Download Review article: the current pharmacological therapies for hepatic

Alimentary Pharmacology & Therapeutics
Review article: the current pharmacological therapies for hepatic
encephalopathy
N. M. BASS
University of California, San Francisco, CA, USA
Correspondence to:
Dr N. M. Bass, UCSF Liver
Transplantation Service, School of
Medicine, University of California,
San Francisco, Box 0538, Rm 357-S,
San Francisco, CA 94143-0538, USA.
E-mail: [email protected]
Publication data
Accepted 29 November 2006
NMB has received honoraria as a
speaker and consultant for Salix
Pharmaceuticals, Inc.
ABSTRACT
Effective treatment options for hepatic encephalopathy are limited.
Based on the principle that intestinal-derived ammonia contributes to
the pathogenesis of hepatic encephalopathy, current therapeutic approaches are directed at reducing bacterial production of ammonia and
enhancing its elimination.
Non-absorbable disaccharides are first-line therapy for hepatic encephalopathy, but published clinical studies evaluating their safety and
efficacy are limited. Alternative therapies such as benzodiazepine receptor antagonists, branched-chain amino acids, and L-ornithine-Laspartate also have limited clinical data supporting their use.
Studies of antibiotics indicate that they are effective in the treatment of
hepatic encephalopathy, but adverse effects and concerns about longterm safety have limited the widespread use of most.
Rifaximin is a minimally absorbed antibiotic that concentrates in the
gastrointestinal tract and is excreted mostly unchanged in faeces. It has
been studied extensively in the treatment of hepatic encephalopathy
and appears to confer therapeutic benefits greater than those of placebo
and non-absorbable disaccharides and at least comparable with those of
systemic antibiotics. Rifaximin was also well tolerated in patients with
hepatic encephalopathy and is not associated with clinical drug interactions or clinically relevant bacterial antibiotic resistance.
In conclusion, non-absorbed antibiotics such as rifaximin offer a
favourable benefit–risk ratio in the treatment of hepatic encephalopathy
and may help to improve patient outcomes.
Aliment Pharmacol Ther 25 (Suppl. 1), 23–31
ª 2006 The Author
Journal compilation ª 2006 Blackwell Publishing Ltd
doi:10.1111/j.1746-6342.2006.03218.x
23
24 N . M . B A S S
INTRODUCTION
Hepatic encephalopathy (HE) is a neuropsychiatric disorder resulting from complications of liver disease that
can significantly impact quality of life. Clinical manifestations of HE range from subtle neuropathic abnormalities to coma and include disturbances in
consciousness, altered neuromuscular activity and
electroencephalogram (EEG) abnormalities.1, 2 The
pathogenesis of HE is thought to involve the accumulation of ammonia because of poor hepatic function
and portosystemic shunting.
Diagnosis of HE is based on clinical presentation in
patients with chronic liver disease, and severity of HE
can be classified as stage 0–4, depending on symptoms
(Table 1).1, 2 The portosystemic encephalopathy (PSE)
index, often measured in studies of HE, is calculated
from clinical HE parameters including mental state, asterixis, time to completion of number connection test,
EEG mean cycle frequency and blood ammonia concentration.3 Diagnosis of subclinical HE is more difficult than that of overt HE, and up to 80% of patients
with cirrhosis present with subclinical disease.1, 2
The prevalence of chronic liver disease in the United
States is c. 5.5 million cases.4 The true incidence and
prevalence of HE is difficult to establish given the
considerable differences in severity of overt disease
and the difficulty in diagnosing subclinical disease.5
Clinical prognosis after developing overt HE is poor,
with 1-year survival estimated at 42% and 3-year
survival estimated at 23%.6 However, most clinical
manifestations of moderate disease are reversible with
effective treatment.7
Therapeutic approaches in HE are directed at reducing bacterial production of ammonia and/or enhancing its elimination. The objective of this review is to
evaluate current pharmacologic therapies available for
the management of HE.
