[2015] hepatic encephalopathy

Hepatic Encephalopathy
Ayman Alsebaey, MD.
Lecturer of Hepatology,
National Liver Institute.
1
FROM BASICS TO UPDATES

History
• Hippocrates (460–371 B.C.) described the association between jaundice and
acute behavioral disturbances.
• GB. Morgagni (1682–1771) reported the history of a noble from Venice who
was an alcohol misuser in the past. This man developed ascites and some
episodes of agitation, and then he developed prolonged episodes of
somnolence and delirium and finally died. His autopsy revealed the existence
of liver cirrhosis (the Morgagni-Laennec cirrhosis).
• Hann et al, 1893; who showed that dogs undergoing experimental portal-
caval shunt develop behavioral changes within 10–40 days after surgery [meat
intoxication syndrome].
2

History
• van Coulert et al 1932; reported the capacity of ammonia to induce coma or
stupor in patients with cirrhosis.
• S. Sherlock et al., 1954; defined hepatic encephalopathy and coined it as
portal-systemic encephalopathy.
• Fazekas, et al 1957; coined new term ‘hepatic encephalopathy’ (HE).
• Rikkers et al 1978; first identification of latent HE.
• H. Schomerus, W. Hamster, 1998: coined MHE.
3

Definition
• HE It is a reversible impairment of neuropsychiatric function.
• It is reversible neuropsychiatric state (brain dysfunction) varying from subtly altered mental status to
deep coma complicating acute or chronic liver disease.
• CONDITIONS OF HE OCCURRENCE:
• Hepatocellular failure: so patients with pure Schistosomiasis and
collaterals don’t develop HE owing to functioning hepatocytes.
• Shunts  the toxic substances bypass the liver :
• FHF: the liver itself is the shunt as nonfunctioning cells.
• Cirrhosis: the blood bypasses the liver through a) external shunts: collaterals b)
internal shunts: seen around the cirrhosis nodules.
• Portocaval anastomoses and TIPS.
4

Prevalence
 Overall: 30%–40% of those with cirrhosis at some time during their clinical course.
 The prevalence of OHE at the time of diagnosis of cirrhosis is 10%–14% in general.
 In decompensated cirrhosis is 16–21%.
 After TIPS: 10-50%.
 CHE: 20-80%.
 The risk for the first bout of OHE is 5%–25% within 5 years after cirrhosis diagnosis.
 Recurrence:
 40% within 1st year after index OHE.
 Subjects with recurrent OHE have a 40% cumulative risk of another recurrence within 6 months, despite
lactulose treatment.
5

6
OVERT [OHE]
Neurological and
neuropsychiatric
abnormalities
20% annual risk in
cirrhosis pts
Prevalence 30-45%
Detected by bedside
clinical tests.
COVERT [CHE]
(Minimal HE)
Normal mental and
neurological status
Prevalence 60-80%
High risk of traffic
violations and accidents.
Abnormal psychometric
tests

Updated
Nomenclature
Of HE Types
7

Clinical diagnostic criteria
West-Haven criteria for HE
Stage Consciousness Intellect and behaviour Neurological findings
0 Normal  Normal
 Normal examination; if impaired
psychomotor testing, then MHE
1 Mild lack of awareness
 Shortened attention span;
impaired addition or subtraction
 Mild asterixis or tremor
2 Lethargic
 Disoriented; inappropriate
behaviour
 Obvious asterixis; slurred speech
3 Somnolent but arousable
 Gross disorientation; bizarre
behaviour
 Muscular rigidity and clonus;
Hyperreflexia
4 Coma  Coma  Decerebrate posturing
9

11
According to the new American Association for the Study of Liver Diseases/European Association for the
Study of Liver guidelines

Pathogenesis
“the
labyrinth”
13

Intestinal Bacteria
• Patients with cirrhosis have bacterial overgrowth that secretes intoxicants
that contribute to HE.
• Bacteria flora contribute to the production of ammonia
• So HE may improve with oral antibiotics.
15

Ammonia Theory
16
Since Pavlov and Nencki in Russia in the 1890's.

Ammonia And The Brain
 Astrocytes are the only cells in the brain that can
metabolize ammonia.
 α keto-glutaric acid
𝑁𝐻3
glutamic acid
𝑁𝐻3
glutamine
 synapsis.
 Glutamine accumulation  astrocyte swelling  brain edema.
 In FHF [type A HE]:
 Marked elevation of the ammonia   glutamate 
excitatory changes  agitation, confusion, seizures and
coma.
 Glutamine is osmolyte so that it causes cerebral edema
and increased intracranial tension.
19

In Patients With Liver Cirrhosis [Type C HE]:
 There mild brain edema and neuro-inhibition status.
• Chronic Exposure To Ammonia Has Another Effects:
A. Release of the osmolytes “myoinositol and taurine” from inside the cell to
counteract the glutamine effect.
B. Downregulated glutamate receptors in the postsynaptic plate.
C. Inactivated glutamate transporters on the astrocyte cell membrane.
D. Over time, some of these cells change in shape and form and become
'Alzheimer type II' astrocytes.
20

Astrocytes
• Astrocytes are the most abundant cells of the central nervous system (CNS)
• Functions:
• The provision of nutrients and mechanical support to surrounding neurones.
• Regulation of ion transport and neurotransmitter uptake in the brain.
• Key components of the blood–brain barrier (BBB).
• Whilst astrocytes are sensitive to the effects of ammonia, neurons are almost
completely unaffected by exposure to this neurotoxin
21

Ammonia Theory Debate
Pros
GIT bleeding and
meet ingestion HE
HE patients have
increased NH3 levels
CSF glutamine α HE
degree
Cons
Injection of ammonia does not cause HE
Serum ammonia does not correlated with HE
degree or Brain levels of NH3
Hyperammonemia in certain enzyme
deficiencies (e.g. Krebs–Henseleit urogenesis cycle) is
never associated with coma.
22

Inflammation theory
Systemic inflammatory response
syndrome (SIRS) and Sepsis effect:
1) Hyperammonemia induction by
amino acid solution  deterioration
of the psychometric test results.
2) After SIRS treatment;
hyperammonemia induction by
amino acid solution  no effect on
the psychometric test results.
23

1) SIRS is associated with increased degranulation of the neutrophils and
release of inflammatory mediators esp. TNF, IL-1, IL-6.
2) MHE have higher inflammatory markers but is not related to levels of
ammonia and the severity of liver disease.
3) Inflammation   TNF  disturb blood–brain barrier   diffusion of
ammonia into astrocytes.
4) Inflammation   neuro-steroids.
5) In animal model: NSAIDS improved HE.
24

Neuro-steroids Theory
• NSs are synthesized in the central and peripheral nervous system, either from
cholesterol or from steroid precursors.
• 8-kDa translocator protein (TPSO) NSs formation and endogenous benzodiazepines.
• Inflammation Ammonia NSs formation.
• Ammonia tricarboxylic acid cycle activity [Krebs cycle]  GABA synthesis
• Action of NSs:
• Affect mainly the GABAA receptor.
• It  GABAergic tone.
• Pros:
• Autopsy  increased density of expression of translocator proteins that regulate neuro-
steroid synthesis.
26

Oxidative And Nitrosative Stress
• HE is related to  production of reactive nitrogen species (RNS) and
reactive oxygen species (ROS) through the N-methyl-D-aspartate receptor
pathways.
• There is interplay between astrocyte swelling and ROS.
• Both causes astrocyte senescence, senescence genes stimulation,
inhibition of astrocyte proliferation
• So cognitive impairment may not resolve after an attack of overt HE.
• Patients following clinical resolution of overt HE have shown persistent and
cumulative deficits in working memory, response inhibition, and learning capacity.
27

