Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or portosystemic shunting. It manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. Ammonia produced in the gut that enters the portal circulation and cannot be cleared by the liver is the main neurotoxin involved. Diagnosis involves clinical assessment using scales like the West Haven criteria and tests such as serum ammonia levels, neuropsychometric tests, and the critical flicker frequency test. Treatment focuses on reducing ammonia levels and symptoms management.

1. Hepatic
Encephalopathy
Dr.Bhargav Kiran
MD General Medicine

2. 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].
History

3. • 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.

4. Definition :
Hepatic encephalopathy is a brain dysfunction
caused by liver insufficiency and/or Porto-systemic
shunting
 It manifests as a widespectrum of neurological or
psychiatric abnormalities ranging from subclinical
alterations to coma.

5. Incidence : Epidemiology
 It develops in 50-70% of patients with Cirrhosis
 Its occurrence is a poor prognostic indicator
 with a projected 1 and 3 year survival rates of 42% and 23 % respectively without
liver transplantation
 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%.
 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.

6. Pathophysiology
 A number of factors have been implicated like
 Production of neurotoxins
 Altered permeability of blood brain barrier
 Abnormal neurotransmission
The best described neurotoxin involved is ammonia
• Once produced it will enter portal circulation and gets metabolized and cleared by hepatocytes
• In cirrhosis and portal HTN reduced hepatocyte functioning contribute to increased circulating
ammonia levels.

7. H pylori
7

8.  Astrocytes are the only cells in the brain that can metabolize
ammonia .
𝑁𝐻3 𝑁𝐻3
 α keto-glutaric acid → → → glutamic acid → → → glutamine
 synapsis.
 Glutamine accumulation  astrocyte swelling  brain edema.
 In FHF [type AHE]:
 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.
Ammonia And The Brain

9.  Increased permeability of blood brain barrier increases the uptake and extraction of
ammonia by cerebellum and basal ganglia
 Acute hyperammonemia appears to have a direct effect on brain edema , astrocyte
swelling and transport of neutrally active compunds such as myoinositol there by
causing HE.
 However Serum Ammonia levels are neither specific nor a sensitive test .

10. CLINICAL PRESENTATION
 Hepatic encephalopathy produces a wide spectrum of nonspecific neurological and psychiatric manifestations.
 In its lowest expression HE alters only psychometric tests oriented toward attention, working memory,
psychomotor speed, and visuospatial ability
 As HE progresses, personality changes, such as apathy, irritability, and disinhibition, may be reported by the
patient’s relatives, and obvious alterations in consciousness and motor function occur.
 Disturbances of the sleep wake cycle with excessive daytime sleepiness are frequent.
 Patients may develop progressive disorientation to time and space, inappropriate behavior, and acute
confusional state with agitation or somnolence, stupor, and, finally, coma.
 The recent ISHEN (International Society for Hepatic Encephalopathy and Nitrogen Metabolism) consensus
uses the onset of disorientation or asterixis as the onset of OHE

11. Asterixis / flapping tremor”
 It is often present in the early to middle stages of HE that precede stupor or coma
 It is actuality, not a tremor, but a negative myoclonus consisting of loss of postural tone.
 It is easily elicited by actions that require postural tone, such as hyperextension of the wrists with
separated fingers or the rhythmic squeezing of the examiner’s fingers.

12. • 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.

13. 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 toxiceffects
 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)
 Cerebral edema (varying degrees)with
astrocyte swelling
 GABA toxiceffects
 Alterations in the cerebral blood flux and in
the oxidative metabolism
 Rarely occurs
Transient focal neurologic
deficits or seizures
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 1
3

14. Symptom Cause Comments
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

15. Symptom
1
5
Cause Comments
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

16. CLASSIFICATION
Hepatic encephalopathy should be classified according to all of the following four factors.
 1. According to the underlying disease, HE is subdivided into
• Type A resulting from ALF
• Type B resulting predominantly from porto-systemic Bypass or shunting
• Type C resulting from cirrhosis
 2.According to its time course, HE is subdivided into
• Episodic HE
• Recurrent HE denotes bouts of HE that occur with a time interval of 6 months or less.
• Persistent HE denotes a pattern of behavioral alterations that are always present and interspersed
withrelapses of overt HE.