NON-ABSORBABLE DISACCHARIDES
Non-absorbable disaccharides are recommended as
first-line pharmacotherapy in current guidelines.2, 7
Disaccharides remain undigested until they reach the
colon, where they function to inhibit bacterial ammonia production and trap ammonia as non-diffusable
ammonium in the intestinal lumen.1, 7
Published studies evaluating the safety and efficacy
of non-absorbable disaccharides are limited. Two trials
of lactulose vs. neomycin determined that the treatments were comparable in efficacy.8, 9 A small metaanalysis determined that lactulose and lactitol were
equally effective in the treatment of HE.10 Approval of
lactulose for the treatment of HE in the United States
was based on a small, open-label clinical study.11
A meta-analysis of 22 randomized trials highlighted
the lack of data supporting the efficacy of nonabsorbable disaccharides.12 Primary endpoints included the number of patients without improvement in
HE and all-cause mortality in 10 clinical studies of
non-absorbable disaccharides vs. placebo or no intervention and 12 clinical studies of non-absorbable
Table 1. Neuropsychiatric staging of hepatic encephalopathy
Stage
Consciousness
Subclinical
Stage 1
Normal
Insomnia, disturbed
sleep pattern
Stage 2
Lethargy
Stage 3
Somnolence, but
patient may be
arousable
Coma,
unresponsive
Stage 4
Personality
and intellect
Ammonia
level
EEG findings
Impaired psychomotor testing
Tremor, constructional apraxia,
uncoordination
Normal
›
Normal
Slightly abnormal
Slowing of triphasic
waves
Slowing of triphasic
waves
Neurologic
Normal
Confusion,
forgetfulness,
agitation
Disorientation,
bizarre behaviour
Disorientation,
aggression
Asterixis, ataxia
››
Asterixis, hyperactive reflexes,
positive Babinski’s reflex
›››
Coma
Decerebrate posture
››››
Slow waves (2–3 cycles
per second)
EEG, electroencephalogram.
Reproduced with permission from Abou-Assi et al.1
ª 2006 The Author, Aliment Pharmacol Ther 25 (Suppl. 1), 23–31
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REVIEW ARTICLE: CURRENT THERAPIES FOR HEPATIC ENCEPHALOPATHY 25
disaccharides vs. antibiotics (including rifaximin,
neomycin, ribostamycin and vancomycin). Nonabsorbable disaccharides compared with no intervention or placebo did not significantly affect mortality
or significantly reduce the risk of no clinical
improvement of HE in a small number of high-quality
clinical studies (i.e. adequate randomization and
blinding). Non-absorbable disaccharides were inferior
to antibiotics in reducing risk of no clinical improvement and in lowering blood ammonia concentrations
but did not differ from antibiotics with respect to
having no impact on all-cause mortality. The authors
concluded that current evidence is insufficient to support or refute the use of non-absorbable disaccharides
for treatment of HE.