Trojan Horse Hypothesis
• It is used to explain the toxic effect of glutamine in
astrocytes.
• Glutamine formed in the cytoplasm  enters the
mitochondrial matrix  cleaved to release
ammonia while still inside the mitochondria  the
released ammonia mediates release of ROS and
RNS through calcium-dependent pathways.
• ROS  nitration of tyrosine residues in
intracellular proteins  affection of the tans-
astrocytic substrate transport and selective
degradation of the permeability of the blood–brain
barrier  ultimately promotes astrocyte swelling
and cerebral edema.
28

Manganese Theory
• MRI of patients with cirrhosis especially after portocaval shunt showed
accumulation of Mg in the basal ganglia.
• It is associated with Alzheimer type II astrocytes.
• So it is responsible for the Parkinsonian symptoms such as tremors.
• It increases NSs level and GABAergic tone.
• HYPONATREMIA:
• is a predictor of the development of OHE in patients with cirrhosis.
29

Genetics Theory
About 40% of cirrhotic patients with minimal HE do not develop
overt HE despite follow up > 7 years.
Cirrhotic patients showing the same degree of liver dysfunction and
suffering from the same precipitant factor (i.e., variceal bleeding)
may, or may not, develop overt HE.
Polymorphisms in the promoter region of K-glutaminase gene
that could influence protein activity in either direction (an increase or
a decrease) in glutaminase activity.
30

Old Theories
• GABAergic theory:
• Bacterial over growth  GABA  escapes metabolism by the liver through collaterals 
brain  neuro-inhibition.
• Cons:
• no increase in cerebral GABA levels can be detected.
• Benzodiazepine theory:
• BZs receptors are related to GABA receptors  neuro-inhibition.
• False neurotransmitter theory:
• There is increases arromatic aa and decreased branched chain aa.
• Aromatic aa form false neurtotransmitors  neuro-inhibition.
• Cons:
• IV octopamine   cerebral catecholamine levels, but does not lead to alteration of consciousness.
• Norepinephrine and dopamine concentrations in the brains of deceased cirrhotics who had HE are
normal.
• Imbalances in plasma amino acid levels are also observed in cirrhotics without HE.
• Treatment of HE by bromocriptine is ineffective.
31

Clinical Examination
• HE is not the only reason of altered mental status in cirrhotic patients.
• So it is a diagnosis of exclusion:
• intra-cranial events, electrolyte abnormalities and sepsis.
• Findings:
• Global motor deficit, hyperreflexia, positive Babinski’s sign.
• Compensatory hyperventilation.
• Fetor hepaticus [dimethyl sulfide; breath of the dead].
• Asterixis
• Persistent encephalopathy:
• Parkinsonian symptoms
• Spastic paraparesis from hepatic myelopathy [post-portocaval shunt].
• Hepatic dementia with attention deficit, dysarthria and apraxia (neuronal loss).
32

Asterixis
• Is a flapping tremor.
• Cause:
• Imbalance between the agonist and
antagonist muscle due to disturbed
diencephalic motor centers
• Detection areas:
• tongue, and the upper and lower
extremities.
• Not specific to the liver:
• Carbon dioxide intoxication, uremia, organ
failure and stroke of basal ganglia.
• Not seen in advanced cases and coma.
33

Symptom Cause Comments
Altered mental status, memory
loss, disorientation, personality
changes, memory impairment,
shortened attention span,
slurred speech, confusion, coma
 Cerebral edema (varying degrees) with
astrocyte swelling
 GABA toxic effects
 Systemic inflammation
 Alterations in the cerebral blood flux and
in the oxidative metabolism
 Altered communication between the astrocyte and the
neuron
 Trojan horse theory: oxidative stress caused by
mitochondrial ammonia accumulation (glutamate
transport)
Transient focal neurologic
deficits or seizures
 Cerebral edema (varying degrees) with
astrocyte swelling
 GABA toxic effects
 Alterations in the cerebral blood flux and
in the oxidative metabolism
 Rarely occurs
Asterixis (flapping tremors)
 Abnormal function of diencephalic motor
centers that regulate the tone of agonist
and antagonist muscles, normally
involved in maintaining posture
 Adams and Foley first described asterixis in 1949 in
patients with severe liver failure and encephalopathy
 Present in early to middle stages of HE
 Not pathognomonic; it occurs with renal failure,
hypercapnia, and stroke affecting basal ganglia
 Asterixis does not occur in advanced HE
 Never seen in coma
 Testing for asterixis
34

Hyperreflexia, hypertonia, or
extensor plantar responses
 Pyramidal involvement  Never seen in coma
Parkinsonian symptoms:
bradykinesia, tremors
 Deposition of manganese in the basal ganglia
(globus pallidus and substantia nigra)
 Manganese induces changes
in astrocytes of the basal ganglia that
promote the formation of Alzheimer
type II astrocytes
 Manganese acts as a neurotoxin to
stimulate translocator proteins on
astrocytes
 Tics or chorea are rare
 Severe Parkinson seen only in chronic
HE
Sleep latency, sleep
fragmentation, inversion of
sleep-wake pattern
 Impaired hydroxylation and sulfation to 6-
sulfatoxymelatonin in the liver
 Ammonia levels
 —
Fetor hepaticus
 Attributed to dimethyl sulfide, a volatile sulfur
compound that can be identified in the breath
and serum of patients with cirrhosis
 Found in cirrhotics with or without HE
35

Hyperventilation  Associated with acidotic pH
 Compensatory mechanism that
decreases the entrance of ammonia
into the brain
 It has also been related to increased levels of estrogens and
progesterone
Hepatic dementia  Pathogenetic mechanism is obscure
 Associated neuronal loss
 In chronic HE
 Fluctuating symptoms with periods of improvement and a subcortical
pattern
 The initial manifestations are attention deficits, visuopractic
abnormalities, dysarthria, and apraxia
 Seen rarely; is reversible after LT/TIPS
Hepatic parkinsonism  Pathogenetic mechanism is obscure
 Associated demyelination along the
pyramidal tract
 In chronic HE
 Resembles Parkinson disease, except for a symmetric presentation
and lack of significant tremor
Hepatic myelopathy  Pathogenetic mechanism is obscure  In chronic HE
 Usually motor abnormalities exceed mental deterioration
 Is characterized by a progressive spastic paraparesis accompanied
by hyperreflexia and extensor plantar responses
 Only a few patients have sensory symptoms or incontinence
 Does not respond to standard therapy
36

Where is the predator or beast in
the image??
37

Where is the enemy in the image??
38

Minimal Hepatic
Encephalopathy
[MHE]
-----------------------------------
The Hidden Unknown
Enemy
39

Definition of Covert MHE
• The presence of measurable cognitive defects in patients with liver disease and/ or
porto-systemic shunting that are not identified by detailed clinical history and
complete neurological examination, including interview of close family members.
• Is detected by abnormalities in neuro-psychometric or neurophysiological tests that
can be performed at the bedside and in the outpatient setting, in the absence of
other known causes of abnormal cognitive tests.
• AASLD/EASL
• CHE is the preclinical stage of OHE
• It consists of MHE and West Haven grade 1 HE due to poor reliability of the grade I
stage.
• OHE starts with grade 2 or with evidence of asterixis and disorientation.
40

Prevalence
• High prevalence of CHE (30-80%) among patients with cirrhosis without overt HE.
• Overt HE develops in >50% of MHE patients within three years.
• Prevalence of CHE increases with increasing severity of liver disease.
• MHE is present in a significant proportion of patients with portal hypertension
without intrinsic liver disease.
• All patients with cirrhosis of the liver should be tested for the presence of MHE.
• RISK FACTORS:
• Alcohol as etiology of cirrhosis, have history of overt HE in the past.
• Advanced liver disease; CTP C, esophageal and gastric varices.
41

