It is likely that a substantial percentage of patients hospitalized for an episode of HE and
who recover will have residual minimal encephalopathy after dismissal.52,53 Therefore, counseling at dismissal about the risks of driving is
important. Some literature has amassed to quantify the magnitude of risk for MVAs in patients
with MHE. Bajaj et al54 evaluated 167 cirrhotic
patients prospectively for 1 year and identied
18 MVAs through Department of Transportation records. Of those 18 MVAs, 16 (89%)
occurred in patients identied as having MHE
by the Inhibitory Control Test compared with
8 of 18 (44%) by standard psychometric tests.
Conversely, it is important to point out that
approximately 55% of patients who did not
have an MVA were identied as having MHE.
Another study assessed real-world driving ability in controls (n48), patients with cirrhosis
without encephalopathy (n10), patients with
MHE (n27), and patients with overt grade 1
HE (n14). Fitness to drive, as deemed by a
driving instructor, was 87% (control), 75%
(no HE), 48% (MHE), and 39% (grade 1
HE).55 An earlier on-road driving study found
a substantial reduction in car handling, adaptation, and cautiousness in patients with MHE
(n14) compared with controls or cirrhotic patients without MHE.56 The instructor had to
intervene on 5 of 14 patients with MHE to avert
an accident. In summary, some patients with
MHE have impaired driving skills, which can
translate into real-world risk of MVAs. Yet, we
do not have widely available and practical tools
to predict who is at risk.
What are the medicolegal ramications for
the provider? No states have specic legislation
that pertains to patients with HE. Only 6 states
have mandatory reporting laws requiring the
physician to report drivers with general medical
impairment: California, Delaware, Nevada, New
Jersey, Oregon, and Pennsylvania. Of the
remaining 44 states, 25 provide legal immunity
to physicians for reporting patients who have
medical impairments.57
We recommend that treating physicians
consider testing for MHE if they are in tertiary
care centers with access to these tests. Patients
found to have MHE should return to their
licensing agency for a road test. It has been suggested, based on positive driving simulator evidence, that patients who have MHE and have
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failed a driving test could be treated with rifaximin and repeat the driving test.58 However, this
strategy cannot be endorsed for all patients at
this time without more evidence. In a costeffectiveness analysis, using the Inhibitory Control Test to diagnose MHE and treatment with
lactulose to prevent MVAs would be cost saving.
Treatment with rifaximin would save costs in
this context only if the monthly cost was less
than $353.59
CONCLUSION
In summary, HE eventually occurs in up to 50%
of cirrhotic patients and heralds a poor prognosis.
Patients with episodic OHE are primarily cared
for in the hospital. Treatment of the hospitalized
patient with episodic OHE can be compartmentalized into induction treatment and maintenance
of remission. Lactulose remains the cornerstone
of treatment for induction and maintenance of
remission. There is now evidence to support the
use of rifaximin as adjunctive therapy for severe
OHE, but it is not yet FDA approved for this indication. Alternatively, neomycin can be used as
adjunctive therapy, but its adverse side effect prole makes it a less attractive choice. Percutaneous
embolization of large portosystemic shunts and
MARS therapy are emerging modalities with evidence to support their use for medically refractory
OHE. Most patients require maintenance medications when dismissed from the hospital, and patient/caregiver education about the role of those
medications and appropriate dose titration for lactulose is crucial. Rifaximin should be added to lactulose treatment for patients with recurrent OHE.
All patients and their families should be counseled
about the risks of MVAs. Mandatory state reporting laws should be followed. It is recommended
that these patients have a tness-to-drive evaluation in the outpatient setting.
Abbreviations and Acronyms: abx = antibiotic; BCAA =
branched-chain amino acids; CHE = covert hepatic encephalopathy; CT = computed tomography; dx = diagnostic;
EEG = electroencephalogram; FDA = Food and Drug
Administration; HE = hepatic encephalopathy; LOLA =
L-ornithineeL-aspartate; MARS = Molecular Adsorbent
Recirculating System; MELD = Model for End-Stage Liver
Disease; MHE = minimal hepatic encephalopathy; MVA =
motor vehicle accident; NG = nasogastric; OHE = overt
hepatic encephalopathy; RCT = randomized controlled trial;
SMT = standard medical treatment
Potential Competing Interests: Dr Kim served as an advisory board member for Salix Pharmaceuticals Inc, Raleigh,

