Presentor – Dr. Nikhil Bhangale
Hepatic encephalopathy is a brain
dysfunction caused by liver insufficiency
and/or Portosystemic shunt(PSS); it
manifests as a wide spectrum of neurological
or psychiatric abnormalities ranging from
subclinical alterations to coma.
(AASLD guidelines 2014)
Oxidative nitrosative stress
Ammonia , hypo-osmotic
swelling,inflammatory cytokines, BZD induce
oxidative and nitrosative stress response in
Response mediated by NMDA receptors
Oxidative / nitrosative stress can promote
covalent modification of tyrosine residues in
This protein tyrosine nitration ,interfere with
protein function and intracellular signal
Shift of balance between inhibitiry and
excitatory neurotransmission towards
Increase in GABAergic tone(due to excess
GABA,endogenous BZD in brain &
upregulation of GABA receptors)
Increased NMDA receptor activation.
Dopamine depletion due to ↑ action of MAO-
Acetyl choline(Ach) levels decresed
Excess protein in diet
Electrolyte disorder- Hyponatremia,hypokalemia
Paracentesis abdominis(large volume >3-5 Lt )
Types of HE according to underlying disease
A – with Acute liver failure (has distinct
features like its associated with Increased ICT
& risk of cerebral herniation)
B – with portosystemic Bypass or shunts
C – with Cirrhosis of liver
Classification of Hepatic
According to time course –
1) Episodic HE
2) Recurrent HE denotes bouts of HE that occur with a
time interval of 6 months or less.
3) Persistent HE denotes a pattern of behavioral
alterations that are always present and
interspersed with relapses of overt HE.
1) Attention span
2) Working memory(WM)
3) psychomotor speed
4) visuospatial ability
often present in the early to middle stages of HE that precede stupor
It is easily elicited by actions that require postural tone
Rapid flexion-extension movements at MCP(metacarpohalangeal)
and wrist joints with lateral movements of fingers
Absent at rest, less marked on movement and maximum on
actuality, not a tremor, but a negative myoclonus consisting of loss
of postural tone(impaired inflow of joint and afferent sensations to
brainstem reticular formation → arryhtmic lapses in posture)
Asterixis is not pathognomonic of HE because it can be observed in
CoAsterixis is also seen in
ventilatory failure (CO2 narcosis)
It is a sour , musty, feculent smell detected on
breath of some patients
Due to presence of mercaptans(byproduct of
Its presence does not correlate with degree or
duration of encephalopathy and its absence
does not exclude hepatic encephalopathy.
Loss of concern for family and friends
Slight impairment of mental function to gross
Constuctional apraxia (inability to make
designs from match or blocks)
Changes in handwriting
Day time sleepiness - Early sign
Disturbed night sleep
voice – monotonus
Positive Babinski sign
Transient focal symptoms
Hypomimia (masked facies, masking of
monotony and slowness of speech
dyskinesia with diminished voluntary
Hepatic myelopathy (HM)
Mainly with surgically created long-standing portocaval
Demyelination of pyramidal tracts →
1) paraplegia with progressive spasticity
3) weakness of lower limbs
4) relatively mild persistent or recurrent mental alterations,
5) without sensory or sphincter involvement.
It does not respond to standard therapy, including ammonia
lowering, but may reverse with liver transplantation (LT).
Prevalence (AASLD guidelines 2014)
Minimal HE (MHE) or covert HE (CHE) occurs in
20%-80% of patients with cirrhosis
The prevalence of OHE is
10%-14% at the time of diagnosis of cirrhosis in general &
16%-21% in those with decompensated cirrhosis.
10%-50% in patients with transjugular intrahepatic
portosystemic shunt (TIPS)
Diagnosis is very easy in setting of known
cirrhosis,precipitating factors and asterixis.
But diagnosis becomes a challenge in absence of
above factors as there is no gold standard test
According to AASLD guidelines –
The diagnosis of HE is through exclusion of
other causes of brain dysfunction.
