222 Gastroenterology & Hepatology Volume 7, Issue 4 April 2011
Current Concepts in the
Pathophysiology and Management
of Hepatic Encephalopathy
R. Todd Frederick, MD
Dr. Frederick is Director of Quality and
Clinical Protocols for the Hepatology and
Liver Transplant Program at California
Pacific Medical Center in San Francisco,
Address correspondence to:
Dr. R. Todd Frederick
2340 Clay Street, 3rd floor
San Francisco, CA 94115;
Hepatic encephalopathy, urea cycle, glutaminase,
ammonia, cerebral edema
Abstract: Hepatic encephalopathy (HE) represents a broad contin-
uum of neuropsychological dysfunction in patients with acute or
chronic liver disease and/or portosystemic shunting of blood flow.
The pathophysiology of this disease is quite complex, as it involves
overproduction and reduced metabolism of various neurotoxins,
particularly ammonia. Recent hypotheses implicate low-grade cere-
bral edema as a final common pathway for the pathophysiology of HE.
Management of this condition is multifaceted and requires several
steps: elimination of precipitating factors; removal of toxins, both by
reducing them at their source and by augmenting scavenging path-
ways; modulation of resident fecal flora; proper nutritional support;
and downregulation of systemic and gut-derived inflammation.
3 broad groups: type A, which occurs in acute liver failure (ALF);
type B, which occurs in patients with bypass shunts; and the most
commonly recognized form, type C, which occurs in patients with
chronic liver disease.1 Several neurologic domains are affected by
HE, including consciousness, personality, emotional status, motor
function, memory, and cognition. This paper will focus primarily
on the pathophysiology and management of type C HE. While
HE remains a diagnosis of exclusion, several interesting develop-
ments in grading and diagnostic testing have recently been sum-
Within the category of type C HE, individual cases may fol-
low different patterns. Many patients suffer from intermittent or
“episodic HE,” with episodes being either precipitated or spontane-
ous. Episodes of HE may be isolated events, but more commonly
they are recurrent, with patients having seemingly normal cognitive
functioning between episodes. Many patients remain on medica-
tions after resolution of these intermittent episodes, as both patients
epatic encephalopathy (HE) represents a broad contin-
uum of neuropsychological dysfunction. As defined by
the Working Party in 1998, HE can be categorized into
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PAT H O P H Y S I O L O G Y A N D M A N A G e M e N T O f H e PAT I c e N c e P H A L O PAT H Y
and clinicians are understandably reluctant to stop treat-
ment even in the absence of current symptomatology.
While HE is generally considered to be a reversible condi-
tion, some new data suggest that patients may not return
to previous levels of cognitive functioning after episodes
of overt HE.3 In addition to episodic HE, another presen-
tation of this condition is “chronic persistent HE,” which
is marked by an ongoing deficit in neuropsychological
functioning; these patients have good days and bad days
but do not achieve complete resolution of symptoms.
The severity of presentation also differs consider-
ably among patients. Some patients present with gross
disorientation, confusion, or frank coma, while other
patients may have fairly mild complaints that are often
only identified and brought to medical attention by the
patient’s spouse or other close companion. Clinicians
typically use the West Haven criteria to categorize these
patients, although scales with more precise determinants
are being studied.
Finally, some HE patients have no outward signs or
symptoms recognizable in a typical clinical setting, but
they nonetheless manifest deficiencies in several psycho-
metric tests. Formerly called “subclinical HE,” this pre-
sentation is now termed “minimal HE” (MHE). Many
clinicians feel that MHE falls within the same spectrum as
overt HE and can be considered to be grade 0 on the West
Haven or Conn scale. A significant proportion of patients
with cirrhosis are found to have MHE if properly tested;
even patients with intact synthetic function or Child-
Pugh class A disease are often impaired. The importance
of diagnosing MHE is becoming increasingly apparent,
since these patients experience decreased global function-
ing, increased falls, impaired driving ability, and reduced
quality of life.4-7
Patients presenting with clinically apparent HE
should be classified using grades 1–4 of the West Haven
criteria; these cases are collectively referred to as “overt
HE.” The need to recognize and treat the diverse and often
subtle presentations of HE is also becoming increasingly
evident, as proper diagnosis and management are critical
in order to improve quality of life, prevent recurrences
and hospitalizations, and potentially prolong lives. Given
the rising prevalence of advanced liver disease, clinicians
should not be surprised to learn that the clinical, social,
and financial impact of HE is also large and continuing
Pathophysiology of Hepatic Encephalopathy
Studies investigating the pathophysiology of HE have
historically focused on the accumulation of various tox-
ins in the bloodstream and brains of animal models and
patients with chronic liver disease and/or portal hyperten-
sion. Ammonia has been implicated as a key molecule in
the disease for over 50 years, due to its frequent elevation
in patients with cirrhosis and known cellular toxicity.9-11
However, evidence now suggests that ammonia is only