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MAYO CLINIC PROCEEDINGS

NC, more than 12 months ago. Dr Leise has been a site

investigator for 2 Salix Pharmaceuticals Inc randomized
controlled trials.
Correspondence: Address to Michael D. Leise, MD, Mayo
Clinic, 200 First St SW, Rochester, MN 55901 (Leise.
Michael@mayo.edu).

REFERENCES
1. Bajaj JS, Cordoba J, Mullen KD, et al. Review article: the design
of clinical trials in hepatic encephalopathy: an International
Society for Hepatic Encephalopathy and Nitrogen Metabolism
(ISHEN) consensus statement. Aliment Pharmacol Ther. 2011;
33(7):739-747.
2. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K,
Blei AT. Hepatic encephalopathy: denition, nomenclature,
diagnosis, and quantication: nal report of the working party
at the 11th World Congresses of Gastroenterology, Vienna,
1998. Hepatology. 2002;35(3):716-721.
3. Bustamante J, Rimola A, Ventura PJ, et al. Prognostic signicance
of hepatic encephalopathy in patients with cirrhosis. J Hepatol.
1999;30(5):890-895.
4. Huang E, Esrailian E, Spiegel BM. The cost-effectiveness and
budget impact of competing therapies in hepatic encephalopathy: a decision analysis. Aliment Pharmacol Ther. 2007;26(8):
1147-1161.
5. Stewart CA, Malinchoc M, Kim WR, Kamath PS. Hepatic encephalopathy as a predictor of survival in patients with endstage liver disease. Liver Transpl. 2007;13(10):1366-1371.
6. Stepanova M, Mishra A, Venkatesan C, Younossi ZM. In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin
Gastroenterol Hepatol. 2012;10(9):1034-1041.e1.
7. Neff Guy W, Frederick RT. Assessing treatment patterns in patients with overt hepatic encephalopathy. Hepatology. 2012;
56(4):945A.
8. Mohammad RA, Regal RE, Alaniz C. Combination therapy for
the treatment and prevention of hepatic encephalopathy. Ann
Pharmacother. 2012;46(11):1559-1563.
9. Volk ML, Tocco RS, Bazick J, Rakoski MO, Lok AS. Hospital
readmissions among patients with decompensated cirrhosis.
Am J Gastroenterol. 2012;107(2):247-252.
10. Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol.
2001;96(7):1968-1976.
11. Bodil A-N, Gluud LL, Gluud C. Non-absorbably disaccharides
for hepatic encephalopathy: systematic review of randomised
trial. BMJ. 2004;328:1046.
12. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol
and lactulose in the treatment of acute portal-systemic encephalopathy: a controlled, double-blind clinical trial. Am J Digest Dis.
1978;23(5):398-406.
13. Strauss E, Tramote R, Silva EP, et al. Double-blind randomized
clinical trial comparing neomycin and placebo in the treatment
of exogenous hepatic encephalopathy. Hepatogastroenterology.
1992;39(6):542-545.
14. Cheong HC, Jeong TG, Cho YB, et al. Metronidazole-induced
encephalopathy in a patient with liver cirrhosis. Korean J Hepatol. 2011;17(2):157-160.
15. Kim KH, Choi JW, Lee JY, et al. Two cases of metronidazoleinduced encephalopathy [in Korean]. Korean J Gastroenterol.
2005;45(3):195-200.
16. Tarao K, Ikeda T, Hayashi K, et al. Successful use of vancomycin
hydrochloride in the treatment of lactulose resistant chronic
hepatic encephalopathy. Gut. 1990;31(6):702-706.
17. Uhl MD, Riely CA. Metronidazole in treating portosystemic
encephalopathy. Ann Intern Med. 1996;124(4):455.
18. Morgan MH, Read AE, Speller DC. Treatment of hepatic
encephalopathy with metronidazole. Gut. 1982;23(1):1-7.