ANTIBIOTICS
The goal of antibiotic therapy in the treatment of HE
is to reduce the mass of enteric bacteria that produce
ammonia.7 Although the efficacy of systemic antibiotics has been demonstrated, adverse effects and concerns about safety have generally limited their
widespread use.2
Neomycin and metronidazole
Antibiotics with activity against urease-producing bacteria (e.g. neomycin, metronidazole) are effective in
reducing intestinal ammonia production. However, the
safety and efficacy of these antibiotics in treatment of
HE have not been adequately demonstrated. One randomized, controlled trial evaluated the efficacy of neomycin vs. placebo in patients with acute HE and
demonstrated no significant difference in time to
improvement of disease symptoms with neomycin 6 g/
day (n ¼ 20) vs. placebo (n ¼ 19).13 Two additional
studies found no significant difference between lactulose and neomycin, concluding that both therapies are
effective for HE.8, 9 However, neither study had adequate design to statistically determine equivalence. No
additional benefit vs. placebo was observed in study of
neomycin-lactulose combination therapy (N ¼ 80),
and the therapy was not well tolerated.14 Additionally,
one small trial compared the efficacy of metronidazole
with neomycin in 18 patients with mild, moderate, or
severe HE.15 Both treatments improved mental state,
asterixis and EEG measurements although neither antibiotic significantly improved mean blood ammonia
levels.15
ª 2006 The Author, Aliment Pharmacol Ther 25 (Suppl. 1), 23–31
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Systemic absorption of antibiotics used to treat HE
may result in serious adverse effects. Neomycin can
directly impact the small-bowel mucosa resulting in
intestinal malabsorption with doses as low as 3 g/
day.2, 16, 17 Neomycin is poorly absorbed following
oral administration, but cumulative systemic absorption following prolonged use can cause hearing loss
and renal failure.2 Metronidazole is also associated
with serious adverse effects including peripheral neuropathy,7 and its elimination by hepatic oxidation may
increase risk of toxicity in patients with chronic liver
disease.18
Rifaximin
Rifaximin is an oral, minimally absorbed antibiotic
(<0.4%) with broad-spectrum in vitro activity against
enteric bacteria.19–22 The tolerability profile of rifaximin is comparable to placebo,22 and no clinical drug
interactions have been reported.21 Because of the lack
of systemic accumulation with rifaximin,20 no dosing
adjustments are required in patients with hepatic
insufficiency.
Rifaximin was approved in the United States in
2004 for non-dysenteric diarrhoea caused by Escherichia coli and is licensed in Europe, Latin America, Asia
and Africa for several indications, including HE. Multiple published studies have evaluated the safety and
efficacy of rifaximin in the treatment of HE3, 23–39 and
representative data are discussed below.
A prospective study was conducted to explore
appropriate doses of rifaximin for the treatment of
HE.3 Patients with stage 1–3 HE received rifaximin
600 mg/day (n ¼ 18), 1200 mg/day (n ¼ 19), or
2400 mg/day (n ¼ 17) for 7 days. A significant reduction in the mean PSE index from baseline was
observed with rifaximin 1200 or 2400 mg/day, but not
600 mg/day (Table 2). These results suggest that rifaximin ‡1200 mg/day is more beneficial than 600 mg/
day in the treatment of HE. The studies included in
this review have all employed a daily dose of
1200 mg.
Rifaximin efficacy in HE has been assessed in a
randomized, double-blind study.3 Patients with HE,
cirrhosis and lactulose or lactitol intolerance received
rifaximin 1200 mg/day (n ¼ 48) or placebo (n ¼ 45)
for 14 days. Rifaximin significantly improved asterixis
compared with placebo (P < 0.01) but did not effectively improve mental state, the primary endpoint of
the study. The lack of statistical difference between
26 N . M . B A S S
PSE index (%)
Rifaximin
(mg/day)
n*
Change from baseline,
mean s.d. (range)
95% CI
600
1200
2400
14
16
16
)6.4 13.7 ()25.0, 25.0)
)10.3 13.7 ()28.6, 32.1)
)10.7 14.9 ()39.3, 14.3)
)14.0, 1.2
)17.4, )3.1
)17.8, )3.6
CI, confidence interval; PSE, portosystemic encephalopathy;
s.d., standard deviation.
*Signifies number of patients for whom data were available.
Adapted from Williams et al.24
rifaximin and placebo may have resulted from the fact
that the majority of patients had mild disease at baseline. In this study, the tolerability profile of rifaximin
was comparable with that of placebo3 and supported
tolerability findings from studies in patients with travellers’ diarrhoea.22 This favourable safety and tolerability profile differentiates rifaximin from other
antibiotics and non-absorbable disaccharides in treatment of HE.
and stage 1–3 HE.30 After 21 days of treatment, neuropsychiatric symptoms and blood ammonia concentrations were significantly reduced vs. baseline in both
groups; however, reduction in blood ammonia concentrations was significantly greater with rifaximin treatment vs. neomycin (Figure 1). Although no patient
administered rifaximin experienced adverse events,
26% of patients administered neomycin showed
increases in blood urea nitrogen and plasma creatinine
levels, and 33% reported nausea, abdominal pain and
vomiting.