Natural history of CHE
 Course:
 Unchanged.
 Improve.
 Deteriorate.
 Develop overt HE.
 CHE α degree of liver dysfunction.
 CHE is associated with:
 worsened survival, increased risk of hospitalization and overt HE development
42

CHE
Impaired
HRQOL
High risk of
OHE
High risk of
mortality
 Ability to
operate
complex
machinery
High risk of
falls
High risk of
accidents
Driving
problems
Higher
prevalence
of sleep
disorders
Burden on
health care
resources
Cognitive
dysfunction
43
Catastrophic
effects of CHE

• Health related quality of life (HRQOL):
• HRQOL is all aspects of human well being, encompassing physical and
cognitive capabilities, functional behavior, emotional status and psychosocial
adjustment
• It is measured by different scores e.g. NHP, SIP, SF-36, CLDQ, NIDDK-QA.
• CHE adversely affects HRQOL:
• Complex activities: e.g. driving, planning a trip
• Impaired social interaction, alertness, emotional behavior, sleep, work, home
management, and recreation and pastimes.
• MHE is associated with decreases appetite  malnutrition HRQOL.
• MHE is associated with depression, anxiety-trait and alexithymic symptoms
HRQOL.
• It may reverses with lactulose, rifaximin or probiotic therapy.
44

• Sleep Disturbances:
• Patients with MHE have more sleep troubles than those without.
• Unsatisfactory night sleep due to delayed sleep onset and multiple night
awakenings resulting in reduced sleep time and excessive daytime
sleepiness.
• Circadian rhythm abnormalities due to toxic effect on suprachiasmatic
nucleus and impaired melatonin clearance.
• Memory and Learning Difficulties:
• Short memory affection.
• Attention deficits  encoding defect and learning impairment.
• Hyperammonemia cGMP  learning impairment.
45

• Driving:
• there is impaired driving performance both by using real road driving tests
or a driving simulator.
• More traffic violations and motor vehicle accidents or collisions.
• Fatigue that develops with work worsens this condition.
• Navigational Skills:
• Navigation is a complex process for safe driving.
• Difficulties in following a map.
• There is more number of illegal turns and accidents.
• There is poor insight of the driving skills, prolonged reaction time,
impaired navigational skills and worsening fatigue.
• Driving simulation is beneficial.
46

• Falls in CHE
• 40% of CHE patients had falls  need for hospitalization.
• impaired attention and visuomotor coordination and slowed reaction time and
psychomotor speed.
• Falling  fractures and associated surgery  morbidity,
decompensation, mortality, disturbances of the
patient family and high economic burden.
• Employment and Socioeconomic Burden :
• 50% of CHE have not regular employment
• slowing of psychomotor function and reduced work performance.
• 60% of blue-collar workers are unfit to work compared to only 20% of
white collar workers.
• Diminished work performance and lost wages
47

Diagnosis
of MHE
Psychome-
tric tests
Stroop
application
Ammonia
Brain
imaging
Lumbar
puncture
EEG
MRI
spectrosc-
opy
Single PET
48

Test Domain Tested Comments
Paper-and-pencil psychometric tests
 Number connection test, part A Psychomotor speed Poor specificity
 Number connection test, part B Psychomotor speed More specific
 Digital symbol test Psychomotor speed/attention Very sensitive
 Serial dotting test Psychomotor speed Psychomotor speed only
 Block design test Psychomotor speed Lasts 20 min
 Line tracing test Psychomotor speed Speed and accuracy
 Repeatable battery for the assessment of
neuropsychological status
Psychomotor speed Used in dementia and brain injury
Computerized psychometric tests
 Inhibitory control test Attention, vigilance, working memory Requires highly functional patient, computer
skilled
 Cognitive drug research Attention + episodic + working memory Requires highly functional patient, computer
skilled
 Stern paradigm Working memory, vigilance, attention ––
Neuropsychological tests
 EEG mean dominant frequency Generalized brain activity Can be performed in comatose patients
 Visual evoked potentials Interval between visual stimulus and activity Highly variable, poor results
 Brainstem auditory evoked potentials Response in the cortex after auditory click
stimuli
Inconsistent response
 Critical flicker frequency Visual discrimination and general arousal Requires highly functional patients 49

50
Test (domains examined) Advantages Disadvantages Diagnoses Outcome prediction
Paper-Pencil
PHES: NCT-A and B, digit symbol test,
line-tracing test, and serial-dotting test
(attention, processing speed, response
inhibition, and visuospatial awareness)
Validated, gold standard
Lack of reference normative data in the
United States
Score of < -4 Score < -6 predicted poor survival
RBANS (visuospatial, attention, language,
immediate and delayed memory)
Has US reference data
Copyrighted, needs interpretation by a
psychologist
Dependent on a psychologist’s
interpretation
Not studied in HE; 2 domains not impaired
in CHE
Computerized
ICT (working memory, response inhibition,
psychomotor speed)
Validated and does not require a
psychologist’s interpretation
Requires high-functioning patients with
working knowledge of a computer
High lures or weighted lures
Significant impairment leads to increased
motor vehicle crashes and violations, and
predicting OHE
CDR (attention, continuity of attention,
speed of memory, and quality of episodic
and working memory)
Not validated in the United States
Requires high-functioning patients with
working knowledge of a computer
Score of -5 to 15
Able to predict resolution of cognitive
dysfunction after transplant and TIPS
Continuous reaction time (sustained
cerebral processing time, reaction time and
response inhibition, and nerve inhibition)
Not validated in the United States
Requires adequate hearing, no reference
data for United States
CFT index of <1.9 --
EncephalApp Stroop Application
(psychomotor speed, cognitive flexibility)
Free, and can be used on a mobile platform.
Has US reference data
Cannot be performed in red-green color-
blind subjects
>190 seconds (on and off time) Longer times can predict OHE episodes
Neurophysiological
EEG (brain activity, mean dominant
frequency)
Can be used on all stages of HE without
learning
Highly variable, requires a neurologist’s
interpretation
Dependent on a neurologist’s interpretation
EEG plus MELD increases accuracy in
predicting prognosis
CFF (visual processing and discrimination,
general arousal)
Test can be administered at bedside
Requires high-functioning patients and
expensive equipment, needs binocular
vision
CFF < 39 Hz Can predict OHE
Evoked potentials (visual, auditory, and
somatosensory)
Sensitive without learning effects
High variable results, requires a
neurologist’s interpretation
Variable, dependent on a neurologist’s
interpretation
Can predict the development of OHE

Paper-and-pencil Psychometric Tests
 Psychometric Hepatic Encephalopathy Score (PHES):
 Validated for MHE diagnosis in Germany, Italy and Spain not USA.
 Number connection test:
 part A [NCT-A]
 part B [NCT-B]
 Digital symbol test [DST]
 Serial dotting test [SDT]
 Block design test [BDT]
 Line “trail” tracing test [LTT]
 96% sensitivity and 100% specificity. If <-4 is diagnostic, <-6 is of poor prognosis.
 If not available then abnormalities in 2 of the tests (at least 2 standard deviations from age-
and education-matched controls) would identify CHE [NCT-A, NCT-B, BDT, DST]
 Easy but time consuming, difficult to interpret, patient must be literate with fine motor
activities [pencil and paper].
51