252

Mayo Clin Proc.

19. Lee JH, Yoon JH, Kim BH, et al. Enterococcus: not an innocent
bystander in cirrhotic patients with spontaneous bacterial peritonitis. Eur J Clin Microbiol Infect Dis. 2009;28(1):21-26.
20. Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients
with medium to severe degree hepatic encephalopathy. Curr
Med Res Opin. 1993;13(2):109-118.
21. Williams R, James OF, Warnes TW, Morgan MY. Evaluation of
the efcacy and safety of rifaximin in the treatment of hepatic
encephalopathy: a double-blind, randomized, dose-nding
multi-centre study. Eur J Gastroenterol Hepatol. 2000;12(2):
203-208.
22. Paik YH, Lee KS, Han KH, et al. Comparison of rifaximin and
lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J. 2005;46(3):399-407.
23. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK.
A randomized, double-blind, controlled trial comparing rifaximin
plus lactulose with lactulose alone in treatment of overt hepatic
encephalopathy. Am J Gastroenterol. 2013;108(9):1458-1463.
24. Takuma Y, Nouso K, Makino Y, Hayashi M, Takahashi H. Clinical trial: oral zinc in hepatic encephalopathy. Aliment Pharmacol
Ther. 2010;32(9):1080-1090.
25. Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc supplementation and amino acid-nitrogen metabolism in patients with
advanced cirrhosis. Hepatology. 1996;23(5):1084-1092.
26. Festi D, Mazzella G, Orsini M, et al. Rifaximin in the treatment
of chronic hepatic en results of a multicenter study of efcacy
and safety. Current Therapeutic Research. 1993;54:598-609.
27. Massa P, Vallerino F, Dodero M. Treatment of hepatic enwith
rifaximin: Double-blind, double-dummy study versus lactulose.
Eur J Clin Res. 1993;4:7-18.
28. Mas A, Rods J, Sunyer L, et al. Comparison of rifaximin and
lactitol in the treatment of acute hepatic encephalopathy: results of a ran double-blind, double-dummy, controlled clinical
trial. J Hepatol. 2003;38:51-58.
29. Riggio O, Ariosto F, Merli M, et al. Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy:
results of a double-blind crossover trial. Dig Dis Sci. 1991;
36(9):1204-1208.
30. Bresci G, Parisi G, Banti S. Management of hepatic encephalopathy with oral zinc supplementation: a long-term treatment. Eur
J Med. 1993;2(7):414-416.
31. Reding P, Duchateau J, Bataille C. Oral zinc supplementation
improves hepatic encephalopathy: results of a randomised
controlled trial. Lancet. 1984;2(8401):493-495.
32. Kircheis G, Nilius R, Held C, et al. Therapeutic efcacy of
L-ornithine-L-aspartate infusions in patients with cirrhosis and
hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology. 1997;25(6):1351-1360.
33. Stauch S, Kircheis G, Adler G, et al. Oral L-ornithine-L-aspartate
therapy of chronic hepatic encephalopathy: results of a
placebo-controlled double-blind study. J Hepatol. 1998;28(5):
856-864.
34. Abid S, Jafri W, Mumtaz K, et al. Efcacy of L-ornithine-L-aspartate
as an adjuvant therapy in cirrhotic patients with hepatic encephalopathy. J Coll Physicians Surg Pak. 2011;21(11):666-671.
35. Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain
amino acids as pharmacological nutrients in chronic liver disease. Hepatology. 2011;54(3):1063-1070.
36. Muto Y, Sato S, Watanabe A, et al. Effects of oral branched-chain
amino acid granules on event-free survival in patients with liver
cirrhosis. Clin Gastroenterol Hepatol. 2005;3(7):705-713.
37. Marchesini G, Bianchi G, Merli M, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a
double-blind, randomized trial. Gastroenterology. 2003;124(7):
1792-1801.
38. Plauth M, Egberts EH, Hamster W, et al. Long-term treatment
of latent portosystemic encephalopathy with branched-chain
amino acids: a double-blind placebo-controlled crossover study.
J Hepatol. 1993;17(3):308-314.