a single component in a multifactorial disease process
Excess ammonia in the body has long been thought to
arise from colonic bacterial species with urease enzyme
activity, predominantly gram-negative anaerobes, Entero
bacteriaceae, Proteus, and Clostridium species.12-14 The
bacterial urease can break down urea derived from the
bloodstream into ammonia and carbon dioxide. Early
investigations into the treatment of HE therefore focused
on incapacitating the bacterial urease enzyme via immune-
mediated mechanisms such as vaccination.15
While the intestinal flora still appear to be a significant
source of ammonia, evidence from animal models of HE
shows that bacteria are not required for the development
of hyperammonemia, suggesting that alternative sources
also play a role in ammonia production.16,17 Research has
shown that enterocytes within the small bowel (and, to a
lesser extent, in the colon) also generate a large amount
of ammonia via intestinal glutaminase as they metabolize
their main energy source, glutamine, into glutamate and
ammonia.18 This endogenous source of ammonia may
even eclipse the production of ammonia by fecal flora.19
Neomycin, a poorly absorbed antibiotic used in the treat-
ment of HE, appears to also have some intrinsic effect
on the activity of intestinal glutaminase and may reduce
ammonia by multiple mechanisms.20
Lending further support to the importance of intes-
tinal glutaminase in the pathophysiology of HE, a group
of Spanish investigators previously found that the gene
encoding for glutaminase was upregulated in patients
with cirrhosis, particularly those with MHE.21 The same
investigators more recently demonstrated a correlation
between specific genetic variations in the promoter region
of this gene that lead to enhanced glutaminase activity and
an increased risk of developing overt HE in patients with
cirrhosis.22 Additionally, evidence suggests an increase in
the expression of intestinal glutaminase in the enterocytes
of rats following insertion of a portacaval shunt, which
may explain some of the increased risk of HE seen follow-
ing this procedure.23
Once ammonia is generated by enterocytes and bac-
teria in the colon, it then travels via the splanchnic venous
system to the liver for detoxification, which occurs largely
via the urea cycle within zone 1 hepatocytes, and, to a
lesser degree, via conversion to glutamine in zone 3 hepa-
tocytes.24 Hyperammonemia is thought to occur because
of a reduction in the metabolic capacity of the liver’s urea
cycle, compounded by the shunting of blood around
the hepatic sinusoids, either through extrahepatic porto-
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f r e D e r I c k
systemic collaterals, surgically created shunts (including
transhepatic intrahepatic portosystemic shunts [TIPS]),
or intrahepatic spontaneous shunts. In fact, excessive
spontaneous shunting is often recognized in patients with
severe persistent or recurrent spontaneous HE.25
Renal Ammonia Flux
While the liver is primarily responsible for metabolism
of ammonia and the gut is primarily responsible for
generation of ammonia, these organs are not the only
ones involved in these processes. The renal contribution
to ammonia flux, which includes both excretion and
production, also needs to be carefully considered and
is largely driven by acid-base status. In terms of excre-
tion, the kidneys can remove a significant amount of
ammonia in the urine, either as ammonium ion (NH4
or in the form of urea. The kidneys can also generate
ammonia by metabolizing glutamine via glutaminase to
ammonia, bicarbonate, and glutamate. This ammonia-
genesis primarily serves a role in acid-base homeostasis,
since bicarbonate is also produced during the reaction;
ammoniagenesis thus serves to buffer systemic acidosis
as well as release hydrogen ions into the urine in the
form of NH4
the urine or returned to the circulation via the renal vein
depends upon several factors, predominantly pH. Under
physiologic conditions, approximately 30–50% of renal
ammonia is released into the urine, while the remainder
is returned to the circulation via the renal vein. However,
during periods of acidosis, the kidneys can increase the
amount of NH4
In contrast, alkalosis causes a significant decrease in
urinary loss of ammonia and can consequently contribute
to hyperammonemia.29 Alkalosis is also believed to trigger
HE events by decreasing the amount of gaseous ammonia
(NH3) that is protonated to NH4
approximately 2% of ammonia exists as gaseous NH3 and
98% is ammonium ion. Since neutral NH3 moves across
the blood-brain barrier more readily than charged NH4
decreased protonation of gaseous ammonia may increase
+. Whether renal ammonia is released into
+ released into the urine several fold.26-28
+; at physiologic pH,
Figure 1. Hypothesis of the multifactorial nature of hepatic encephalopathy. Various neurotoxins and NTs act independently
or perhaps synergistically to cause astrocyte swelling and subsequent astrocyte dysfunction. In addition, increased "GABA-ergic
tone" and depletion of Ach may contribute to neurologic dysfunction in patients with hepatic encephalopathy. A vicious cycle
may perpetuate the disease, as ROS trigger astrocyte swelling, and further swelling causes production of more ROS and RNS and
subsequent mitochondrial energy failure.
Ach=acetylcholine; AChE=acetylcholinesterase; BBB=blood brain barrier; GABA=gamma aminobutyric acid; Gln Synth=glutamine synthetase;
NMDA=N-metyhl-D-aspartic acid; NT=neurotransmitter; RNS=reactive nitrogen species; ROS=reactive oxygen species.