Repeated battery for the assessment
of neuropsychological status (RBANS)
• RBANS has been used for the evaluation of Alzheimer’s
disease, schizophrenia, traumatic brain injury in 20-25m.
• Was tested in a selected population of patients with cirrhosis
awaiting liver transplantation.
• It has not been specifically validated in HE.
• The test has 2 domains, cortical and subcortical.
• HE patients predominantly perform worse in the sub-cortical
component.
• The applicability of RBANS in practice is limited because it
must be administered and scored by a psychologist.
53

Neuropsychological Tests
• They are offered under the supervision of a neurologist and require
specialized equipment, personnel and time.
• EEG and Visual evoked potentials:
• have not been shown to provide diagnostic information critical for the diagnosis of
CHE
• Brainstem auditory evoked potentials
• Critical flicker frequency
54

Critical Flicker Frequency (CFF)
• Flicker light is going on and off repeating.
• No need for a psychologist, short period of time & minimal
costs.
• Principle:
• In HE the retinal cells like astrocytes undergoes edema “hepatic
retinopathy”
• Light from 60Hz and gradually decreasing till flickering.
• The subject has to press a button as soon as the impression of fused
light switches to flickering light.
• CFF threshold of 38–39 Hz
• After patient training, done 8 times and the mean value is calculated as
CFF.
• Drawbacks:
• Not validated in USA.
• It requires intact binocular vision and absence of red-green blindness.
• Fogging of glasses. Age, medications.
• Moderated sensitivity and specificity so should be used for follow up.
55
Pulsating
light emitting
diode
The HEPAtonorm™ Analyzer consists of a) hand
held control unit b) headset c) patient stop button

Computerized Psychometric Tests
• Inhibitory Control Test
• Cognitive Drug Research
• Scan Test
56

Inhibitory Control Test (ICT)
• It is a computerized that assesses inhibition, attention span, vigilance, and working memory.
• ICT is the most currently available computerized tests for HE.
• It has been used in the description of traumatic brain injury,
schizophrenia and attention deficit disorder.
• Principle:
• ICT consists of 1728 stimuli, 40 lures and 212 targets that are presented within 13 min after a training run:
• The principle of this test is based on 'targets' and 'lures'.
• Patients are shown a series of different alphabet sequences that flash on the computer screen one after
another, and are expected to respond when 'X' is followed by 'Y' and vice versa—a so-called 'target'.
• Patients are told not to respond to a 'lure'—when 'X' followed by 'X' or 'Y' is followed by 'Y'.
• A lure response greater than five (out of 40 attempts) detects MHE with high sensitivity.
• Clinic personnel were able to administer ICT with minimal training and it was found to be cheaper than
psychometric test administration.
• CHE is diagnosed when patients have longer reaction times, a lower rate of target
responses, and a higher rate of lure responses with a sensitivity and specificity of 87% and
77%, respectively.
57

The Cognitive Drug Research (CDR)
• The CDR consists of five psychometric subsets that test attention power,
attention continuity, speed of memory and quality of episodic and working
memory.
• These tests have 50 parallel forms and have population norms for the UK.
• This test has shown good correlation with the gold-standard PHES test and is
popular in the UK.
58

Scan Test
• Scan Test is also a computerized test that measures reaction time to visual
stimuli, reaction time to choice, and scan reaction time based on the
Sternberg paradigm.
• It is not available in the USA, but has been validated in Europe as a good
psychometric test that prognosticates cirrhosis.
• It has also been endorsed as a test that is clinically useful in CHE diagnosis
59

The Stroop Smartphone Application
• It is developed by Bajaj et al., 2013.
• It is a short and recently validated test, simple, easy, no need for psychologist.
• EncephalApp—Stroop Test is available as a free download on iTunes.
• It measures psychomotor speed and cognitive flexibility and have been
validated for the diagnosis of CHE.
• It consists of identifying the color of symbols presented, delineating the correct color of a color word
that is a different color than the word itself (e.g., red in a green-colored font), and reaction times.
• It assesses time to correctly identify a series of symbols with different colors (off-time) and printed
words with different colors (on-time).
• A cut-off time of more than 190 seconds identified CHE with excellent accuracy.
• OHE patients do worse than those without OHE.
• It correlated with accidents and illegal turns in driving simulation tests.
60

Serum Ammonia Levels
• Levels of arterial and venous ammonia may correlate positively with the
severity of HE.
• Elevated ammonia level is not diagnostic of HE.
• Routine measurement of ammonia levels in the blood is not recommended.
• Difficult precautions:
• Blood sample should be collected from a stasis-free vein (that is, without using a
tourniquet or clenching and taking care not to cause turbulence or hemolysis or
release of ammonia from the muscles) and must be immediately transported on ice to
the laboratory to be analyzed within 20 min in lithium heparin– or sodium heparin–
containing (green top) Vacutainer because heparin inhibits the release of ammonia
from red blood cells..
• Artifactual increase in ammonia levels can be seen in patients with mild exertion prior to sampling and
spontaneous release of ammonia from red blood cells in blood samples left at room temperature.
62

Lumbar puncture
• CSF shows increase of glutamine and aromatic amino acids.
• You may do to exclude meningitis, encephalitis or subarachnoid
hemorrhage.
• Do not do
• LC patients have coagulopathy, LP is associated with bleeding.
• In FHF, LP increases brain herniation.
63

SINGLE-PHOTON EMISSION COMPUTED
TOMOGRAPHY [SPET]
• SPECT studies the spatial distribution of radioactive tracer technetium Tc 99
and its local metabolism in the brain.
• CHE patients have increased blood flow in the basal ganglia.
• SPET is more available and less expensive than PET.
• Small studies are done till now, so still of limited use.
64

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• For Free
• Stoop Test
• Inhibitory Control Test
• Trail Marking Test
• Line Drawing Test
65

66
MRI technique Imaging abnormality Clinical correlate
T1-weighted imaging  Bilateral, symmetrical, high-
intensity signal in the basal ganglia
(globus pallidus and substantia
nigra)
 Attributed to preferential deposition of manganese in the
basal ganglia
 Found in patients with cirrhosis who have substantial
portosystemic shunts
 No quantitative relation to severity of HE
 Reverses after liver transplantation
Proton spectroscopy
(1H MRS)
 Increase in glutamate and
glutamine signals
 Decrease in myoinositol and
choline signals
 Homeostatic compensatory metabolic changes occur in
the astrocytes of patients with chronic liver failure that
prevent massive cerebral edema
 Changes seen on MRS imaging usually correlate with the
severity of HE
 Changes resolve after liver transplantation
Magnetic transfer ratio  Mild, diffuse reduction in magnetic
transfer ratio in the white matter
 Reflects mild cerebral edema
T2-weighted FLAIR
sequence and diffusion
weighted imaging
 Diffuse increase in white matter
signal intensity in the cerebral
hemispheres and the corticospinal
tract
 Observed changes because of cerebral edema
 Could explain neurologic abnormalities in patients with
cirrhosis
Abbreviations: FLAIR, fluid attenuation inversion recovery; HE, hepatic encephalopathy; MRS, magnetic resonance spectroscopy.