In another randomized trial, patients with cirrhosis
and chronic stage 1–2 HE received rifaximin 1200 mg/
day (n ¼ 25) or neomycin 3 g/day (n ¼ 24) for 14
consecutive days per month for 6 months.32 Both rifaximin and neomycin significantly reduced mean
blood ammonia concentrations and reduced neuropsychiatric symptoms at end of treatment (Figure 2).32
250
Ammonia (µg/dL)
Table 2. Mean change from baseline in PSE index in
patients with hepatic encephalopathy treated with rifaximin 600, 1200 or 2400 mg/day
Rifaximin 1200 mg/day (n = 25)
Neomycin 3 g/day (n = 24)
200
150
100
*
*
50
Comparison with other antibiotics
0
Rifaximin has been compared with other antibiotics
(e.g. neomycin, paromomycin) in the treatment of
HE.23, 30–35 In a randomized, double-blind study, rifaximin 1200 mg/day (n ¼ 15) was compared with neomycin 3 g/day (n ¼ 15) in 30 patients with cirrhosis
Figure 2. Blood ammonia concentrations in patients with
hepatic encephalopathy treated with rifaximin 1200 mg/
day or neomycin 3 g/day. *P < 0.001 vs. baseline. Data
from Miglio et al.32
B
250
Rifaximin 1200 mg/day (n = 15)
250
200
Neomycin 3 g/day (n = 15)
200
150
†
100
*
50
0
Rifaximin 1200 mg/day (n = 15)
Neomycin 3 g/day (n = 15)
Ammonia (µg/dL)
Time (s)
A
Day 180
Day 0
150
*
100
*‡
50
0
Day 0
Day 21
Day 0
Day 21
Figure 1. (A) Number connection test performance and (B) blood ammonia concentrations in patients with hepatic
encephalopathy treated with rifaximin 1200 mg/day or neomycin 3 g/day. *P < 0.001 vs. baseline; P < 0.025 vs. baseline;
à
P < 0.005 vs. neomycin. Data from Pedretti et al.30
ª 2006 The Author, Aliment Pharmacol Ther 25 (Suppl. 1), 23–31
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REVIEW ARTICLE: CURRENT THERAPIES FOR HEPATIC ENCEPHALOPATHY 27
Comparison with non-absorbable disaccharides
Rifaximin has also been compared with non-absorbable
disaccharides.23, 26–29, 37, 39 Overall, both rifaximin and
disaccharides reduced blood ammonia levels and
improved neuropsychiatric symptoms. However, rifaximin was associated with earlier, more marked
improvements and was better tolerated than the nonabsorbable disaccharides.
Rifaximin 1200 mg/day (n ¼ 50) was compared with
lactitol 60 g/day (n ¼ 53) administered for 5–10 days
in patients with HE stage 1 (30%), 2 (49%), or 3
(21%).26 Both treatment groups exhibited improvement
in neurologic parameters and reductions in blood
ammonia concentrations. However, the overall PSE
index improved more with rifaximin than with lactitol
(Table 3), a finding attributed to greater improvement
in EEG results and blood ammonia levels with rifaximin. Comparable percentages of patients exhibited
clinical improvement at the end of treatment (82% for
rifaximin and 80% for lactitol).
In patients with stage 1, 2 or 3 HE, rifaximin
1200 mg/day (n ¼ 20) significantly improved blood
ammonia concentrations, EEG results, overall HE
score, asterixis score and mental state compared with
lactulose 60 g/day (n ¼ 20) (P < 0.05 for each assessment).28 No drug-related adverse events were reported
with rifaximin, whereas GI effects, including nausea
(n ¼ 5), flatulence and diarrhoea (n ¼ 13), and
abdominal cramps (n ¼ 3), were reported with lactulose.
