• Hippocrates (460-370 BC) described a patient
with hepatitis who ‘barked like a dog, could
not be held and said things which could not be
• Hepatic encephalopathy (HE) is a
potentially reversible , neuropsychiatric
syndrome characterized by changes in
cognitive function, behaviour, and
personality, as well as by transient
neurological symptoms and characteristic
EEG patterns associated with acute and
chronic liver failure.
• Clinical spectrum ranges from minor signs of
altered brain function to deep coma.
• The concordance of neuropsychiatric
manifestation in pt of liver dis should be
treated as HE unless proved otherwise.
Classification of HE
• Type A: HE associated with Acute liver failure
• Type B: HE associated with portal-systemic
Bypass, no intrinsic hepatocellular disease
• Type C: HE associated with Cirrhosis and portal
hypertension or portal-systemic shunts:
– Episodic HE: precipitated, spontaneous, recurrent
– Persistent HE: mild, severe, treatment-dependent
– Minimal HE
Ammonia intoxication hypothesis
Amino acid imbalance hypothesis(BCAA/AAA↓)
The gamma-aminobutyric acid hypothesis
Trace elements like zinc
Role of associated inflammation
Clinical features of HE
• For descriptive purposes, features of
encephalopathy can be separated into
• Hypersomnia appears early and progresses to
reversal of the normal sleep pattern. Reduction of
spontaneous movement, a fixed stare, apathy, and
slowness and brevity of response are early signs.
• Further deterioration results in reaction only to
intense or noxious stimuli.
• Coma at first resembles normal sleep, but progresses
to complete unresponsiveness.
• These include childishness, irritability and loss
of concern for family.
• Even in remission the patient may present
similar personality features suggesting frontal
Varies from slight impairment of organic
mental function to gross confusion.
• Slow and slurred and the voice is
monotonous. In deep stupor, dysphasia
• This is a sour, fecal smell in the breath, due to volatile
substances normally formed in the stool by bacteria.
• These mercaptans if not removed by the liver are
excreted through the lungs and appear in the breath.
• Fetor hepaticus does not correlate with the degree
or duration of encephalopathy and its absence does
not exclude HE.
Flapping tremor (asterixis)
• This is due to impaired inflow of joint and other afferent
information to the brainstem reticular formation resulting in
lapses in posture.
• It is demonstrated with the patient’s arms outstretched and
fingers separated or by hyperextending the wrists with the
• The rapid flexion-extension movements at the
metacarpophalangeal and wrist joints are often accompanied
by lateral movements of the digits.
• Absent at rest, less marked on movement and maximum on
sustained posture, the tremor is usually bilateral, although not
bilaterally synchronous, and one side may be affected more
than the other. In coma the tremor disappears.
• A ‘flapping’ tremor is not specific for hepatic precoma.
• Deep tendon reflexes are usually exaggerated.
Increased muscle tone is present at some stage and
sustained ankle clonus is often associated with
rigidity. During coma patients become flaccid and
lose their reflexes.
• The plantar responses are usually flexor becoming
extensor in deep stupor or coma.
• The clinical course fluctuates, and frequent
observation of the patient is necessary.
Clinical grading of HE
Flapping tremorClinical signsClinical grade
Infrequent at this
Alert, euphoric, occasionally
concentration, slow mentation
and affect, reversed sleep
Easily elicitedDrowsiness, lethargic,
Usually presentStuporose but easily rousable,
marked confusion, incoherent
Usually absentComa, unresponsive but may
respond to painful stimulus
Minimal hepatic encephalopathy
• Alternative terms were proposed to avoid medical
errors induced by a name that could implicate
that the condition is below the threshold of
• The current consensus is to use the term
‘MHE’, as proposed by the Working Party
commissioned by the 11th World Congress of
Gastroenterology in 1998.
• Prevalence is as high as 84% in patients with
Predisposing factors for HE development
Short fatty acidsSedativesHyponatremiaHigh-protein diet
– Bilateral synchronous slowing of the waves frequency
(with an increase in wave amplitude) from the normal
-rhythm down to the range
– Useful for diagnosis and to assess treatment
– Occur early
– Non-specific. However, in a conscious patient with liver
disease are virtually diagnostic.
– Usually clear and under normal pressure
– Maybe increased protein conc. but cell count is
– Glutamic acid and glutamine may be increased
• Neuropsychological tests:
– Especially used in clinical research
– Psychometric Hepatic Encephalopathy Score (PHES):
• A standardized test battery including 5 different tests
• Its use is restricted to the study of mild and minimal HE.
Other causes of encephalopathy or disturbed
consciousness in cirrhotic patients
• Severe hyponatremia
• Respiratory failure
• Severe sepsis
• Intracranial bleed
• Acute alcoholism
• Wernicke’s encephalopathy
• Status epilepticus
• Zinc deficiency
• Drug overdose
• Post ictal
• CNS sepsis
• Delirium tremens
• Functional psychoses
Management of precipitating factors
prophylaxis for stress ulcers
Correct abnormality, avoid
diuretics, fluid restriction
Avoid NSAIDs, control
sepsis, correct circulating
• It is important in cirrhotic patients to avoid protein
restriction any longer than is necessary.
• In the acute case, a short period of protein
deprivation may not be harmful but prolonged
restriction of protein in the cirrhotic patient
without encephalopathy is inappropriate.
• If animal protein is not well tolerated, vegetable
protein may be used.
• In the acute attack of HE dietary protein is
reduced to 20 g/day.
• During recovery, protein is added in 10g
increments on alternate days.