67
Diagnostic test Advantages Disadvantages
Serum levels of ammonia
Positively correlated with the severity of HE Does not change approach to diagnose and manage HE
Can be challenging to take appropriate blood samples in the clinic
Clinical scales for OHE
West Haven criteria
Well-established classification criteria (in use for ≈30 years)
Used in multiple studies of OHE
Interobserver variation influences test results (especially for low grades of HE)
HE Scoring Algorithm
Minimal variability in results between different test sites
Characterizes low grades of HE
Time consuming (which may be a limiting factor in the outpatient setting)
Neuropsychometric tests ('paper and pencil' tests) for MHE
Psychometric HE score
Specifically designed to diagnose subtle cognitive changes in patients with MHE
Endorsed as the 'gold standard' by the Working Party at the 1998 World Congress
of Gastroenterology, Vienna, Austria
Poor test of memory
Difficult to interpret and score
Excessive reliance on measuring fine motor skills
Unpopular in USA (lack of US-specific normative data and availability)
Repeatable Battery for the
Assessment of Neurological
Status
Tests can be completed rapidly (within 25 min) Difficult to interpret and score
Excessive reliance on measuring fine motor skills
Computerized psychometric tests for MHE
Inhibitory control test
Detects MHE with high sensitivity
Validated against existing psychometric tests
Studies using this test have mostly been conducted in a single institution located in either
Wisconsin or Virginia, USA
CDR system
Correlates well with neuropsychometric tests Time consuming, which could be a limiting factor
Trial run needed before formal testing
Neurophysiologic tests
Critical flicker frequency
High sensitivity and specifity
Correlates well with neuropsychometric tests
Widely used in clinical trials
Lack of widespread availability in the USA to permit use in ambulatory patients
Electroencephalography HE associated with slow frequency of electrical activity Variable sensitivity for the diagnosis of HE (43–100%)
Brain imaging
MRI
Multiple techniques available
Identifies several brain abnormalities associated with HE (e.g. levels of glutamate)
Can be expensive (especially the newer techniques that show low grades of cerebral edema)
CT
Useful for excluding other causes of encephalopathy
Identifies conditions that worsen HE (subdural hematoma or a cerebrovascular
event)
Poor detection of low grades of cerebral edema in most patients with HE
Risk associated with radiation exposure
Abbreviations: CDR, Cognitive Drug Research computerized assessment; HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy.

Treatment of Hepatic Encephalopathy
69

HE
TREATMENT
Overt HE
[OHE]
Special
cases
[FHF,
TIPS]
Covert HE
[CHE]
70

Overt Hepatic Encephalopathy [OHE]
Treatment
71

OvertHepatic
encephalopathytreatment
Exclusion of other causes
of encephalopathy
Identification of
precipitating factor
Empiric treatment launch
Reassessment after 72 hr.
72

1st step is to exclude other causes e.g. meningitis, encephalitis.
Identification of the precipitating factor e.g. GIT bleeding.
90% of patients can be treated with just correction of the precipitating
factor
Start empiric therapy.
A rapid response means right diagnosis.
ICU admission for comatosed one.
If no response after 48-72hr:
Wrong diagnosis so MRI of the brain should be done to exclude CNS
causes.
Missed so untreated precipitating factor.
Missed a synchronous causes of encephalopathy.
Inadequate treatment.
73

Treatment
Precipitating
factor ttt
Enema ??
Nutrition &
BCAS
Medical
therapy
Non-
absorbable
disaccharides
Lactulose
Lactilol
Antibiotics
Rifaximin
Neomycin,
paromomycin
Ammonia
lowering agent
Ammonia
scavengers
Lola
Ornithine
phenylacetate
Na benzoate
Na & glycerol
phenylbutrate
Spherical
carbon
adsorbent
Polyethylene
glycol
Experimental
Zinc
Probiotics
Combination
therapy
Embolization of
portosystemic
shunt
Secondary
prophylaxis
Artificial liver
support
Liver
transplantation
75

Treatment Of The Precipitating Factor
GI bleeding
Octreotide, IV PPI, endoscopic or angiographic therapy
Blood transfusions, correction of coagulopathy
NG lavage to remove blood from stomach
Infection Antibiotic therapy
Sedating medications Discontinue benzodiazepines, narcotics, consider flumazenil or naloxone
Electrolyte
abnormalities
Discontinue diuretics, perform serial paracentesis if needed
Correct hypokalemia or hyperkalemia, hyponatremia
Constipation Provide laxatives and enemas
Renal failure
Discontinue diuretics
Albumin administration
Discontinue nephrotoxic medications
77

Enema???
Cons to enema:
 Difficult for nursing staff.
 Variable efficacy due to variation in the indwelling and drug exposure time.
 It should be done by placing the pt in Trendelenburg left lateral decubitus
position, right decubitus position, then a position in which the upper part of
the body is elevated to maximize the exposure of the entire colon.
Pros:
 Is a safe and effective method for obtunded patients if oral administration is
not possible least aspiration e.g HE III.
 Lactulose also can be given rectally (300 mL in 700 mL of saline)
78

Nutrition
Old concept:
 Protein restriction is useful as decreasing the nitrogenous load, NH3.
New concept:
 Patients with cirrhosis must eat at least 1.2 – 1.5 g/kg of protein daily.
 divided between at least 4 meals every day, and patients should take a late
evening snack to reduce protein breakdown during the overnight fast
 Branched-chain amino acids (BCAAs) and vegetable protein or dairy
products should be added when HE develops.
 Muscles are alternative pathway for NH3 metabolism in patients with
cirrhosis “ammonia sink”.
 Lack of protein diet causes muscle wasting (sarcopenia), cachexia with increased
episodes of encephalopathy.
79

Vegetable-based protein
 Less ammoniogenic so better tolerated by cirrhotic patients.
 It may causes bloating and flatulence in some patients.
 It has 2 actions:
 High fiber content that increases colonic motility and purgation.
 It decreases the colonic pH reducing ammonia absorption.
80

Branched-chain Amino Acids
Valine, Leucine, and Isoleucine
 Pros:
 Action:
 BCAAs  glutamate formation +NH3  glutamine in the muscle, so cirrhotic patients have low serum
BCAAs levels.
 Leucine promote protein synthesis by the liver  ammonia formation.
 Recent studies and meta-analysis: BCAAs augments rapid recovery from HE without
survival effect.
 Apart from encephalopathy; BCAAs improve levels of serum albumin, increase progression-
free survival and reduce both the number of hospitalizations and the length of hospital stays in
patients with cirrhosis.
 Dose: 0.25 g/kg body weight.
 Cons:
 Expensive with poor availability.
 IV preparation are not effective so use only oral formulas.
81

Non-absorbable Disaccharides
 They are the 1st line therapy [Cochrane review found insufficient evidence to either support or
refute the use of lactulose].
 Members: Lactulose and Lactilol [more palatable and less GIT upsets].
 Action:
 Laxative effect  ammonia elimination.
 Reduced NH3 synthesis and absorption:
 Lactulose  intestinal bacteria  acetic and lactic acid  pH [acidic media]
  the synthesis and absorption of ammonia.
 It increases movement of NH3 from blood to the GIT.
 Lactulose  colonic lactate and H ions NH3 NH4 non absorbable form.
 Promote the growth of beneficial acid resistant, non–urease-producing bacteria
[difficult to prove].
82
Medical Therapy

Dose:
15–30 ml given twice a day to induce 2–3 soft bowel movements
daily.
Added to enema: 1-3 L of 20% lactulose is more effective than
tap water in comatosed patients to avoid aspiration [lack
evidence].
Adverse effects: sweet taste, bloating, over treatment
[dehydration] and hypokalemia.
Risk factors for failure of lactulose therapy:
High MELD, high total leukocyte count,
Low serum sodium, low MAP,
HCC
83
Medical Therapy

Cons:
Studies were small and underpowered.
Variable efficacy.
Insufficient evidence showing that lactulose is efficacious for
OHE
Meta-analysis by Als-Nielsen et al 2004:
 when compared to placebo or no intervention, nonabsorbable
disaccharides had no statistically significant effect on mortality, but did
show to reduce the risk of no improvement of OHE.
Pros:
clinical anecdotal experience and comfort with the use of
lactulose, which accounts for the lack of placebo RCTs for HE.
84
Medical Therapy