• Altered gene expression
• Protein tyrosine nitration
Symptoms of hepatic encephalopathy
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PAT H O P H Y S I O L O G Y A N D M A N A G e M e N T O f H e PAT I c e N c e P H A L O PAT H Y
passage of ammonia across the blood-brain barrier and
exacerbate HE in the setting of alkalosis. However, stud-
ies measuring the partial pressure of ammonia (gaseous
NH3 vs NH4
whether the partial pressure of ammonia accurately cor-
relates with HE stage.30,31
Another factor that may contribute to pathologic
hyperammonemia is the reduced excretion of ammonia
and urea that occurs in patients with reduced perfusion
and a decreased glomerular filtration rate. This situation
is common in cirrhotic patients with dehydration and
prerenal azotemia and often occurs secondary to excessive
diuresis or diarrhea. A simple saline infusion can amelio-
rate this hyperammonemia by allowing for enhanced renal
ammonia excretion.32 Some data suggest that the kidneys
can also provide net ammonia removal during periods of
hyperammonemia, such as those induced by portacaval
shunting in rats, in patients with cirrhosis, or in healthy
controls with induced hyperammonemia.33-35 In the set-
ting of either simulated or clinical gastrointestinal bleed-
ing, in contrast, ammoniagenesis by the kidneys increases
up to 6-fold and seems to account for the majority of the
hyperammonemia seen in this setting.36
Finally, the impact of hypokalemia in exacerbat-
ing HE is modulated by the kidneys. As less potassium
reaches the collecting tubules, more hydrogen ions
are moved into the cells, leading to a state of relative
intracellular acidosis. The kidneys then generate more
ammonia and bicarbonate from glutamine in an effort
to balance the acid-base status of the patient. Through
these complex mechanisms of acid-base homeostasis, the
kidneys have the capacity to both improve and exacer-
bate the ammonia balance.
+) have shown conflicting results in terms of
Ammonia Flux in Muscle
Another organ that is critical in regulating ammonia
flux is the skeletal musculature. Skeletal myocytes pro-
vide ammonia metabolism by incorporating ammonia
into glutamine via glutamine synthetase. Although the
metabolic activity of glutamine synthetase in muscle
is relatively low, the extensive muscle mass throughout
the body gives skeletal muscle a significant capacity for
ammonia metabolism. This glutamine production and
ammonia removal may surpass that of the failing liver,
but this process does not appear to lower the total burden
of ammonia in the body, since the glutamine produced by
myocytes is recirculated, and ammonia is regenerated at
other sites via glutaminase.19 Glutamine therefore appears
to be a temporary means of detoxifying ammonia, but it
does little in terms of ammonia excretion. Consequently,
controversy remains as to whether muscle wasting and
cachexia can lead to worsening of HE simply by reducing
the body’s ability to metabolize ammonia. More likely,
catabolism itself presents the larger problem, as it releases
excessive glutamine (and other amino acids) from muscle
into the circulation, which leads to subsequent ammonia
production via kidney and gut glutaminases.
While ammonia is strongly associated with HE, the exact
mechanisms of ammonia-induced neurologic dysfunction
remain unclear. The target of ammonia toxicity in the
brain appears to be the astrocyte, with development of
Alzheimer type II astrocytosis being a probable histopath-
ologic consequence of ammonia toxicity. One proposed
mechanism for ammonia-induced neurologic dysfunction
is cerebral edema. Glutamine, produced by the metabolism
of ammonia via glutamine synthetase within astrocytes,
acts as an intracellular osmole and attracts water into the
astrocytes, which leads to swelling and appears to induce
oxidative dysfunction of the mitochondria. While cerebral
edema is widely accepted as a major contributing cause of
HE in ALF, cerebral edema also appears to play a role in
type C HE, as evidenced by magnetic resonance spectro-
scopy, although edema is typically more prominent and
clinically compromising in the former group.37,38 The
low-grade edema seen in type C HE appears to induce
neurologic dysfunction directly rather than via the sub-
sequent rise in intracranial pressure seen in type A HE.
Occasionally, however, patients with an acute exacerba-
tion of chronic liver disease will also present with intra-
cranial hypertension in the setting of HE, which can lead
to fatal cerebral herniation.39,40
In another mechanism of astrocyte toxicity, ammo-
nia appears to directly trigger oxidative and nitrosative
stress in the astrocyte by increasing intracellular calcium,
leading to mitochondrial dysfunction and cellular energy
failure via opening of the mitochondrial transition pore.