February 2014;89(2):241-253

http://dx.doi.org/10.1016/j.mayocp.2013.11.009
www.mayoclinicproceedings.org

MANAGEMENT OF HEPATIC ENCEPHALOPATHY

39. Les I, Doval E, Garcia-Martinez R, et al. Effects of branchedchain amino acids supplementation in patients with cirrhosis
and a previous episode of hepatic encephalopathy: a randomized study. Am J Gastroenterol. 2011;106(6):1081-1088.
40. Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet
for episodic hepatic encephalopathy: results of a randomized
study. J Hepatol. 2004;41(1):38-43.
41. Plauth M, Cabre E, Campillo B, et al. ESPEN Guidelines on
Parenteral Nutrition: hepatology. Clin Nutr. 2009;28(4):
436-444.
42. Laleman W, Simon-Talero M, Maleux G, et al. Embolization of
large spontaneous portosystemic shunts for refractory hepatic
encephalopathy: a multicenter survey on safety and efcacy.
Hepatology. 2013;57(6):2448-2457.
43. Singh S, Kamath PS, Andrews JC, Leise MD. Embolization of
spontaneous portosystemic shunts for management of severe
persistent hepatic encephalopathy [published online June 14,
2013]. Hepatology. http://dx.doi.org/10.1002/hep.26575.
44. Banares R, Nevens F, Larsen FS, et al. Extracorporeal albumin
dialysis with the molecular adsorbent recirculating system in
acute-on-chronic liver failure: the RELIEF trial. Hepatology.
2013;57(3):1153-1162.
45. Hassanein TI, Tofteng F, Brown RS Jr, et al. Randomized
controlled study of extracorporeal albumin dialysis for hepatic
encephalopathy in advanced cirrhosis. Hepatology. 2007;46(6):
1853-1862.
46. Pares A, Deulofeu R, Cisneros L, et al. Albumin dialysis improves hepatic encephalopathy and decreases circulating
phenolic aromatic amino acids in patients with alcoholic hepatitis and severe liver failure. Crit Care. 2009;13(1):R8.
47. Ruggero MA, Argento AC, Heavner MS, Topal JE. Molecular
Adsorbent Recirculating System (MARS) removal of piperacillin/tazobactam in a patient with acetaminophen-induced
acute liver failure. Transpl Infect Dis. 2013;15(2):214-218.
48. Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized

Mayo Clin Proc. n February 2014;89(2):241-253

www.mayoclinicproceedings.org

49.

50.
51.

52.

53.

54.

55.

56.

57.

58.

59.

controlled trial of lactulose versus placebo. Gastroenterology.

2009;137(3):885-891:891.e1.
Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no
therapy. Am J Gastroenterol. 2012;107(7):1043-1050.
Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081.
Riggio O, Efrati C, Catalano C, et al. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology. 2005;42(5):1158-1165.
Bajaj JS, Schubert CM, Heuman DM, et al. Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology. 2010;138(7):2332-2340.
Riggio O, Ridola L, Pasquale C, et al. Evidence of persistent
cognitive impairment after resolution of overt hepatic encephalopathy. Clin Gastroenterol Hepatol. 2011;9(2):181-183.
Bajaj JS, Saeian K, Schubert CM, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality
beyond the driving test. Hepatology. 2009;50(4):1175-1183.
Kircheis G, Knoche A, Hilger N, et al. Hepatic encephalopathy
and tness to drive. Gastroenterology. 2009;137(5):17061715.e1-9.
Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs tness to drive. Hepatology. 2004;
39(3):739-745.
Cohen SM, Kim A, Metropulos M, Ahn J. Legal ramications for
physicians of patients who drive with hepatic encephalopathy.
Clin Gastroenterol Hepatol. 2011;9(2):156-160:quiz e117.
Prakash RK, Brown TA, Mullen KD. Minimal hepatic encephalopathy and driving: is the genie out of the bottle? Am J Gastroenterol. 2011;106(8):1415-1416.
Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM. Diagnosis and
treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: a cost-effectiveness analysis. Hepatology.
2012;55(4):1164-1171.

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