Comparison of Non-absorbable Disaccharides and Placebo or No Treatment for Hepatic
Encephalopathy.
Trial
Study
design
Patients No Treatment Assessment Efficacy
Simmons et al Parallel AHE + CHE 26
Lactulose/g
lucose
Clinical grading, ammonia, stool
production
Lactulose = glucose
Uribe et al Parallel AHE 15
Lactulose
enema
Mortality, clinical grading Lactulose > placebo
Lanthier et al Crossover CHE 5 6 months
Clinical examination, psychometric
tests, ammonia levels, EEG, cerebral
blood flow
Lactulose = lactitol
Heredia et al Parallel AHE 40 5 days
Mortality, clinical grading, PSE grade,
adverse events
Riggio et al Parallel CHE + MHE 31 6 months
PSE index, new episodes of HE,
adverse events
85

Antibiotics
 Neomycin:
 It was the first antibiotic that was used.
 It inhibits the intestinal glutaminase plus reduced ammonia production by bacteria.
 Dose: 3-4g/day.
 Side effects: Ototoxicity, nephrotoxic [??].
 Metronidazole:
 Though effective but associated with resistance and peripheral neuropathy.
 Paromomycin and vancomycin
 Is associated with bacterial resistance.
 Vancomycin-resistant enterococcus
86
Medical Therapy

Rifaximin
 Is minimally absorbed drug with very low systemic absorption and a high barrier to
resistance.
 Recent meta-analysis: is equal or superior to lactulose with less abdominal pain.
 It is equal to neomycin but more NH3 lowering action with less side effects.
 Rifaximin monotherapy is unproven so usually combined with lactulose.
 Action:
 Broad spectrum drug with low risk of resistance.
 It acts against Gram-positive and Gram-negative organisms, both aerobes and
anaerobes.
 Acts mainly in the small intestine with marked lowering bacterial effect.
 Dose:
 550mg /12hr.
 AE: flatulence, abdominal pain, headaches, and constipation.
87
Medical Therapy

Rifaximin for Hepatic Encephalopathy.
Trial Study design
No of
patients
Duration of
treatment
Assessment Efficacy
Festi et al
Lactulose (open-
label)
21 21
Neurological signs of HE, asterixis score,
HRNB, EEG, ammonia levels
Rifaximin = lactulose
Massa et al
Lactulose
(double-blind)
40 15
HE index severity, mental status,
cancellation tasks, HRNB, EEG
Rifaximin > lactulose
Mas et al
Lactitol (double-
blind)
103
5–10 days
Mental status, asterixis score, EEG,
ammonia levels, PSE index,
psychometric tests
Rifaximin = lactitol
Paik et al
Lactulose (open-
label)
54
7 days Ammonia levels, flapping tremor, mental
status, HE index, psychometric tests
Rifaximin = lactitol
Jiang et al Meta-analysis 264 – –
Rifaximin = disaccha
rides
Eltawil et al Meta-analysis 565 – –
Rifaximin = disaccha
rides
88

Ammonia Lowering Agent
Ammonia Scavengers: LOLA
 L-Ornithine-L-Aspartate (LOLA) supplies substrates for urea cycle and
glutamine synthesis.
 Not available in USA.
 Actions:
  urea production by increasing carbamyl phosphate synthetase in periportal
hepatocyte.
  liver and muscle glutamine by increasing GLN synthetase
 It is a promising drug though most studies used I.V. form on HE I-II patients.
 Oral route needs more evaluation.
 IV preparations are better than oral ones.
89
Medical Therapy

Ammonia Scavengers: Na Benzoate
 It combines with glycine so decreasing serum ammonia.
 Approved in urea cycle defects and hyperammonemia.
 Usually used in combination with sodium phenylacetate (Ammonul®) or
sodium phenylbutyrate (Buphenyl®).
 High sodium content (1-2g/day):
 Salty taste so not palatable.
 Fluid retention with ascites
 Hypernatremia with altered mental status so not useful in HE patients.
90
Medical Therapy

Ammonia Scavengers: Na & Glycerol Phenylbutrate
 Sodium phenylbutyrate (SPB):
 SPB  phenylbutyric acid  phenylacetate + glutamine  phenylacetylglutamine
 urine.
 High sodium content  ascites.
 Glycerol phenylbutyrate (GPB); Ravicti®:
 is an oral prodrug of Na phenylbutyrate that is safe in cirrhotic patients.
 nearly tasteless, odorless, sodium-free liquid compound.
 Approved in urea cycle defects and hyperammonemia.
 Still phase III in HE (Clinicaltrials.gov, NCT00999167).
 6 mL twice a day for 16 weeks .
 improved outcomes, decreased ammonia levels.
 Useful in treatment and prevention of recurrent HE.
92
Medical Therapy

Ammonia Scavengers: Ornithine Phenylacetate
 L-Ornithine-phenylacetate [LOPA]:
 Is similar to LOLA
 OP (OCR-002) combines ornithine and PAA.
 It supplies urea cycle with ornithine.
 Phenylacetate + glutamine  phenylacetylglutamine [easily excreted].
 Still phase IIb decompensated cirrhosis for overt HE.
93
Medical Therapy

Ammonia Scavengers: Spherical Carbon Adsorbent
AST-120:
 It is a spherical carbon adsorbent (0.2-0.4 mm microspheres).
 It was approved in Japan in 1991 to improve uremia and
delay the initiation of dialysis in patients with chronic renal insufficiency.
 It is safe for prolonged use as being or degraded or adsorbed from
 It has minimal interference with digestive enzymes or drug absorption.
 It binds very small molecules in the gut e.g. TNF-α, lipopolysaccharide, or
endotoxin, and block their absorption.
 It has also ammonia lowering properties.
Still phase II study.
94
Medical Therapy

Ammonia Scavengers: Polyethylene Glycol
 PEG is used for bowel preparation before colonoscopy
 Idea is rapid clearance of gut bacteria (4-L dose of PEG).
 Clinicaltrials.gov, NCT01283152.
 More effective than lactulose as treatment for OHE with less hospital stay.
 Less ammonia lowering effect than lactulose [? Dehydration related effect].
 There were no significant changes in serum sodium, creatinine, or BUN after either
PEG or lactulose treatment.
 The data are promising as a treatment for acute OHE.
95
Medical Therapy

Ammonia Scavengers Appearance
Mechanism of
Action/Byproduct
Dosage Approved Use
Sodium benzoate  White or colorless
crystalline powder
• 1 mol of Nitrogen
removed/mole of
benzoate after
conjugated with glycine
• 5.5 g/m2 IV over
90–120 min, repeat
daily
• Urea cycle disorders
Food preservative
Sodium phenylacetate  White to off-white
crystalline powder
• 2 mol of Nitrogen
removed/mole of PAA
after conjugated with
glutamine
• Urea cycle disorders
GPB  Colorless to pale
yellow liquid
• Nitrogen removal in the
form of urinary PAGN
• 5–12.4 g/m2 daily • Urea cycle disorders
OP  Crystalline salt • Nitrogen removal in the
form of urinary PAGN
• 10 g IV daily • Possibly future
approval for overt HE
AST-120  Charcoal powder • Binding of neuroactive
substances (including
ammonia) in the GI
tract
• 6–12 g IV daily • Delaying dialysis in
chronic kidney disease;
uremic symptoms
96

Experimental Agents
Zinc:
Is a cofactor of urea cycle.
Zinc replacement is not harmful, but it does not seem to have a
place in the management of HE.
Can be used only with zinc deficient patients or resistant to usual
treatment/
97
Medical Therapy