Additional proposed mechanisms of neuronal dysfunc-
tion include ammonia-induced RNA oxidation, activa-
tion of mitogen-activated protein kinases, and activation
of nuclear factor-κB, all of which can lead to enhanced
cytokine activity and an inflammatory response, as well as
impaired intracellular signaling.41
In addition to ammonia, many other molecules have
been implicated in the pathogenesis of HE. Neuros-
teroids, such as allopregnanolone, appear to allosterically
modulate the gamma-aminobutyric acid (GABA)-A
receptors in the brain, enhancing the effects of GABA on
these inhibitory receptors, thus leading to a suppressed
sensorium via increased “GABA-ergic tone.”42,43 These
neurosteroids are produced in the brain and are elevated
in patients with HE.44
Benzodiazepines also modulate GABA-A receptors,
which may explain some of the similarities between HE
and benzodiazepine use. In addition, benzodiazepines
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f r e D e r I c k
appear to trigger astrocyte swelling via a direct receptor-
mediated effect. Endogenous benzodiazepines are believed
to arise from bacterial production and can also activate
the GABA-A receptors. Elevations in these “endozepines”
have been found in some cirrhotic patients with HE but
not in others, and whether endogenous benzodiazepines
are a significant contributor to HE remains unclear.45-48
Indole and oxindole are byproducts of bacterial tryp-
tophan metabolism with sedating properties that have
been recently implicated as potential contributors to the
pathogenesis of HE.49 Other putative toxins involved in
HE pathogenesis include mercaptans, short-chain fatty
acids, false neurotransmitters (eg, octopamine), manga-
nese, and GABA.50-54
Finally, another proposed mechanism for the dev-
elopment of HE suggests that activity of neuronal
acetylcholinesterase (AChE) is increased in the brains
of cirrhotic patients and animal models with type C HE,
which results in a reduction of acetylcholine by up to
50–60%.55,56 These changes appeared to be independent
of hyperammonemia. Interestingly, no changes in AChE
activity has been found in rats with type A or B HE.55,57,58
Nonetheless, interesting and encouraging experimen-
tal data are now emerging in both animal models and
patients regarding the use of AChE inhibitors for treat-
ment of HE.55,59
Low serum sodium levels are quite common in patients
with cirrhosis and portal hypertension due to the activa-
tion of antidiuretic hormone (vasopressin) that occurs
secondary to the decrease in effective arterial volume
related to splanchnic arterial vasodilation. Unfortunately,
chronic hyponatremia leads to depletion of intracellular
organic osmolytes, 1 of which, myoinositol, plays a pri-
mary role in intracellular water regulation. Osmolytes
present in astrocytes provide a cellular defense against
intracellular swelling and can be rapidly accumulated
or depleted according to osmotic sensors. One theory is
that chronic hyponatremia causes astrocyte osmolytes to
be depleted; the cell then cannot compensate well during
periods of hyperammonemia or inflammation, leading to
astrocyte swelling, low-grade cerebral edema, oxidative
and nitrosative stress, and astrocyte dysfunction. While
hyponatremia may not be sufficient to trigger HE alone,
it can be considered a “second hit” that places osmotic
stress on the astrocyte. Indeed, hyponatremia has been
shown to be a significant predictor for development of
overt HE in patients with cirrhosis.60,61
Finally, a growing body of literature implicates an inflam-
matory milieu—in conjunction with hyperammonemia
or other neurotoxic molecules—as being key to the
precipitation of HE. This inflammation may be related
to infection, gastrointestinal bleeding, obesity, or disequi-
librium of resident fecal flora in the cirrhotic patient with
enhanced translocation and increased rates of bacterial
overgrowth. Infection has been shown to worsen the pro-
gression of HE and cerebral edema in patients with ALF,
and proinflammatory cytokines seem to act synergisti-
cally with ammonia in causing cerebral edema.62-64 Over-
active neutrophils with excessive degranulation activity
and enhanced production of inflammatory cytokines
may also play a role in this pathogenesis. Additionally,
alterations in toll-like receptor 4, a receptor responsible
for recognition of gram-negative bacteria, may be at
least partly responsible for the inflammatory state in the
cirrhotic patient. Polymorphisms of this receptor that
occur in cirrhotic patients may increase both the risk
of infection and the risk of HE.65 The blockade of this
receptor is therefore being studied as a mechanism for
treating both HE and ALF.
Treatment of Hepatic Encephalopathy
Treatment of HE has evolved slowly over the last 50 years,
with several breakthroughs occurring during this time.
However, clinicians currently operate in somewhat of
a vacuum regarding formal treatment guidelines, as the
most recent sanctioned clinical guidelines for overt HE
were published a decade ago; updated guidelines from the
American Association for the Study of Liver Diseases are
expected soon.66 Nonetheless, treatment can be structured
around several key management principles that paral-
lel the pathophysiology of the disease: management of
precipitating factors, reduction of ammonia (and perhaps
additional toxins), modulation of fecal flora, modulation
of neurotransmission, correction of nutritional deficien-
cies, and reduction of inflammation. Additional manage-
ment strategies for less common clinical scenarios will also
Management of Precipitating Factors
The majority of HE episodes are precipitated by an event
rather than spontaneous, with infection being the most
common, although its frequency appears to be declin-
ing.67-70 Often, precipitants are overt and obvious, but a
careful history and physical examination are required in
order to identify other, less dramatic contributing causes.
Gastrointestinal bleeding commonly precipitates HE,
even after it is successfully abated; occult chronic gastro-
intestinal blood loss can also lead to HE and should be
evaluated and treated if possible.71
Dehydration, often in the setting of aggressive diuresis
with volume contraction alkalosis and electrolyte distur-
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bances, is a particularly common cause of HE in patients
with ascites and edema. Individuals who have undergone
TIPS insertion for fluid overload are particularly suscepti-
ble to dehydration or excessive diuresis if medications are
not appropriately tapered after the TIPS procedure. Such
dehydration-induced HE usually responds to fluid resus-
citation and electrolyte repletion.32 Clinicians should note
that albumin seems to play a significant role in treatment
of such patients, while other colloids may be less helpful.72
Unfortunately, a mainstay of treatment for chronic persis-
tent HE, lactulose, can lead to severe volume depletion
and hypokalemia due to excessive stooling, paradoxically
exacerbating the disease that the well-meaning clinician
intended to ameliorate. Treatment of HE should include
repletion of electrolytes (often lost with overzealous use of
diuretics and disaccharides [DS]), particularly potassium,
as potassium deficiency can exacerbate hyperammonemia
by upregulating renal glutaminase and ammoniagenesis.
