Hepatic Encephalopathy from Harrison 19th Edition, Schiffs 11th Edition and some Internet Sources Prepared in March, 2018.

1. Hepatic
Encephalopathy
Dr.V.B.Kasyapa.J.
II year, MD – Gen.
MODERATOR: Dr.K.Venkateswarlu MD
Prof., Dept. of GM.

2. Introduction
 Brain dysfunction caused by liver insufficiency
and/or portosystemic shunting, and manifests as a
wide spectrum of neurological/ psychiatric
abnormalities ranging from subclinical alterations
to coma.
 Even with only porto-systemic anastomoses,
without intrinsic liver pathology, HE is rare.
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3. Classification
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4. Definitions
 Overt HE is the clinical manifestation of HE where
changes in consciousness and motor abnormalities are
observed.
 Minimal HE is defined as patients with completely normal
neurologic examination but who have cognitive deficits in
specific domains which are detected by psychometric
tests.
 Covert HE is a new term that has been proposed to
encompass minimal HE and the mildest form of overt HE.
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6. Little More For Understanding
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7. Pathogenesis
 (MC) culprit – Gut derived toxins (by Bacteria
in colon & enterocytes)
 Referring Introduction,
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8. Introduction
 A broad range of neurologic & neuropsychiatric
impairments seen in patients with significant
underlying liver disease.
 Even with only porto-systemic anastomoses,
without intrinsic liver pathology, HE is rare.
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9. Pathogenesis
 (MC) culprit – Gut derived toxins (by Bacteria in
colon & enterocytes)
 Referring Introduction
 It seems many of the patients still have Minimal HE.
 There will be increased hepatic artery flow for lack of
portal perfusion.
 But if there are any added proximal (ex: lienorenal)
shunts  multiple bouts of overt HE.
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11. Ammonia
 Major mediator, Correlates with Astrocyte oedema.
 Florid oedema  seizures, coma (in Acute LF) 
>200µmol/L S.NH3
 In Chronic LF  mild oedema
 There will not be any ↑ICP features, because
 Pre existing cerebral atrophy (in Alcoholic LD)
 Compensatory extrusion of intracellular Myoinositol; due to
↑Glutamine (from NH3 + Glutamate)
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12. GABA/Benzodiazepine System
 Best studied
 ↑sensitivity of Astrocyte (peripheral) BZD receptors &
↓susceptibility of synaptosomes for solubilisation
causing ↑ GABA receptors  ↑Accumulation of GABA
& BZD (not to the level of coma)  ↑ Neurosteroids
(allopregnanolone, tetra hydro-deoxy-corticosterone) in
Astrocytes  Feed forward mechanism.
 Supported by reversal of HE by FLUMAZENIL
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13. Endogenous opiates
 In cholestatic liver disease,
 Accumulation of these cause Pruritus
 Supported by reversal by NALOXONE
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14. Amino acid imbalance
 ↓ Branched chain amino acids (Leu, Ilu, Val): they are
mainly used up by skeletal muscle to produce
Glutamate
 ↑Aromatic amino acids (Phe, Tyr, Try)
 Loss of competition for cross over at BBB.
 Accumulation of AAA in brain
 False neurotransmitters & Serotonin production with
↑intracellular Glutamine
 Reversal with oral BrAA
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15. Inflammation/Sepsis
 It can be an independent Risk Factor for
Encephalopathy.
 It can modulate the expression of overt HE
 Oral glutamine challenge test can be done
 There will be no impairment if there are no raised
inflammatory markers
 May be due to inflammatory effect on BBB
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16. Gene modulation
 Allelic mutation in glutaminase gene
 ↑Glutaminase transcriptional activity
 ↑Ammonia & Glutamine
 ↑ Risk of Overt HE
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17. Colonic Microbiota
 There is retrospective evidence showing a
difference in microbiota that resides in colon,
between a normal person and a cirrhotic
person.
 Ammoniogenic bacteria outgrows other
species; reason still unknown.
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18. Clinical Features
 Subtle findings
 Reversal of sleep-wake cycle (first), forgetfulness,
alterations in hand writing, difficulty in driving
 Worst findings
 Asterixis, agitation, disinhibited behaviour, seizures,
coma
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21. Diagnosis
 Any change in mental status or prior
performance in psychometric assays in
patients with known or strongly suspected
underlying cirrhosis should be considered to
be HE, unless proven otherwise.
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22.  If we see HE with preserved liver function (ex:
Ⓝ PT, INR & LFT)
 Suspect,
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25. Modified West Havens Criteria
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26. HESA (Hepatic encephalopathy Scoring Algorithm)
 combines clinical impressions with
neuropsychological performances to
characterize HE.