Experimental Agents
 Probiotics:
 Probiotics are live microbiologic dietary supplements that alter the intestinal balance of
microflora in the gut e.g. Lactobacilli and Bifidobacteria
 They reduce bacterial translocation and subsequent endotoxemia .
 Useful in patients with CHH not OHE.
 Its use in management of high grade HE is lacking and different strains may have
different effects on HE should be kept in mind.
 In a Cochrane meta-analysis of 7 CHE/OHE trials there were no reported differences of probiotics compared
with lactulose with respect to a reduction in ammonia levels and improvement in mental status.
 The analysis did show an advantage of probiotics compared with no treatment in all-cause mortality, number of
adverse events, and HRQOL.
 Regular use of probiotics in the management of HE still need more data.
98
Medical Therapy

Combination Therapy
 The evidence evaluating the use of combination therapy for the treatment of
HE does not support its widespread use.
 The combination of rifaximin and lactulose may be considered in the treatment
of HE and in patients refractory to monotherapy.
 RECENT STUDY:
 Sharma et al., 2013 should combined rifaximin and lactulose are better than
lactulose monotherapy.
99
Medical Therapy

Embolization of portosystemic shunt
 Patients with persistent or chronic encephalopathy usually have porto-
systemic shunt especially spleno-renal shunt.
 It can be embolized by angiography [balloon-occluded retrograde transvenous
Obliteration] using coils.
100
Medical Therapy

Post-TIPS HE
 Lactulose and rifaximin are of no benefit in preventing post-TIPS HE.
 The only effective therapy is to decrease the the diameter of the stent.
101
Medical Therapy

Secondary Prophylaxis
 There is no primary prophylaxis ???.
 No drug was shown to prevent 1st HE episode after TIPS [Riggio
et al., 2005].
 ??? Prevention of CHC to OHE.
 Secondary prophylaxis.
 It is the prevention of second HE episode after index episode.
 Lactulose can be used.
 46% recurrence of OHE due to lactulose misuse.
 Combined lactulose and rifaximin have a decreasing risk of both breakthrough HE
episodes as well as hospitalizations when compared with lactulose alone.
 Probiotics [VSL#3] in a recent study is equal to lactulose [Agrawal et al., 2012].
102
Medical Therapy

Secondary Prophylaxis
When to stop secondary prophylaxis:
 Usually it is used indefinitely.
 Exception:
Controlled precipitating factor as variceal bleeding HE.
Improving liver condition as treated AIH, antiviral for HCV, HBV
etc.
103
Medical Therapy

104
Secondary Prophylaxis of Hepatic Encephalopathy.
Secondary Prophylaxis of Hepatic Encephalopathy.
Trial
Type of
prophylaxis
Study design
No of
patient
(n)
Duration of
treatment
Assessment Efficacy
Riggio et al Primary Lactulose and lactitol in
portosystemic shunt
31 6 months PSE index Lactulose = lactitol
Sharma BC et al Secondary Lactulose (open-label)
in cirrhosis with
previous HE
140 14 months Psychometry
and CFF
Lactulose > no
treatment
Bass et al Secondary Rifaximin + lactulose
(randomized, double-
blind, placebo-
controlled) in cirrhosis
with previous HE
299 6 months HE clinical Rifaximin > placebo
Agrawal et al Secondary Lactulose, probiotics
(open-label trial) in
cirrhosis with previous
HE
235 12 months Psychometry
and CFF
Lactulose = probiotic
s

Artificial Liver Support
• Not studied well
• In a small trial of 56 patients:
• MARS with albumin infusion did not show faster recovery from HE.
• Only a mortality benefit in albumin treated group.
• May be used for refractory cases without survival benefit.
105
Medical Therapy

Liver Transplantation
 Liver transplantation resolves both hepatic dysfunction and portal
hypertension
 It usually results in complete resolution of HE.
 Indication:
 recurrent or treatment resistant cases.
 MELD obstacle:
 HE does not necessarily correlate with MELD score.
 Patients with HE may be disadvantaged in the era of MELD-based organ allocation
despite a serious impact of HE on productivity, health, and survival.
106

•Most studies in CHE have not measured outcomes
data such as
•hospitalizations,
•OHE prevention,
•death,
•but rather had end points such as improvement in
HRQOL and cognitive testing.
108

Non-absorbable dissacharides
Lactulose therapy:
 resulted in improved abnormal psychometric tests , HRQOL and
decreased the progression to overt HE [primary prophylaxis].
The laxative effect [30-60 mL/day] and titration to 2–3 soft bowel
movements per day make adherence to lactulose classically low.
Poor tolerance:
 Diarrhea, abdominal pain/cramping, nausea, and flatulence.
 Overuse resulted in dehydration and hyponatremia with worsening of HE.
109

Rifaximin
 Dose: 550 mg bid. Recent study half dose is equal.
 Actions:
 it does not seem to alter the normal fecal flora and, thus, is not associated with Clostridium
difficile colitis.
 It reduced Veillonellaceae and an increased in Eubacteriaceae.
 Clinical Benefits in CHE patients:
 It is associated with improved cognitive function, reduced endotoxemia, abnormal psychometric
tests, HRQOL.
 reduced total driving related errors, specifically speeding tickets and navigation of illegal turns
 decreased the progression to OHE.
 Pros:
 Patients adhere to it better than lactulose.
 Cons:
 Expensive drug but weight against progression to OHE and hospitalization costs.
110

Probiotics
 Probiotics:
 They are live microorganisms that alter the balance of intestinal microflora,.
 Synbiotics:
 They are probiotics with the addition of fermentable fiber.
 Clinical benefits:
 30 days synbiotic treatment resulted in a decrease in intestinal pH, blood ammonia levels, and
reversal of MHE.
 Probiotic yogurt treatment reversed CHE and prevented progression to OHE.
 VSL # 3 (3 capsules daily—108 CFU)  50% reduction in progression to OHE.
 Phase I; Lactobacillus had reduced levels of endotoxemia, tumor necrosis factor-a, and
dysbiosis
 Larger studies with a longer duration of follow-up are required with
standardization of probiotic formulations.
111

LOLA
 Clinical benefits:
 It resulted in improved abnormal psychometric tests , HRQOL and decreased the
progression to overt HE.
 Side effects:
 Nausea, cough, muscle cramps, and less frequently diarrhea
 Cons:
 Few studies with small sample size.
 A recent study [Alvares-da-Silva et al., 2013] there was no difference in the whole
psychometric battery evaluation between patients treated with LOLA and
placebo.
112

113
Published Egyptian Studies

Advantages and disadvantages of the therapeutic agents most studied for the management of covert hepatic encephalopathy
Drug Advantages Disadvantages Evidence
Probiotics Excellent tolerability
Palatable food product
Inexpensive
No adverse events
No prescription required
Decreases CHE
Prevents OHE
Multiple cultures
Unregulated medical food
Optimal dose and duration
unknown
 Liu et al
 50% vs 13% reversal of CHE (P<.05). Decreased ammonia and endotoxin levels (P = .05).
Improved Child-Pugh scores (P = .04)
 Bajaj et al
 70% vs 0% with placebo in reversal of CHE (P = .03). 0% developed CHE vs 25% in placebo
 Lunia et al
 50% decrease in development of OHE (P<.05)
 Vlachogiannakos et al
 57% decrease in CHE vs placebo (P<.01). >80% compliance with therapy
Lactulose Inexpensive
Cost-effective
Improves quality of life
Decreases CHE
Diarrhea
Abdominal pain
Bloating
Compliance (ADR)
Poor palatability
 Dhiman et al
 57% resolution of CHE. Improvement in psychometric testing (P = .04)
 Prasad et al
 HRQOL (Sickness Index Profile) improved (P = .002)
 Sharma and Sharma
 53% improved CHE during treatment
Rifaximin Excellent tolerability
Decreases CHE
Improves quality of life
Expensive
Not cost-effective
 Bajaj et al
 91% vs 61% with placebo improved psychometric testing (P<.05). Psychosocial HRQOL
improved (P = .04). Decreased driving errors on simulators (76% vs 31%; P = .13)
 Sidhu et al
 75% vs 20% placebo cleared CHE (P<.0001). Total HRQOL improved with 8 wk of therapy
 Bajaj et al
 Not cost-effective at current pricing
LOLA, oral Decreases rates of OHE 6 mo after
discontinuation
MELD/Child-Pugh scores improved
6 mo after discontinuation
Not shown to decrease CHE
No improvement in QOL or
depression/anxiety scores
Limited experience
 Alvares-da-Silva et al
 No statistically significant change in CHE, QOL, or depression/anxiety scores. OHE developed
in 5% of LOLA vs 37.9% in placebo group 6 mo after discontinuation of therapy (P = .016).
MELD/Child-Pugh scores improved 6 mo after discontinuation (P<.001)
114

