HEPATIC ENCEPHALOPATHY

The term hepatic encephalopathy (HE) encompasses a wide

array of transient and reversible neurologic and psychiatric
manifestations usually found in patients with chronic liver
disease and portal hypertension, but also seen in patients
with acute liver failure. HE develops in 50 to !0 of
patients with cirrhosis, and its occurrence is a poor prognostic
indicator, with pro"ected one# and three#year survival
rates of $% and %&, respectively, without liver transplantation.
' (ymptoms may range from mild neurologic disturbances
to overt coma.%,& HE is often triggered by an inciting
event that results in a rise in the serum ammonia level. The
precise underlying pathophysiologic mechanisms are not well understood, and the
mainstay of therapy is the elimination
of the precipitating event and e)cess ammonia.$ *iver
transplantation generally reverses HE.
PATHOPHYSIOLOGY
+ number of factors, occurring alone or in combination,
have been implicated in the development of HE. These
factors may differ in acute and chronic liver disease and
include the production of neuroto)ins, altered permeability
of the blood#brain barrier, and abnormal neurotransmission
(,ig. -%#'). The best#described neuroto)in involved in HE
is ammonia, which is produced primarily in the colon,
where bacteria metaboli.e proteins and other nitrogenbased
products into ammonia. Enterocytes synthesi.e
ammonia from glutamine.$#/ 0nce produced, ammonia
enters the portal circulation and, under normal conditions,
is metaboli.ed and cleared by hepatocytes. 1n cirrhosis and
portal hypertension, reduced hepatocyte function and portosystemic
shunting contribute to increased circulating
ammonia levels. +rterial hyperammonemia is observed in
up to -0 of patients with HE, although serum levels are
neither sensitive nor specific indicators of its presence.
1ncreased permeability of the blood#brain barrier increases
the upta2e and e)traction of ammonia by the cerebellum
and basal ganglia.!#- +cute hyperammonemia appears to
have a direct effect on brain edema, astrocyte swelling, and
the transport of neurally active compounds such as myoinositol,
and thereby contributes to HE.'0#'%
0ther alterations in HE affect neuronal membrane
fluidity, central nervous system (34() neurotransmitter
e)pression, and neurotransmitter receptor e)pression and
activation.'&,'$ The 5#aminobutyric acid (6+7+)8ben.odia.epine
system has been the most well studied. +lthough
34( ben.odia.epine levels and 6+7+ receptor concentrations
are unchanged in animal models of HE, increased
sensitivity of the astrocyte (peripheral#type) ben.odia.epine
receptor enhances activation of the 6+7+#ben.odia.epine
system.'5,'/ This activation occurs in part through a
feed#forward system in which production of neurosteroids
(allopregnanolone and tetrahydrodeo)ycorticosterone) by astrocytes further activates
the 6+7++#ben.odia.epine
receptor system.'!,'9 0ther factors that influence 34( neurotransmission,
including serotonin (5#hydro)ytryptamine,
5#HT),'-#%' nitric o)ide (40), circulating opioid peptides,
manganese, and increased o)ygen free radical production,
have also been postulated to contribute to HE.$
,inally, hyperammonemia, particularly in acute liver
failure, also increases astrocyte glutamine production via
glutamine synthetase. The rise in astrocyte glutamine and
glutamate concentrations contributes to factors associated
with 34( dysfunction.5,%%,%&
CLINICAL FEATURES AND DIAGNOSIS
HE may present as a spectrum of reversible neuropsychiatric
symptoms and signs, ranging from mild changes in cognition
to profound coma, in patients with acute or chronic
liver disease. 1t is often precipitated by an inciting event
(e.g., gastrointestinal bleeding, electrolyte abnormalities,
infections, medications, dehydration). The diagnosis of HE,
therefore, re:uires careful consideration in the appropriate
clinical situation. 0ccasionally, HE may be the initial presentation
of chronic liver disease. (ubtle findings in HE
may include forgetfulness, alterations in handwriting, difficulty
with driving, and reversal of the sleep#wa2e cycle.%$,%5
0vert findings may include asteri)is, agitation, disinhibited
behavior, sei.ures, and coma. 0ther causes of altered mental
status, particularly hypoglycemia, hyponatremia, medication
ingestion, and structural intracranial abnormalities
resulting from coagulopathy or trauma, should be considered
and rapidly e)cluded in patients suspected of
having HE.
4o specific laboratory findings indicate the presence of
HE definitively. The most commonly used test to assess a
patient with possible HE is the blood ammonia level. +n
elevation in the blood ammonia level in a patient with cirrhosis
and altered mental status supports a diagnosis of HE.