17. Updated
Nomenclature
Of HE Types
1
7

18.  3.According to the existence of precipitating factors, HE is subdivided into
• Nonprecipitated
• Precipitated
 The precipitating factors should be specified.
 Precipitating factors can be identified in nearly all bouts of episodic HE type C and should be
actively sought and treated when found

19. Clinical diagnostic criteria
1
9
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

20. Newly Designed One
2
0

21. According to severity

22. 2
2

24. 11
According to the newAmericanAssociation for the Study of Liver Diseases/EuropeanAssociation for the Study of
Liver guidelines

25. 2
5

26. HE DESCRIPTION with CLINICAL EXAMPLE
 The HE patient should be characterized by one component from each of the four columns.
 Example of a recommended description of a patient with HE: “The patient has HE, Type C,
Grade 3, Recurrent, Precipitated (by urinary tract infection).”

27. Differential Diagnosis

28. Diagnosis : Tests
 Portosystemic encephalopathy (PSE) syndrome test : This test battery
consists of five paper-pencil tests that evaluate cognitive and psychomotor
processing speed and visuomotor coordination.
 The tests are relatively easy to administer and have good external validity.
 The Continuous Reaction Time (CRT) test: The CRT test relies on
repeated registration of the motor reaction time (pressing a button) to
auditory stimuli (through headphones).
 The most important test result is the CRT index, which measures the stability of the
reaction times.

29. 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)
 Easy but time consuming, difficult to interpret, patient must be literate with
fine motor activities [pencil and paper].
51

30. 52

31. 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. 3
1

32. Neuropsychological Tests
3
2
• 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

33. 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:
• ot 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.
Pulsating
light emitting
diode
3
3
The HEPAtonorm™ Analyzer consists of a) hand
held control unit b) headset c) patient stop button

34. The Stroop SmartphoneApplication
• 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. 3
4

35. 3
5

36. 67
Diagnostic test Advantages Disadvantages
Serum levels of ammonia
Positively correlated with the severity ofHE Does not change approach to diagnose and manageHE
Can be challenging to take appropriate blood samples in theclinic
Clinical scales for OHE
West Haven criteria
Well-established classification criteria (in use for ≈30years)
Used in multiple studies ofOHE
Interobservervariation influencestest results (especially for low grades of HE)
HE Scoring Algorithm
Minimal variability in results between different testsites
Characterizes low grades ofHE
Time consuming (which may be a limiting factor in the outpatientsetting)
Neuropsychometric tests ('paper and pencil' tests) for MHE
Psychometric HE score
Specifically designed to diagnose subtle cognitive changes in patients withMHE
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 andscore
Excessive reliance on measuring fine motorskills
Unpopular in USA (lack of US-specific normative data andavailability)
Repeatable Battery for the
Assessment of Neurological
Status
Tests can be completed rapidly (within 25min) Difficult to interpret andscore
Excessive reliance on measuring fine motorskills
Computerized psychometric tests for MHE
Inhibitory control test
Detects MHE with highsensitivity
Validated against existing psychometrictests
Studies using this test have mostly been conducted in a single institution located ineither
Wisconsin or Virginia,USA
CDR system
Correlates well with neuropsychometrictests Time consuming, which could be a limitingfactor
Trial run needed before formaltesting
Neurophysiologic tests
Critical flicker frequency
High sensitivity and specifity
Correlates well with neuropsychometric tests Widely
used in clinicaltrials
Lack of widespread availability in the USA to permit use in ambulatorypatients
Electroencephalography HE associated with slow frequency of electricalactivity Variable sensitivity for the diagnosis of HE(43–100%)
Brain imaging
MRI
Multiple techniquesavailable
Identifies several brain abnormalities associated with HE (e.g. levels ofglutamate)
Can be expensive (especially the newer techniques that show low grades of cerebraledema)
CT
Useful for excluding other causes ofencephalopathy
Identifies conditions that worsen HE (subdural hematoma or a cerebrovascular event)
Poor detection of low grades of cerebral edema in most patients withHE
Risk associated with radiationexposure
Abbreviations: CDR, Cognitive Drug Research computerized assessment; HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy;OHE, overt hepatic encephalopathy.