Rifaximin also compared favourably with lactulose in
a study of patients with mild HE.29 Patients received rifaximin 1200 mg/day (n ¼ 20) or lactulose 120 mg/day
(n ¼ 20) for the first 2 weeks of each month for
90 days. Both treatments improved mental state vs.
baseline, and improvements were significantly greater
with rifaximin therapy than with lactulose therapy
after 60 and 90 days of treatment (P < 0.05 and
P < 0.02, respectively). Reductions in PSE index were
significantly greater with rifaximin vs. lactulose at 15,
30, 60 and 90 days (P < 0.05). No drug-related adverse
effects were reported with rifaximin, whereas GI
effects, including abdominal pain (n ¼ 10) and nausea
(n ¼ 5), were reported with lactulose.
In another study, patients with cirrhosis and HE
(n ¼ 58) received rifaximin 1200 mg/day or lactulose
30 g/day for 15 days.27 Study endpoints included
improvement in mental status, asterixis, Reitan number connection test, EEG, and blood ammonia levels
and were assessed at baseline and days 3, 6, 9, 12 and
15. Compared with lactulose, rifaximin significantly
improved all clinical parameters at various time points
(P < 0.05 for each significant time point), excluding
the Reitan test and asterixis. Rifaximin exhibited a
more favourable safety profile than lactulose with no
reports of diarrhoea, dyspepsia, or anorexia.
Cost effectiveness of treatment
One single-centre, retrospective chart review compared
the frequency of hospitalizations and related outcomes
in patients with HE treated with lactulose 60 cc/day
for ‡6 months followed by treatment with rifaximin
1200 mg/day for ‡6 months.40 Rifaximin significantly
lowered the mean number of reported hospitalizations
(0.5) compared with lactulose (1.6) (P < 0.001). In
addition, mean time spent hospitalized was
Table 3. Improvement in
hepatic encephalopathy
parameters in patients treated
with rifaximin 1200 mg/day
or lactitol 60 g/day
Blood ammonia (g/dL)
Mean PSE index
Mean improvement in HE (%)
Rifaximin
1200 mg/day
(n ¼ 50)
Lactitol
60 g/day
(n ¼ 53)
Baseline
End
Baseline
End
P-value*
121
0.61
–
70
0.14
70
124
0.55
–
109
0.21
62
0.008
0.01
0.008
HE, hepatic encephalopathy; PSE, portosystemic encephalopathy.
* Rifaximin vs. lactitol at end of treatment.
Including number connection test.
Data from Mas et al.26
ª 2006 The Author, Aliment Pharmacol Ther 25 (Suppl. 1), 23–31
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28 N . M . B A S S
significantly lower during rifaximin treatment
(0.4 weeks) vs. lactulose (1.8 weeks) (P < 0.001). These
findings translated into hospitalization charges four
times lower with rifaximin ($14 222 per day) than lactulose ($56 635 per day) (charges calculated in 2005
dollars).40
In contrast, another study employed decision analysis with Markov modelling to determine the cost
effectiveness of six treatment strategies (including no
treatment, lactulose, lactitol, neomycin, rifaximin and
rifaximin salvage in patients with intolerance or no
response to lactulose) in patients with subclinical to
stage 2 HE.41 Using discounted cost per life years
gained as the primary outcome, the authors
determined that rifaximin was not cost effective as
first-line HE therapy. However, they concluded that
rifaximin salvage therapy in patients failing lactulose
was a highly cost-effective treatment option in mild to
moderate HE.41
In summary, multiple clinical studies have demonstrated rifaximin is at least comparable with nonabsorbable disaccharides in treatment of HE, is more
effective in lowering blood ammonia concentrations
and demonstrates a favourable tolerability profile.