7lood ammonia levels may be elevated in the absence of
HE, however, because of gastrointestinal bleeding or the
ingestion of certain medications (e.g., diuretics, alcohol,
narcotics,
valproic acid).'5,%/,%! 1n addition, blood ammonia
levels may be elevated in the presence of HE, even in the
absence of cirrhosis and portal hypertension, in patients
with metabolic disorders that influence ammonia generation
or metabolism,
such as urea cycle disorders (see 3hapter
!/) and disorders
of proline metabolism (Table -%#').%9,%-
;se of a tourni:uet when blood is drawn and delayed processing
and cooling of a blood sample may raise the blood
ammonia level.'5 <easurement of arterial ammonia offers
no advantage over measurement of venous ammonia levels
in patients with chronic liver disease.&0 1n patients with acute
liver failure, however, elevated arterial ammonia levels ('50
to %00 mg=d* or higher) may be predictive of the presence of
brain edema and herniation (see 3hapter -&).'%,&',&%
0f the scoring systems used to grade the severity of
HE, the >est Haven system, based on a scale of 0 to $, is
the most widely used in clinical practice (Table -%#%).%5
+lthough clinically useful, the >est Haven criteria are
insensitive and have led to the development of standardi.ed
psychometric tests and rapid bedside mental status assessments
to aid in the diagnosis of HE and facilitate research.&&#&!
0ne simple paper and pencil test, the portosystemic encephalopathy
syndrome test (?(ET), evaluates the patient@s
attention, concentration, fine motor s2ills, and orientation
and has been shown to be highly specific for the diagnosis
of HE.&&,&9 The development of these tests has led to recognition
of the syndrome of minimal HE, in which abnormalities
are observed on testing but clinically recogni.able alterations
of HE are minimal or not detected. The presence of minimal HE is common in
patients with cirrhosis, appears
to influence the patient@s :uality of life and driving ability,
and confers an increased ris2 that overt HE will develop in
the patient. >hether treatment of minimal HE confers any
benefit is an area of active investigation.%$,&-#$'
+ number of novel imaging and functional tests have been
studied in the diagnosis of HE. <agnetic resonance spectroscopy
(<A() has been used to measure brain concentrations
of choline and glutamine noninvasively.$% <agnetic
resonance (<A) T' mapping with partial inversion recovery
(T+?1A) has been investigated as a means to measure
changes in the brain :uantitatively over clinically relevant
measurement times.&& >hether <A#based techni:ues can be
standardi.ed and become practical diagnostic tests is uncertain.
The critical flic2er fre:uency test, a simple light#based
test that has been used to assess cerebral corte) function in
a number of disorders, has been shown to be a reliable
mar2er of minimal HE and may become a clinically useful
screening test.&$#&/
TREATMENT
3urrent treatments for HE are directed primarily toward
the elimination or correction of precipitating factors (ebleeding, infection,
hypo2alemia, medications, dehydration),
reduction in elevated blood ammonia levels, and
avoidance of the to)ic effects of ammonia in the 34(. 1n the
past, dietary protein restriction was considered an important
component of the treatment of HE. (ubse:uent wor2,
however, has suggested that limiting protein#calorie inta2e
is not beneficial in patients with HE.$&#$5 Begetable and dairy
proteins are preferred to animal proteins because of a more
favorable calorie#to#nitrogen ratio. +lthough branchedchain
amino acid supplementation may improve symptoms
modestly, the benefits of such supplementation are not sufficient
to "ustify its routine use.$
4onabsorbable disaccharides have been the cornerstone
of the treatment of HE. 0ral lactulose or lactitol (the latter
is not available in the ;nited (tates) are metaboli.ed by
colonic bacteria to byproducts that appear to have beneficial
effects by causing catharsis and reducing intestinal pH,
thereby inhibiting ammonia absorption.$/ These agents
improve symptoms in patients with acute and chronic HE
when compared with placebo but do not improve psychometric
test performance or mortality. The most common
side effects e)perienced by patients who ta2e lactulose are
abdominal cramping, flatulence, diarrhea, and electrolyte
imbalance. *actulose may also be administered per rectum
(as an enema) to patients who are at increased ris2 of aspiration,
although the efficacy of enema administration has not
been evaluated.
0ral antibiotics also have been used to treat HE, with the
aim of modifying the intestinal flora and lowering stool pH
to enhance the e)cretion of ammonia. +ntibiotics are generally
used as second#line agents after lactulose or in patients
who are intolerant of nonabsorbable disaccharides. 4eomycin
has been approved by the ;.(. ,ood and Crug +dministration
(,C+) for use in acute HE in a dose of ' to & g
orally every si) hours for up to si) days but has been used
more commonly off#label to treat chronic HE in doses of 0.5
to ' g every '% hours, in addition to lactulose. The efficacy
of neomycin in acute or chronic HE, however, is not clearly
established,$! and ototo)icity and nephroto)icity caused by
neomycin have been reported, particularly in patients with
pree)isting renal dysfunction.$ Aifa)imin has been studied
and approved by the ,C+ for the treatment of chronic HE
on the basis of the results of a multicentered, randomi.ed,
controlled trial in which the overall clinical efficacy and
rate of side effects were similar in patients treated with
lactitol and those treated with rifa)imin.$9 The usual dose
is $00 mg orally three times daily. Two systematic reviews
of randomi.ed controlled trials that compared rifa)imin with other therapies
(nonabsorbable disaccharides and
other antibiotics) for the treatment of acute or chronic HE
have confirmed that the efficacy and side effect profiles are
comparable.$-,50 0ther antibiotics, including metronida.ole
and vancomycin, have been reported to be effective in small
trials and case series, but the data to support their use are
insufficient.