37. LABORATORY TESTING
 High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic
value in HE patients with CLD.
Brain Imaging :
 Magnetic Resonance Spectroscopy (MRS)
 MR T1 mapping with partial inversion recovery (TAPIR)
They are used to measure clinical parameters quantitatively.

38. 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
 Reverses after liver transplantation
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
 Reverses after liver transplantation
Abbreviations: FLAIR, fluid attenuation inversion recovery; HE, hepatic encephalopathy; MRS, magnetic resonance spectroscopy.

39. Latest Guidelines : In DIAGNOSIS
Hepatic encephalopathy should be treated as a continuum ranging from
unimpaired cognitive function with intact consciousness through coma
The diagnosis of HE is through exclusion of other causes of brain
dysfunction
Hepatic encephalopathy should be divided into various stages of
severity, reflecting the degree of selfsufficiency and the need for care
Overt hepatic encephalopathy is diagnosed by clinical criteria and can
be graded according the WHC and the GCS

40. The diagnosis and grading of MHE and CHE can be made
using several neurophysiological and psychometric tests that
should be performed by experienced examiners
Testing for MHE and CHE could be used in patients who
would most benefit from testing, such as those with impaired
quality of life or implication on employment or public safety
Increased blood ammonia alone does not add any diagnostic,
DE staging, or prognostic value for HE in patients with CLD.
A normal value calls for diagnostic reevaluation

41. TREATMENT : General principles
An episode of OHE (whether spontaneous or precipitated) should be
actively treated
Secondary prophylaxis after an episode for overt HE is recommended
Primary prophylaxis for prevention of episodes of OHE is not required,
except in patients with cirrhosis with a known high risk to develop HE .
Recurrent intractable OHE, together with liver failure, is an indication
for LiverTransplantation

42. SPECIFIC APPROACH TO OHE TREATMENT
A four-pronged approach to management of HE is recommended
1. Initiation of care for patients with altered consciousness: airway and ICU
management
2. Alternative causes of altered mental status should be sought and treated.
3. Identification of precipitating factors and their correction:
Controlling precipitating factors in the management of OHE is of paramount importance and
cornerstone treatment because nearly 90% of patients can be treated with just correction of
the precipitating factor
4. Commencement of empirical HE treatment

43. 4
3

44. 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
Embolizationof
portosystemic
shunt
Secondary
prophylaxis
Artificial liver
support
Liver
transplantation
75

45. Treatment Of The Precipitating Factor
45
GI bleeding
Octreotide, IV PPI, endoscopic or angiographictherapy
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

46. 46

47. Nonabsorbable Disaccharides : Lactulose
Theyare the 1st line therapy
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

48. 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 48

49. 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. 49

50. BCAAs
 An updated meta-analysis of eight randomized, controlled trials (RCTs) indicated
that oral BCAA-enriched formulations improve the manifestations of episodic HE
whether OHE or MHE .
 There is no effect of IV BCAA on the episodic bout of HE
 L-ornithine L-aspartate (LOLA)
 An RCT on patients with persistent HE demonstrated improvement by IV LOLA
in psychometric testing and postprandial venous ammonia levels.
 Metabolic Ammonia Scavengers : Ornithine phenylacetate /Glyceryl
phenylbutyrate (GPB)
 These agents, through their metabolism, act as urea surrogates excreted in urine

51. Glutaminase Inhibitors
Portosystemic shunting up-regulates the intestinal
glutaminase gene so that intestinal glutaminase inhibitors
may be useful by reducing the amounts of ammonia
produced by the gut.

52. Nutrition
 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
 Oral BCAA supplementation may allow recommended nitrogen
intake to be achieved and maintained in patients intolerant of dietary
protein

53. Liver Transplantation
53
 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.