Constipation is also believed to be a frequent cause of
HE, presumably because it increases the amount of time
that ammonia and other toxins can be absorbed from the
gastrointestinal tract; simple osmotic stool softeners and
avoidance of dehydration can help to prevent constipa-
tion. Possible noncompliance with lactulose should also
Electrolyte derangements commonly precipitate HE
events, particularly in the setting of hypokalemia and
hyponatremia. Hyponatremia itself can cause neurologic
dysfunction, which may be difficult to differentiate from
the manifestations of HE. Cerebral edema appears to be
a commonality between these 2 neurologic syndromes.
Treatment of hyponatremia requires saline resuscitation
for patients with hypovolemia and water restriction
or vasopressin antagonists for patients with euvolemic
or hypervolemic hyponatremia. Whether treatment of
hyponatremia with a vasopressin antagonist will also be
effective for treatment or prevention of HE remains an
Finally, many patients with advanced liver disease
also suffer from anxiety, depression, chronic pain, or
sleep disorders; as a result, these patients commonly take
sedating medications intended to improve their quality
of life. Because these sedatives, particularly those in the
benzodiazepine and opiate classes, often trigger or exac-
erbate underlying HE, they should be removed from the
regimen of HE patients as quickly as possible.
Reduction of Ammonia and Other Toxins
Although clinical trials have produced inconsistent evi-
dence of overall clinical improvement associated with
ammonia reduction, this intervention has nonetheless
been a main goal of HE treatment for the past 4 decades,
and decreased ammonia is often cited as a significant
endpoint of clinical trials assessing HE treatments. While
hyperammonemia alone is insufficient to explain the spec-
trum of symptoms seen in HE, a significant correlation is
seen between the degree of ammonia elevation and the
stage of HE.31,73 The clinical significance of hyperammo-
nemia is more pronounced in the setting of type A HE,
where cerebral edema and death have been significantly
correlated with the degree of hyperammonemia.74
The mainstay of ammonia reduction for type C HE
over the past 40 years has been nonabsorbable DS such
as lactulose (b-galactosidofructose) in the United States
and lactitol (b-galactosidosorbitol) in Europe. However,
the efficacy of these agents has been called into question
by a widely cited meta-analysis that examined DS versus
placebo or antibiotics for the treatment of HE.75 The
authors of this study concluded that the body of evidence
for the use of DS in HE is limited and of poor quality;
they also found that DS appears to be no better than
placebo and worse than antibiotics for treatment of this
disease. However, more recent data regarding the use of
lactulose for prevention of HE recurrence appears more
promising.76,77 Despite the questionable benefit of lactu-
lose in well-designed trials, most clinicians still believe in
the efficacy of DS, and lactulose continues to be widely
prescribed for HE.
The mechanism of action through which DS works is
multifaceted. While intestinal “hurry” is their best-known
mechanism for eliminating fecal waste products, includ-
ing ammonia, DS are much more than simple cathartics.
Upon entering the colon, DS are cleaved into monosac-
charides by the bacterial flora, some of which (eg, Lac
tobacilli and Bifidobacteria) can then incorporate these
monosaccharides into subsequent generations of bacteria,
thereby gaining a growth advantage. The unincorpo-
rated monosaccharides are also utilized as fuel for the
bacteria. This fermentation process generates lactic acid
and hydrogen ions, thereby acidifying the fecal stream
within the colon and causing subsequent protonation of
ammonia molecules (NH3) into ammonium ions (NH4
Because the charged NH4
colonocyte, the ion remains trapped within the colonic
lumen. In addition, this protonation reaction can allow
for movement of NH3 from the bloodstream back into
the colonic lumen in a classic example of stoichiometry
(NH3 + H+➝ NH4
has been postulated for DS involves transformation of the
fecal flora: reduction of urease-producing bacteria (which
are not given a growth advantage with DS) in favor of the
proteolytic species (eg, Lactobacilli and Bifidobacteria).
In this regard, DS can be considered a prebiotic—ie, a
“meal” for the bacterial biomass.
Another mechanism for reducing ammonia involves
the use of so-called ammonia scavengers, such as intra-
+ is poorly absorbed across the
+). Another mechanism of action that
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f r e D e r I c k
venous sodium benzoate and sodium phenylacetate
(Ammonul, Ucyclyd Pharma) or a prodrug of phenylac-
etate, oral sodium phenylbutyrate (Buphenyl, Medicis);
both of these scavengers are approved for use in patients
with urea cycle disorders and hyperammonemia (mostly
children). Oral sodium benzoate (Ucephan, B Braun) is
also sometimes used off-label for ammonia scavenging. It
is available as a powder and can be obtained from spe-
cialty pharmacies. These compounds work by combining
with glycine (in the case of benzoate) or glutamine (in the
case of phenylacetate) to form water-soluble and renally
excretable compounds (benzoylglycine or hippurate
and phenylacetylglutamine, respectively) that eliminate
ammonia through the urine.
The use of these drugs is a way to bypass the satu-
rated urea cycle, but these agents still require intact renal
function for elimination of ammonia. Also, while these
products are available in the United States, they are not
approved for HE. One downside to their use is their
large therapeutic dose (measured in grams per day)—
which leads to a significant sodium load (1–2 g/day at
therapeutic doses) that may contribute to fluid reten-
tion in cirrhotic patients—as well as poor palatability. A
new compound, glycerol phenylbutyrate (HPN-100,
Hyperion Therapeutics), is a prodrug of sodium phen-
ylbutyrate with a much lower anticipated therapeutic
dose requirement and improved palatability. Glycerol
phenylbutyrate is currently being evaluated for type C
HE and recently met the primary endpoint in a phase
III trial of urea cycle disorders.