1n addition to antibiotics, several other agents that may
modify intestinal flora and modulate ammonia generation
or absorption have been evaluated as potential treatments
for HE. +carbose, an intestinal D#glucosidase inhibitor
used to treat type % diabetes mellitus, inhibits the intestinal
absorption of carbohydrates and glucose and results in
their enhanced delivery to the colon. +s a result, the ratio
of saccharolytic to proteolytic bacterial flora is increased,
and blood ammonia levels are decreased. + randomi.ed,
controlled, double#blind, crossover trial has demonstrated
that acarbose improves mild HE in patients with cirrhosis
and adult#onset diabetes mellitus.5' (imilarly, probiotic
regimens have been used to modify intestinal flora and
diminish ammonia generation. ,our small studies have
suggested that these agents may be beneficial in humans
with mild HE.$0,5%#55 These agents merit further evaluation
and may be alternatives for patients who do not tolerate
lactulose.
(trategies to enhance ammonia clearance may also be
useful in the treatment of HE. (odium ben.oate, sodium
phenylbutyrate, and sodium phenylacetate, all of which
increase ammonia e)cretion in urine, are approved by
the ,C+ for the treatment of hyperammonemia resulting
from urea cycle en.yme defects and may improve HE in
cirrhosis (see 3hapter !/). +dministration of sodium ben.oate,
however, results in a high sodium load, and the efficacy
of this agent is not clearly established.$,5/ The combination
of intravenous sodium phenylacetate and sodium ben.oate
(+mmonul, ;cyclyd ?harma, (cottsdale, +ri.) in HE is
being studied. +dministration of .inc, which has been used
because .inc deficiency is common in patients with cirrhosis5!#
5- and because .inc increases the activity of ornithine
transcarbamylase, an en.yme in the urea cycle, may also
improve HEE however, clear efficacy has not been established.
E)tracorporeal albumin dialysis using the molecular
adsorbent recirculating system (<+A() has resulted in a
reduction in blood ammonia levels and improvement in
severe HE in patients with acute#on#chronic liver failure
(see 3hapter -&)./0 ,urther studies are needed to clarify
whether albumin dialysis has a role in treatment of HE.
,inally, l#ornithine8l#aspartate (*0*+), a salt of the amino
acids ornithine and aspartic acid that activates the urea
cycle and enhances ammonia clearance, has been shown in
several randomi.ed controlled studies to improve HE compared
with lactulose/'#/&E however, this agent is not available
in the ;nited (tates.
,luma.enil is a specific ben.odia.epine (6+7++ receptor)
antagonist that has been used in patients with HE. 1t
improves the degree of encephalopathy and electrophysiologic
findings in appro)imately one fourth of patients with
grade & or $ HE. 1t has a short half#life and a number of
potential side effects, including sei.ures, arrhythmias, and
withdrawal symptoms, that limit its clinical usefulness
Table 92-1 Cifferential Ciagnosis of Hyperammonemia
+cute liver failure
3hronic 2idney disease
3igarette smo2ing
3irrhosis
6astrointestinal bleeding
1nborn errors of metabolism
?roline metabolism disorders
;rea cycle disorders (e.g., carbamyl phosphate synthetase 1
deficiency, ornithine transcarbamylase deficiency,
argininosuccinate lyase deficiency, N#acetyl glutamate synthetase
deficiency)
<edications
+lcohol
Ciuretics (e.g., aceta.olamide)
4arcotics
Balproic acid
<uscle e)ertion and ischemia
?ortosystemic shunts
Techni:ue and conditions of blood sampling
High body temperature
High#protein diet
Tourni:uet use
GRADE
Impairme!
INTELLECTUAL FUNCTION NEUROMUSCULAR FUNCTION
0 4ormal 4ormal
<inimal, subclinical 4ormal e)amination findings. (ubtle changes in wor2 or
driving
<inor abnormalities of visual perception or on psychometric
or number tests
' ?ersonality changes, attention deficits, irritability,
depressed state
Tremor and incoordination
% 3hanges in sleep#wa2e cycle, lethargy, mood and
behavioral changes, cognitive dysfunction
+steri)is, ata)ic gait, speech abnormalities (slow and slurred)
& +ltered level of consciousness (somnolence), confusion,
disorientation, and amnesia
<uscular rigidity, nystagmus, clonus, 7abins2i sign,
hyporefle)ia
$ (tupor and coma 0culocephalic refle), unresponsiveness to no)ious stimuli
<odified from the >est Haven 3riteriaE in ,erenci ?, *oc2wood +, <ullen F, et al.
Hepatic encephalopathyGdefinition, nomenclature, diagnosis, and :uantificationH
,inal report of the wor2ing party at the ''th >orld 3ongresses of 6astroenterology,
Bienna, '--9. Hepatology %00%E &5H!'/#%'.
$ (tupor and coma 0culocephalic refle),
unresponsiveness to no)ious stimuli