However, these results should be interpreted in the
context of the limitations imposed by the small
sample sizes and unblinded design of many of the
studies.
OTHER THERAPIES
Sodium benzoate
Sodium benzoate reduces serum ammonia levels by
increasing ammonia excretion in urine;1 however, limited data support the benefits of sodium benzoate therapy for HE. One prospective study compared the
efficacy of sodium benzoate (n ¼ 38) with lactulose
(n ¼ 36) in patients with cirrhosis or surgical portosystemic anastomosis who presented with an HE
exacerbation.42 Sodium benzoate improved symptoms
of HE in 80% of patients compared with 81% receiving lactulose (20%). A similar incidence of adverse
events was observed between the two groups.42
Branched-chain amino acids
A primary function of the liver is to regulate amino
acid supply to peripheral tissues. The balance of physiologic amino acid concentrations is altered in patients
with liver disease with an increased ratio of aromatic
to branch-chain amino acids.43, 44 It has been suggested that restoring the appropriate balance of amino
acid levels might benefit HE patients.43 Anecdotal
reports have provided some support for this notion;45
however, results from controlled studies indicate there
is no consensus concerning the benefits of branchedchain amino acid (BCAA) therapy in HE.43, 46–48 One
study compared BCAA therapy with dietary protein
supplementation in patients with cirrhosis.46 Oral
BCAA supplements (n ¼ 17) and dietary protein
(n ¼ 20) were equally effective in restoring the nitrogen balance from negative to positive in all patients.
A meta-analysis reviewed clinical trials evaluating the
efficacy of BCAA therapy in patients with cirrhosis
and acute HE.47 Although pooled analysis of five clinical studies demonstrated significant mental recovery
from high-grade HE in patients treated with BCAAs,
two studies reported an increased mortality risk. A
more recent analysis reviewed controlled BCAA studies
for the treatment of chronic HE.48 Only two trials
could be evaluated, and authors concluded that large,
multicentre studies are needed to confirm the use of
BCAA therapy in HE.
Dopamine agonists
Altered dopaminergic transmission has also been
implicated in HE pathogenesis.2 However, there is a
paucity of data on the benefit of dopaminergic agonists in HE therapy. One randomized study compared
the efficacy of the dopamine agonist bromocriptine vs.
placebo in seven patients with cirrhosis and chronic
PSE.49 In this small study, bromocriptine was not
superior to placebo, and three patients experienced
constipation during treatment.
Benzodiazepine receptor antagonists
Benzodiazepines exert depressant effects on the central
nervous system by binding to the c-aminobutyric acid
(GABA)–benzodiazepine receptor complex.7 It has been
suggested that ‘endogenous benzodiazepines’ may
cause neuroinhibitory effects in patients with HE.2
Antagonism of this effect with the benzodiazepine
receptor antagonist flumazenil has been evaluated.
Intravenous flumazenil (n ¼ 265) improved neurologic
scores in 18% of patients with stage 3 HE and 15% of
patients with stage 4 HE, compared with 4% and 3%
of patients, respectively, treated with placebo
ª 2006 The Author, Aliment Pharmacol Ther 25 (Suppl. 1), 23–31
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REVIEW ARTICLE: CURRENT THERAPIES FOR HEPATIC ENCEPHALOPATHY 29
(n ¼ 262).50 Flumazenil also improved EEG recordings
vs. placebo. The authors concluded that flumazenil is
beneficial only in patients with cirrhosis and severe
HE;50 further studies are necessary to determine the
benefits of flumazenil in patients with subclinical,
mild, or moderate HE.
Other therapies
L-ornithine-L-aspartate
lowers serum ammonia levels
by providing substrates for the intracellular metabolic
conversion of ammonia to urea and glutamine.1, 2
Results from controlled trials suggest that ornithineaspartate reduces ammonia levels and provides
therapeutic benefits in patients with chronic mild to
moderate HE.51, 52 One study compared ornithineaspartate 20 g/day for 7 days with placebo in 126
patients with cirrhosis, hyperammonaemia (>50 lmol/L)
and chronic HE.51 Ornithine-aspartate significantly
improved venous ammonia concentration (P < 0.01),
mental status (P < 0.001) and PSE index (P < 0.01).