A newer avenue being explored for reduction of
ammonia is the use of orally ingested, activated charcoal.
A compound called AST-120 (Ocera Therapeutics), a
spherical carbon adsorbent, has been studied in patients
with mild HE and cirrhotic patients with pruritus. This
compound’s known capability for adsorbing small mol-
ecules—not only ammonia, but also lipopolysaccharides
and cytokines—makes it an attractive therapeutic option
for HE. A pilot study showed that AST-120 had efficacy
equivalent with lactulose and fewer adverse events.78
Other data have noted a reduction in ammonia and cere-
bral edema following treatment with AST-120 in animal
models of cirrhosis. A larger trial of AST-120 in patients
with mild type C HE, the ASTUTE trial, has recently
been completed, and results are anticipated soon.
For patients with severe HE who do not respond to
traditional therapies, clinicians may consider the use of
an extracorporeal device for “liver dialysis.” Currently, the
only such system that is clinically available in the United
States is the molecular adsorbent recirculating system
(MARS, Gambro), also known as albumin dialysis, which
is indicated for acute poisoning. A large randomized
controlled study was conducted in the United States for
patients with severe HE not responding to standard care.
Patients receiving MARS demonstrated more rapid and
significant improvements in HE, but no benefit in mortal-
ity was found in this group of patients with terminal liver
failure.79 Other devices, including bioartificial machines
with hepatocytes, have been studied for treatment of HE,
but none are currently approved in the United States.80,81
Finally, certain patients with ongoing hyperammo-
nemia and persistent HE despite removal of precipitat-
ing factors and optimal therapeutic management will
be recognized as having large or extensive spontaneous
portosystemic shunting. These shunts may be amenable
to embolization via percutaneous catheterization, but
experience in the United States remains limited.
Modulation of Fecal Flora
The gut microbiome’s influence is becoming increasingly
recognized across many diverse disease states, including
inflammatory bowel disease, irritable bowel syndrome,
and obesity. Bacterial flora also appear to play a significant
role in the pathogenesis of HE, and modification of this
flora—either through antibiotics, probiotics, or prebiot-
ics—is important for the successful treatment of this dis-
ease. Prebiotics (of which lactulose and fermentable fibers
are examples) may directly enhance the growth of bacterial
strains that are potentially beneficial to the host (ie, Bifi
dobacteria and Lactobacilli), thereby indirectly reducing
the influence of potentially more harmful resident flora
(ie, urease-producing species). Prebiotics also come in the
form of indigestible fibers and have shown benefit for the
management of HE, particularly MHE, both when used
alone and when used in combination with probiotics (in
which case they are termed “synbiotics”).82-84
Probiotics have also been studied (either alone or as
synbiotics) for the treatment of HE and have shown some
benefit, mostly in the setting of minimal disease.84-88 The
bacterial species that appear to be most successful include
Lactobacilli and Bifidobacteria. Investigators in Belgium
have also demonstrated improvements in both acute and
chronic animal models of HE when these animals were
treated with genetically enhanced species of Lactobacilli
that had augmented ammonia-consumption capabilities.89
Probiotics may also improve overall liver function, perhaps
by reducing translocation and subsequent endotoxemia
and by ameliorating the hyperdynamic circulation.84
On the other side of the treatment spectrum, anti-
biotics have been clearly proven to treat HE, particularly
when used to prevent recurrent exacerbations. Rifaximin
(Xifaxan, Salix) is a poorly absorbed relative of rifamycin
that has broad antibacterial activity against both aerobes
and anaerobes. Rifaximin has a preferential site of action
in the small bowel (presumably due to its enhanced solu-
bility in bile) where it typically lowers the bacterial load
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PAT H O P H Y S I O L O G Y A N D M A N A G e M e N T O f H e PAT I c e N c e P H A L O PAT H Y
100–1,000-fold; however, it stops short of obliterating all
flora and is less effective in the colon.90 A large randomized
controlled study investigating rifaximin versus placebo in
patients who were already using lactulose (91% of both
arms) showed a highly statistically significant benefit for
rifaximin in preventing recurrences of HE and decreasing
hospitalizations related to HE over a 6-month period.91
In an exploratory analysis, the trial also demonstrated
an improvement in quality of life in patients receiv-
ing rifaximin, as assessed by the Chronic Liver Disease
Other antibiotics used to treat HE include neomycin
(an aminoglycoside), metronidazole (for anaerobes only),
paromomycin, and oral vancomycin. These antibiotics
all have considerable limitations either related to safety
(ie, ototoxicity and nephrotoxcity with neomycin; neu-
rologic toxicity with metronidazole) or resistance (oral
vancomycin); for these reasons, these agents have largely
been replaced by rifaximin, which is now approved by
the US Food and Drug Administration for treatment of
HE. The mechanism of action for antibiotics in HE is
assumed to be related to modulation of bacterial flora,
but this hypothesis has not been proven. One postulated
mechanism of action is the correction of small intestinal
bacterial overgrowth, which is frequently identified in
cirrhotic patients, although this explanation remains
controversial.93 Studies evaluating antibiotics for the treat-
ment of HE have shown reductions in ammonia levels,
but some researchers have speculated that the benefit of
antibiotics also arises from an anti-inflammatory effect or
downregulation of intestinal glutaminase activity. Studies
are still needed to examine the effects of chronic antibi-
otic administration on fecal flora, as well as their effect
on cytokines and other markers of inflammation in HE.