• Any relapse is treated by a return to the
Protein restriction in HE:
necessary or illogical ?
• Evidence suggests that protein intake plays only a
limited role in precipitating encephalopathy.
• In fact, measures taken to suppress endogenous
protein breakdown are more effective than dietary
restrictions in reducing the load of amino acids on
the decompensated liver.
(lactulose and lactilol)
• Since the 1980s, non-absorbable disaccharides have been
considered as the standard treatment for HE.
• Recent guidelines state that lactulose ( -galactosido-fructose) is
the first line pharmacological treatment for HE.
• When given by mouth lactulose reaches the cecum where it is
broken down by bacteria predominantly to lactic acid. The
osmotic volume of the colon is increased. The fecal pH drops.
• The growth of lactose-fermenting organisms is favored and
organisms such as bacteroides, which are ammonia formers, are
• Lactulose more than doubles the colonic output of
bacterial mass and ‘soluble’ nitrogen which is no
longer available for absorption as ammonia.
• The aim of treatment is to produce acid stools
• The dose is 10-30 ml, 3 times a day and is adjusted
to produce 2 semi-soft stools daily.
• Side-effects include flatulence, diarrhea and
• Lactilol ( -galactoside sorbitol) is a second-
generation disaccharide easily produced in
chemically pure crystalline form, which can be
dispensed as a powder.
• It is not broken down or absorbed in the small
intestine, but is metabolized by colonic bacteria.
• It seemed to be as effective as lactulose in chronic
and acute portal-systemic encephalopathy.
Patients responded more quickly to lactilol than
lactulose, and there was less diarrhea and
• The value of enemas in patients with hepatic
coma must be emphasized.
• Lactulose or lactose enemas may be used and
are superior to water.
• All enemas must be neutral or acid to reduce
• Neomycin given orally, is very effective in decreasing
gastrointestinal ammonium formation.
• Little neomycin is absorbed from the gut although blood
levels have been detected and impaired hearing or deafness
may follow its long-term use.
• Thus it should only be used for the acute case for 5-7 days
(4-6 g/day in divided doses).
• It should be used with particular caution in patients with
• In acute hepatic coma, lactulose is given, and neomycin
added if the response is slow or partial.
• Metronidazole (200 mg 4 times per day orally)
seems to be as effective as neomycin.
• Because of dose-related CNS toxicity, it should not be
used long term.
• A synthetic antibiotic structurally related to rifamycin.
• Displays a wide spectrum of antibacterial activity against
Gram-negative and Gram-positive bacteria, both aerobic and
• A very low rate of systemic absorption.
• This will minimize both antimicrobial resistance and systemic
• Safe in all patient populations and also in the long term.
Sodium benzoate and L-ornithine-L-aspartate
• Sodium benzoate promotes urinary excretion of
ammonia and is as effective as lactulose and is less
• L-ornithine-L-aspartate treatment promotes hepatic
removal of ammonia by stimulating residual hepatic
urea cycle activity and promoting glutamine synthesis,
particularly in skeletal muscle.
• The use of bromocriptine or L-dopa is restricted to
cases of chronic HE with important extrapyramidal
• Flumazenil had a significant beneficial effect
on short-term improvement of HE in patients
with cirrhosis and a highly favorable
• Flumazenil had no significant effect on
recovery or survival.
• At the moment, flumazenil may be
considered for patients with chronic liver
disease and HE, but cannot be
recommended for routine clinical use..
Branched-chain amino acids (BCAA)
• Infusions of solutions containing a high concentration of
BCAA have been used to treat acute and chronic HE.
• Results have been extremely conflicting, perhaps related
to differences in the nature of amino acid solutions, the
ways of administration and the patients studied.
• Inhibits the upper gastrointestinal enzymes (alpha-
glucosidases) that convert carbohydrates into
• It also promotes the proliferation of intestinal
saccharolytic bacterial flora that produce
mercaptans, benzodiazepine-like substances, and
ammonia. Their reduction could improve hepatic
• In cases of chronic HE the reduction or obliteration of
large spontaneous porto-systemic anastomoses, or
shunts previously done by surgery or TIPSS, can be a
• A surgical shunt occlusion or the shunt may be
occluded by invasive radiology with the insertion of a
balloon or a steel coil.
• Risk of bleeding.
Artificial Extracorporeal Liver Support ‘Liver
• Patients frequently die while on the transplantation
waiting list because of organ scarcity.
• Systems supporting liver function may be useful to:
– Avoid further complications due to the typical toxic state.
– ‘Bridging' the patients to the transplantation.
– In the event of an acute decompensation of a chronic liver
disease, sustain liver function long enough to permit the
organ's regeneration and functional recovery.
• Novel treatments introduced to improve
detoxification, mainly of the protein-bound substances:
– Molecular adsorbent recirculation system (MARS): albumin
– Prometheus systems: novel device for fractionated plasma
separation via an albumin-permeable filter that was developed to
improve removal of albumin-bound toxins.
• Different experiences have proved the efficacy of MARS
mainly in the treatment of HE, while data on survival are
still limited to small case series.
• Initial studies have proven clinical use of Prometheus to be
feasible and safe.
• This may be the ultimate answer to the
problem of chronic HE.
• Any patient who has presented an episode of
HE should be evaluated for this procedure.
• Proceed with early liver transplantation before
the development of important organic brain
lesions on sustained HE.
• Identification and treatment of the precipitating
• Intervention to reduce the production and absorption
of gut-derived ammonia and other toxins.
• Prescription of agents to modify neurotransmitter
balance directly or indirectly. These are of limited
clinical value at present.