Adverse events consisted of mild GI disturbances and
were reported in 5% of patients administered
ornithine-aspartate. A second study evaluated the efficacy of oral ornithine-aspartate 18 g/day for 14 days
in 66 patients with cirrhosis, hyperammonaemia, and
stable, chronic HE.52 Ornithine-aspartate significantly
improved blood ammonia concentrations, mental state
grade and PSE index compared with placebo (P < 0.05
for each comparison), and no adverse events were
reported. These findings point to L-ornithine-L-aspartate as a promising HE treatment that deserves further
evaluation.
Levocarnitine has been suggested to lower blood
ammonia levels by enhancing metabolic energy production.1, 53 In 150 patients with mild or moderate HE,
levocarnitine significantly reduced serum ammonia
levels and improved mental status compared with placebo (P < 0.05).54 However, in an earlier clinical study,
following rectal ammonium administration in patients
with cirrhosis, levocarnitine provided no significant
protection against increases in ammonia levels compared with placebo.55
One controlled study evaluated treatment acarbose
in 107 patients with mild or moderate HE.56 Acarbose
150–300 mg/day significantly decreased blood ammonia levels and improved number connection test scores
vs. placebo (P < 0.01). However, acarbose was associated with adverse events including abdominal bloating/pain, flatulence and increased frequency of bowel
ª 2006 The Author, Aliment Pharmacol Ther 25 (Suppl. 1), 23–31
Journal compilation ª 2006 Blackwell Publishing Ltd
movements. The mechanism whereby acarbose
improves clinical manifestations of HE is unknown,
and its use as a therapeutic agent requires further
study.
CONCLUSIONS
Hepatic encephalopathy is a complex disease with
clinical manifestations ranging from subtle neuropathic abnormalities to coma. Limited treatment options
are available for HE patients, underscoring the need
for safe, well-tolerated therapies with documented
efficacy. Based on the principle that accumulation of
unmetabolized ammonia contributes to HE pathogenesis, therapeutic approaches are targeted at reducing
bacterial production of ammonia and enhancing its
elimination.
Non-absorbable disaccharides are recommended as
first-line pharmacotherapy; however, published studies
evaluating their safety and efficacy are limited. Therapies such as sodium benzoate, dopamine agonists and
benzodiazepine receptor antagonists are alternative
options for treatment of HE, but studies confirming
the efficacy and safety of these agents are lacking.
Antibiotic therapy has shown considerable potential
for the treatment of HE, but concerns about safety following systemic absorption have generally limited
their use.
The non-absorbed antibiotic rifaximin has been
extensively studied, and available evidence indicates
that rifaximin provides greater therapeutic benefits
than placebo and non-absorbable disaccharides and
at least comparable benefits with other antibiotics in
the treatment of HE. The favourable tolerability profile of rifaximin clearly differentiates it from lactulose, the use of which is limited by unpredictable,
severe diarrhoea. Additionally, rifaximin lacks the
toxicity of aminoglycoside antibiotics such as neomycin, which can cause hearing loss and renal
injury.
The clinical studies reviewed herein should be considered in the context of the challenges in conducting
clinical studies in HE – a therapeutic area characterized by lack of validated measurements for assessing
clinical symptoms, and a very ill patient population
with multiple comorbidities and medication regimens.
Thus, in addition to the need for effective, welltolerated therapies, further study is required to determine the optimal method for assessing the benefits of
treatment in patients with HE.
30 N . M . B A S S
ACKNOWLEDGEMENT
GUARANTOR OF SUBMISSION
Grant/research support (Salix Pharmaceuticals, Inc.).
N. M. Bass, MD.
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