But following tests may aid in diagnosis-
1) Thorough Neurological examination- changes
in mental state,memory
2) Serum ammonia level –
But serum levels of NH3 are neither sensitive nor specific for its presence in
blood,as affected by site or method of collection.
Blood ammonia levels may be a useful indicator of HE in the absence of cirrhosis
and portal hypertension, as in patients with metabolic disorders that
influence ammonia generation or metabolism, such as urea
Special tests for MHE
1) Portosystemic encephalopathy (PSE) syndrome test –
PHES(Psychometric Hepatic Encephalopathy Score)
five paper-pencil tests
2) The Critical Flicker Frequency (CFF) test - fused light
(presented from 60 Hz downward) appears to be
flickering to the observer
3) The Continuous ReactionTime (CRT) test - repeated
registration of the motor reaction time (pressing a
button) to auditory stimuli (through headphones)
4) The Inhibitory ControlTest (ICT) - computerized test of response
inhibition and working memory
X →Y orY→ X press button
X→ X orY→Y Don’t press button
5) The Stroop test - evaluates psychomotor speed and
cognitive flexibility by the interference between
recognition reaction time to a colored field and a
written color name.
6) The SCANTest - computerized test that measures
speed and accuracy to perform a digit recognition
memory task of increasing complexity.
7) Electroencephalography examination
Portosystemic encephalopathy (PSE) syndrome test
five paper-pencil tests
Progressive slowing of normal alpha(8-13Hz)
Burst of slow activity in theta range(4-8Hz)
Triphasic waves or arrythmic delta activity, seen in
more severe grade of encephalopathy
Coma – slow , low voltage delta activity with
sequences of electric silences.
Triphasic waves – not pathognomonic,since also
observed in other metabolic encephalopathies (like
uremia,hypercapnia,hyponatremia) & with drug
CT,MRI of brain –
To rule out other causes of cerebral dysfuncion
may show Manganese deposition in globus pallidus in
cirrhosis, responsible for upregulation of BZD receptors
,resulting in HE.
MRS(magnetic resonance spectrometry)
PET(positron emission tomography),SPET(single photon
emission tomography) with radiotracer imaging– both
provide mainly biochemical information of metabolic
SPEM (smooth pursuit eye movements) –
conjugate gaze movements used to track or
pursue smooth trajectory of small targets.
Shows clear disruption in MHE & more
pronounced disruption with OHE.
Evoked potentials (P300 latency ) – for
MSE,it has a diagnostic potential.
A) elimination or correction of precipitating causes
B)Decrease ammonia levels –
I. Nonabsorbable Disaccharides
II. antibiotics, such as rifaximin
III. oral branched-chain amino acids (BCAAs)
IV. intravenous (IV) L-ornithine L-aspartate (LOLA)
VI. other antibiotics.
Like lactulose / lactitol -is the first choice for treatment of
Mechanism of action-
Synthetic disaccharide monosaccharide +VFA(volatile
fatty acids) + Hydrogen ions + methane .
VFA substrate for bacterial growth, which forms bulk
H+ ions decreases pH , acidic gut environment
Decreases pH causes
1) Leeching of NH3 from circulation into colon , which are then
used by bacteria for protein synthesis
2) Decrease proliferation of harmful bacteria in gut, so decreasing
3) NH3 converted to NH4 ions , which are less readily absorbed
Acts as probiotic – helps in growth of good
bacteria like bifidobacterium,lactobacillus
and supresses NH3 forming bacteria
Reduction of intestinal NH3 production –
through inhibition of glutaminase activity
Dosage – 15-30 ml ,two – four times/day,
Dose needs to be titrated ,so as to pass 2-3
Can be given as rectal enema
Overuse has its risks like
hypernatremia, and severe perianal skin
irritation. overuse can even precipitate HE.
Antibiotics - Rifaximin
aim of modifying the intestinal flora
(selectively eliminate urease producing
Rifaximin is an effective add-on therapy to
lactulose for prevention of OHE recurrence
Other antibiotics – metronidazole, Neomycin
(also a known glutaminase inhibitor)
oral branched-chain amino
oral BCAA-enriched formulations improve the
manifestations of episodic HE whether OHE or
There is no effect of IV BCAA on the episodic
bout of HE.