Finally, acarbose, an α-glucosidase inhibitor used in
the management of diabetes, has also been studied for
the treatment of HE. By reducing glucose absorption
from the intestine, this drug may promote the survival of
primarily saccharolytic (rather than proteolytic) bacteria,
thereby reducing the generation of ammonia. A random-
ized, double-blind, crossover trial of acarbose in diabetic
patients with mild HE demonstrated reductions in
ammonia concentrations and improvements in number
connection tests and HE grades.94 Further clinical trial
data are needed before this drug can become more widely
used for this indication.
Modulation of Neurotransmission
The final common pathway for the pathophysiology of
HE appears to be altered neurotransmission, manifested
as upregulation of both GABA neuroinhibitory recep-
tors and N-methyl-D-aspartic acid–glutamate excitatory
receptors, resulting in a clash of combined inhibitory and
excitatory signals. Targeting this derangement has long
been an avenue for HE management, and trials have been
conducted with flumazenil, naloxone, bromocriptine,
levodopa, and AChE inhibitors, many of which have met
with minimal clinical success. When faced with a coma-
tose patient with HE, a therapeutic trial of flumazenil or
naloxone is certainly appropriate if benzodiazepine or opi-
ate ingestion has been identified or suspected. However,
the effect of these drugs is short-lived, and minimal evi-
dence exists to support their use.95,96 More recently, a pilot
study of the AChE inhibitor rivastigmine in patients with
moderate HE showed a benefit in psychometric testing.59
Correction of Nutritional Deficiencies
Patients with advanced liver disease often face tremendous
difficulties in maintaining proper nutritional balance.
Many factors are involved in their poor nutrition, includ-
ing poor dietary absorption (particularly of fat-soluble
vitamins), poor intake (due to confusion, weakness, or
ascites), and a baseline hypercatabolic state. This imbal-
ance often leads to a wasting syndrome due to protein-
calorie malnutrition. Since skeletal muscle appears to
play some role in controlling the flux of ammonia in
the body, muscle mass depletion may lead to worsening
of HE, although this effect has not been consistently
Zinc is another potentially important factor in terms
of nutritional deficiencies. Zinc serves as a cofactor for
several of the enzymes involved in the urea cycle; thus,
zinc deficiency, which is common in cirrhotic patients,
may decrease the efficiency of the urea cycle. A recent ran-
domized, open-label trial suggests that zinc supplementa-
tion may provide a benefit in patients with HE.97
A product that is frequently used for treatment of
HE outside of the United States is L-ornithine L-aspartate
(LOLA), which is believed to act by supplying substrates
for the urea cycle and glutamine synthesis that may oth-
erwise become depleted in cirrhotic patients with general-
ized protein malnutrition and amino acid deficiencies.
The data regarding LOLA’s use in HE were published in
a meta-analysis of 3 trials and demonstrated a significant
benefit in patients with grade I–II HE, but not with mini-
mal HE.98 However, this product is not currently available
in the United States.
A new compound that is similar to LOLA, L-orni-
thine phenylacetate (LOPA), also known as OCR-002
(Ocera Therapeutics), has been developed and is currently
being tested as a treatment for HE. This agent may work
by increasing the supply of ornithine to the urea cycle,
thereby enhancing the incorporation of ammonia into
glutamine. Ammonia is then scavenged by subsequently
conjugating phenylacetate with glutamine to form phen-
ylacetylglutamine, which is then excreted in urine. Results
230 Gastroenterology & Hepatology Volume 7, Issue 4 April 2011
f r e D e r I c k
are eagerly awaited from a recently completed phase I
trial of LOPA in patients with HE, and the company has
announced plans for a phase II trial to begin in 2011.99
Another approach to addressing nutritional deficien-
cies in cirrhotic patients with HE focuses on correcting
the Fischer ratio: the balance between branched-chain
amino acids (BCAA) and aromatic amino acids (AAA).
This ratio is typically 3:1 in the healthy population, but
it becomes inverted in cirrhotic patients. The benefits of
BCAA (valine, leucine, and isoleucine) are believed to
be 2-fold: They are essential for protein production, and
they are critical for the prevention of catabolism, which
can worsen HE. AAA, on the other hand, appear to be
precursors of “false” neurotransmitters such as octopa-
mine or phenylethylamine. These have been implicated
in the pathogenesis of HE because of their potential to
inhibit neurotransmission via nonfunctional competitive
blockade of receptors. A surplus of AAA can also cause
problems related to the production of neurotoxic phenols
and downregulation of the synthesis of excitatory neu-
rotransmitters, such as norepinephrine and dopamine,
thus further contributing to neurologic dysfunction.52
By supplementing diets with BCAA, patients are able to
continue adequate protein intake, reduce catabolism and
muscle breakdown (which helps to maintain the ammonia
clearance provided by muscle), and prevent the synthesis
of false neurotransmitters. A meta-analysis of BCAA sup-
plementation supported its use for improving the rate of
recovery from episodic HE but did not demonstrate a
survival advantage.100 BCAA supplements are limited in
clinical practice due to poor palatability and higher costs.