117
Trial Treatment
Total
patients
Study
design
Assessment Efficacy
Covert hepatic encephalopathy
Horsmans et al
Lactulose vs
placebo
14 RCT
Psychometric tests, ammonia
levels
Lactulose > placebo for
psychometric tests
Watanabe et al
Lactulose vs no
treatment
36 RCT
Psychometric tests, ammonia
levels
Lactulose > no treatment for
psychometric tests
Dhiman et al
Lactulose vs no
treatment
26 RCT Psychometric tests Lactulose > placebo
Prasad et al
Lactulose vs no
treatment
61
NB-
RCT
Psychometric tests, HRQOL
psychometric tests and HRQOL
Sharma et al
Lactulose vs
lactulose +
probiotics vs
probiotics alone
105
NB-
RCT
3 psychometric tests, ammonia
levels
Lactulose + probiotics > lactulose >
probiotics for all parameters
Bajaj et al
Rifaximin vs
placebo
42
DB-
RCT
Total driving errors, cognitive
performance, SIP, ammonia levels,
inflammatory cytokines
Rifaximin > placebo for total driving
errors, cognitive performance, SIP,
and anti-inflammatory markers
Sidhu et al
Rifaximin vs
placebo
94
DB-
RCT
2 psychometric tests, SIP
Rifaximin > placebo for all
parameters

118
Trial Treatment
Total
patients
Study
design
Assessment Efficacy
Covert hepatic encephalopathy
Lunia et al Probiotics vs placebo 160 OL-RCT
Psychometric tests, CFF, glucose and
lactulose hydrogen breath test, ammonia
levels
Probiotics > placebo for all parameters
Bajaj et al
Probiotic (Lactobacillus GG)
vs placebo
30 RCT Endotoxemia, TNF-α levels, dysbiosis
Lactobacillus > placebo for all
parameters
Pratap Mouli
et al
Probiotic (VSL#3) vs lactulose120 OL-RCT Psychometric tests, ammonia levels
VSL #3 = lactulose (noninferior) for all
parameters
Stauch et al LOLA vs placebo 66 RCT
CHE (psychometric tests), ammonia levels,
PEI, WHC grade
LOLA > placebo for all parameters
Kircheis et al LOLA vs placebo 114 DB-RCT
CHE (psychometric tests), ammonia levels,
PEI, WHC grade
LOLA > placebo for all parameters
Mittal et al
LOLA vs lactulose vs no
treatment vs probiotics
160 OL-RCT
Psychometric tests, ammonia levels,
HRQOL
LOLA = lactulose = probiotics for all
parameters
Poo et al LOLA vs lactulose 20 OL-RCT
Psychometric tests, WHC grade, asterixis,
EEG
LOLA = lactulose for ammonia levels
LOLA > lactulose for WHC grade,
asterixis, psychometric tests, EEG
Sharma et al
LOLA vs rifaximin vs
probiotics vs placebo
124 RCT Psychometric tests, CFF
LOLA = rifaximin = probiotics >
placebo for all parameters
Alvares-da-
Silva et al
LOLA vs placebo 64 DB-RCT
Psychometric tests, CFF, EEG, ammonia
levels, Beck’s anxiety-depression, HRQOL,
prevention of OHE
LOLA > placebo for prevention of OHE

119
Trial Treatment
Total
patients
Study
design
Assessment Efficacy
Acute episode of overt hepatic encephalopathy
Simmons et al
Lactulose vs
glucose
26 RCT
WHC grade, ammonia
levels, stool production
Lactulose = glucose for all
parameters
Rodgers et al
Lactulose vs
sorbitol
6
Cross-over
RCT
WHC grade, EEG, ammonia
levels
Lactulose = sorbitol for all
parameters
Uribe et al
Lactulose or
lactitol (enema)
vs placebo
15 DB-RCT Mortality, WHC grade
Lactulose > placebo for all
parameters
Elkington et al
Lactulose vs
sorbitol
7
DB cross-
over RCT
Stool pH, ammonia levels,
EEG
Lactulose vs sorbitol for all
parameters
Festi et al
Rifaximin vs
lactulose
21
DB, DD-
RCT
Neurologic signs of HE,
asterixis score, EEG, HNRB,
ammonia levels
Rifaximin = lactulose for all
parameters
Buci et al
Rifaximin vs
lactulose
58
DB, DD-
RCT
Neurologic status, asterixis
score, cancellation tasks,
HRNB EEG, ammonia levels
Rifaximin > lactulose

120
Trial Treatment
Total
patien
ts
Study
design
Assessment Efficacy
Acute episode of overt hepatic encephalopathy
Massa et al Rifaximin vs lactulose 40 DB, DD-RCT
HE index severity, mental status,
cancellation tasks, HRNB, EEG
Rifaximin > lactulose for all
parameters
Fera et al Rifamixin vs lactulose 40 DB, DD-RCT
Mental status, asterixis score,
cancellation tasks, HRNB, EEG,
ammonia level, PSI
parameters
Mas et al Rifaximin vs lactitol 103 DB, DD-RCT
Mental status, asterixis score,
EEG, PSI, psychometric tests
Rifaximin = lactitol for mental
status and asterixis score;
Rifxamin > lactitol for PSI,
psychometric tests, and EEG
Leevy et al Rifaximin vs lactulose 145 Cross-over
WHC grade, asterixis score,
hospitalizations
parameters
Paik et al Rifaximin vs lactulose 54 OL-RCT
Ammonia levels, flapping tremor,
mental status, HE index,
psychometric tests
Rifaximin = lactulose for all
parameters
Sharma et al
Rifaximin + lactulose vs
lactulose
120 DB-RCT
Reversal of HE, mortality, hospital
stay
Rifaximin + lactulose >
lactulose for all parameters

121
Trial Treatment
Total
patient
s
Study
design
Assessment Efficacy
Secondary prevention of OHE
Sharma et al Lactulose vs placebo 140 OL-RCT
Psychometric tests, CFF,
ammonia levels, re-
admission for HE, mortality
readmission for HE
Bass et al
Rifaximin vs placebo
(>90% patients on
lactulose)
299 DB-RCT
Time to first breakthrough
HE, time to first HE-related
hospitalization
Rifaximin > placebo for all
parameters
Agrawal et al
Lactulose vs
probiotics vs no
therapy
235 RCT
Psychometric tests, CFF,
ammonia levels, secondary
prevention of OHE, mortality
Lactulose = probiotics > no
therapy for secondary
prevention of OHE
Dhiman et al
Probiotic (VSL#3) vs
placebo
130 DB-RCT
Secondary prevention of
OHE, all-cause
hospitalizations, CTP and
MELD scores
Probiotics > placebo for all
parameters

[2015] hepatic encephalopathy

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