Leucine → potent stimulator of production of
hepatocyte growth factor by stellate cells, so
might stimulate liver regeration.
Improve albumin synthesis, decrease insulin
resistance,decrease HCC occurance, improve
L-ornithine L-aspartate (LOLA)
Can be given Intravenously (preferred) or Oral
salt of the amino acids ornithine and aspartic
acid and provides key substrates to &
promotes metabolic pathway,urea
cycle,resulting in detoxification of ammonia.
L-ornithine phenylacetate - would participate in
the clearance of ammonia in muscles and the
liver through glutamine synthesis
Glutamine + phenylacetate
Excreted by kidney
intestinal α-glucosidase inhibitor used to
treat type 2 diabetes mellitus
inhibits the intestinal absorption of
carbohydrates and glucose and results in
their enhanced delivery to the colon
the ratio of saccharolytic to proteolytic
bacterial flora is increased, and blood
ammonia levels are decreased.
Drugs which increase ammonia
Conjugate with glycine, excess nitrogen
excreted in urine as hippurate
high sodium load,so cautious use is advised.
Efficacy is not clearly established yet.
zinc deficiency is common in patients with
Poor zinc levels → impaired activity of urea
cycle enzymes in liver & glutamine
zinc increases the activity of ornithine
transcarbamylase, an enzyme in the urea
cycle, may also improve HE
producing) bacteria in the gut
Flumazenil- selective BZD antagonist
not frequently used. It transiently improves
mental status in OHE without improvement
on recovery or survival.
Laxatives - Simple laxatives alone do not
have the prebiotic properties of
disaccharides,so not useful.
Albumin - daily IV albumin showed no effect
on resolution of HE,but was related to better
Bromocriptine - (2.5 mg OD to max 5 mg BD)
for Deficits in dopaminergic
neurotransmission in HE
Hypertonic saline(23.4%) – some studies
shown reduction in brain volume due to
resolution of edema.
Shunt occlusion – vascular
Nasogastric intubation – for patients unable
to take orally & also for those who are at risk
of aspiration due to depressed sensorium.
only treatment option for HE that does not
improve on any other treatment.
Artificial liver support system
(MARS, molecular adsorption recirculating
Purifies blood by removal of albumin
bound and water soluble molecules. It removes
NH3,endotoxin, inflammatory mediators.
Malnutrition is often underdiagnosed, and
approximately 75% of patients with HE suffer
from moderate-to-severe protein-calorie
malnutrition with loss of muscle mass and
Chronic protein restriction is detrimental
because patients’ protein requirements are
relatively greater than that of healthy patients
and they are at risk of accelerated fasting
metabolism. Malnutrition and loss of muscle
bulk,sarcopenia, is a risk factor for development
Daily energy intakes should be 35-40 kcal/kg
ideal body weight
Daily protein intake should be 1.2-1.5 g/kg/day
Small meals or liquid nutritional supplements
evenly distributed throughout the day and a late-
night snack should be offered.
Vegetable protein is better tolerated than
animal protein, benefits related to dietary fibre
on colonic function, decrease transit time ,
decrease in intraluminal pH, increase in fecal
Other experimental drugs
Metabolic Ammonia Scavengers –
1) Ornithine phenylacetate,
2) Glyceryl phenylbutyrate (GPB)
Such drugs have been used for treatment
of inborn errors of the urea cycle.
Rivastigmine – Ach levels are decreased , so
rivastigmine improves psychometric
Sildenafil - ↓ function of NO-cGMP pathway,
so , ↓ extracellular cGMP levels. Sildenafil
improves cGMP levels & restore learning
ability & intellectual function.
AST-120 (cremezin) –
oral adsorbent used in Japan to delay
initiation of dialysis in patients with ESRD.
Binds ammonia, bile acids, inflammatory
ammonia leads to overstimulation of