The most important recent development in nutri-
tional supplementation for HE is reversal of the long-held
belief that protein restriction is beneficial for patients with
episodic or persistent HE. A study evaluating low-protein
versus normal-protein diets for patients with episodic HE
demonstrated that both groups showed similar rates of
improvement; however, the protein-restricted group suf-
fered from accelerated protein catabolism.101
Finally, some evidence from an Italian center sup-
ports supplementation with carnitine, either L-carnitine
or its acetylated form, for treatment of HE.102-104 Confir-
mation of these positive results in other centers is needed.
Reduction of Inflammation
Patients with cirrhosis have a significantly increased risk
of infection related to their relative immunosuppression
and dysfunctional reticuloendothelial system. This risk is
almost 5 times that of noncirrhotic patients hospitalized
for other indications. Indeed, infection, a prototypi-
cal inflammatory state, is a common precipitant of HE
because these infections often manifest without typical
signs and symptoms. Clinicians must aggressively search
for and treat these infections in patients presenting with
HE. Many practitioners assume an infectious process is
involved in the presentation of more severe cases of HE
and begin empiric antimicrobial therapy while body fluid
analyses and cultures are performed. In addition, standard-
of-care treatment demands the systematic performance of
diagnostic paracentesis for any patient with ascites who
is admitted to the hospital with decompensation. Anti-
biotics are clearly indicated in the treatment of infections
in patients with HE, and many of these HE events will
improve with conservative management alone—intrave-
nous fluids, antibiotics, drainage of abscesses, and rest.
Even in the absence of an active infection, patients
with cirrhosis are in a relatively proinflammatory state,
marked by elevated levels of endotoxin, tumor necrosis
factor (TNF)-α, and other proinflammatory cytokines, as
well as upregulation of certain toll-like receptors.105 This
inflammatory state may be related to bowel wall edema
due to portal hypertension or delayed transit time with
subsequent translocation of bacteria and/or endotoxin
into the bloodstream. Whether antibiotics given to HE
patients without active infection have an impact on the
relative inflammatory state of cirrhosis is unclear, but
antibiotics do appear to improve the hyperdynamic circu-
lation of cirrhosis and reduce both the risk of hepatorenal
syndrome and death.106
Other potential HE therapies that have an anti-
inflammatory role include pentoxifylline and the activated
charcoal product AST-120. A recent large randomized
controlled trial of pentoxifylline versus placebo in patients
with Child-Pugh class C cirrhosis showed no benefit in
overall mortality, but the study authors did demonstrate
a significant reduction in complications of cirrhosis,
including development of HE, in patients treated with
pentoxifylline. Pentoxifylline is thought to work in these
patients because of its anti–TNF-α activity, as TNF-α
is typically elevated in patients with cirrhosis. A study
comparing pentoxifylline with placebo or another agent
for the treatment or prevention of HE is needed before
pentoxifylline can become accepted as therapy for HE.
Other potential anti-inflammatory therapies for HE
should also be explored. With its distinct mechanism of
action, AST-120 may be able to bind very small mol-
ecules in the gut—such as TNF-α, lipopolysaccharide,
or endotoxin—and thereby block their absorption.
AST-120 is currently being evaluated for use in patients
with mild HE.
The current management of HE requires prompt recog-
nition of the disease state (particularly in its earliest or
mildest stages), careful identification and amelioration
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PAT H O P H Y S I O L O G Y A N D M A N A G e M e N T O f H e PAT I c e N c e P H A L O PAT H Y
of precipitating factors, and judicious prescribing of a
therapeutic arsenal that is often multifaceted and must be
tailored to each patient. Nonabsorbable DS (lactulose in
the United States) remain the mainstay of therapy for the
majority of patients with episodic or mild persistent HE.
Nonabsorbable antibiotics (particularly rifaximin) with or
without DS have become the standard-of-care treatment
for patients with recurrent or persistent HE, after removal
of underlying precipitating factors where possible.
Whether antibiotics will also become the standard-of-care
treatment for patients with milder forms of the disease
(particularly minimal HE) depends on the outcomes of
anticipated trials in this patient population, but prelimi-
nary data look promising.5,107 Ammonia scavengers have
a role in the treatment of patients who are intolerant to
DS and/or antibiotics, unable to afford antibiotics, or
suffering from persistent or recurrent HE despite use of
DS and/or antibiotics (particularly if they are confirmed
to be hyperammonemic). Despite the lack of robust
data, supplementation with oral zinc and/or L-carnitine
seem to be reasonable treatment options for patients
with HE, particularly if deficiencies of these molecules
are confirmed by laboratory testing. Other interesting
compounds under study for HE—including AST-120,
HPN-100, LOPA, acarbose, and rivastigmine—will
require additional data before being accepted into the
routine management of HE. Finally, due to the severity
of the underlying liver disease and the prediction of poor
long-term survival, all patients with overt HE should be
considered for liver transplantation.
Dr. Frederick is an advisor and member of the Speakers’
Bureau for Salix, an advisor and member of the Data and
Safety Monitoring Board for Hyperion, and an advisor
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