 To overcome variability in assessment of
lower grades of HE.
 Shows early promise.
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27. CHESS (Clinical HE Staging Scale)
 It has 9 questions
 Not much useful for
minimal HE.
 0-9 scores.
 Higher the score,
severe the HE.
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28. ISHEN (International Society for HE & Nitrogen metabolism)
 Mainly divided HE in to two categories
 Covert HE: Minimal HE + Stage 1 WHC
 Overt HE: Stage 2,3&4 WHC
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29. Neurologic assessment
 Hypertonia, Hyper-reflexia, Extensor plantar
reflexes, Transient decerebrate posturing,
Nystagmus, Ataxic finger nose & knee heel
test, Dysdiadokinesia.
 Signs of progressive cerebral dysfunction
 Dementia, Motor deficits, etc..
 (MC) motor: disruption of smooth pursuit of
eye movements (SPEM)
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31. Asterixis
 Flapping tremor. Failure to actively maintain posture/ position.
 Postural lapse that occurs consists of series of rapid,
involuntary, flexion – extension movements of wrist (Hepatic
Flap).
 MOA: abnormal function of supraspinal motor centres.
 Seen in Grade II HE on WHS; also in RF, CHF, Resp.F,
Frontal lobe lesions, Hypokalaemia.
 Other places to appreciate: Tongue protrusion, dorsiflexion of
foot, fist clenching, forced eye closure.
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33. Lab diagnostic tests
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34. Serum Ammonia testing
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35. CSF Amino acids
 Glutamate (in astrocytes  Glutamine)
 2 fold increase
 ↑Phe, Tyr (precursors of Dopamine, NE)
 Most predictable risk in AA relating to degree
of neurologic deterioration
 CSF Alanine
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36. Psychometric Tests
 Paper-pencil tests
 PHES (Psychometric HE Score)- gold standard
 Number connection test A,B; Serial dotting test; Digit symbol test; Line
tracing test
 Domains: motor speed, accuracy, visual perception, visuospatial
orientation, visual construction, concentration, attention & memory(to
lesser extent)
 RBANS (Repeatable Battery for Assessment of Neuropsychological
Status)
 Four alternative forms (A D); 20-30 min
 Correlates with MELD score
 Remarkable learning effect  little useful with close intervals
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38.  Computer based tests: for minimal HE
 ICT(Inhibitory Control Test): 6 runs/2 min
 For deficits in attention, response inhibition.
 Also used in ADD, Schizophrenia, Brain injury.
 XY/YX  space bar; XX/YY refrain
 >5 lure response  Minimal HE (88% sensitivity)
 CDR(Cognitive Drug Research Test)
 7 tests
 5 domains (power of attention, continuity of attention,
quality of episodic memory, quality of working
memory, speed of memory)
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39.  Critical Flicker Fusion Frequency Test: 15 min
 Principle: Hepatic retinopathy
 Muller cells in retina = Astrocytes (similar changes)
 Changes in light frequency perception by retina
 60Hz  ↓0.1Hz/sec first perception of light
pulses; <39Hz  Minimal HE
 Prerequisite: binocular vision
 No learning effect
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40. EEG
 To objectively quantify the degree of physiologic changes in brain
& to study its correlation with other tests.
 In research setting;
 To monitor effects of therapy, portosystemic shunt insertion, surgery &
OLT
 In clinical setting; for severely impaired
 Generalized slowing of background EEG activity (in other
encephalopathies)
 ↓Amplitude of waves
 Triphasic waves & bursts of slow activity in theta & delta range
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42. Newer
 ANESS (Artificial Neural Network Expert
System Software)
 SEDACA (Short Epoch, Dominant Activity,
Cluster Analysis)
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43. Brain Imaging
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45. Treatment
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46. Supportive care
 Nasogastric tube for delivery of Lactulose.
 Elective intubation (in severe HE),
 To prevent aspiration of Lactulose & GI bleed.
 NG tube feeding,
 After initial recovery phase of GI bleed and
initial washout.
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48. BrAA supplementation
 They are mainly used up to produce more and more
glutamate.
 So, using BrAA supplement may cause more detriment,
as per many authors.
 So they suggest adding,
 α-keto glutarate (to prevent Glutamine breakdown by
enterocytes).
 Phenyl butyrate (to increase Glutamine excretion by
kidneys).
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49. Precipitating factors
 (MI) aspect of therapy
 Many patients have >2 simultaneous
factors
 (MC) overall – Sepsis
 (MC) in CLD – Upper GI bleed (it is
more ammoniogenic compared to other
proteins  d/t lack of isoleucine in
RBC)
 Do gut lavage & catharsis
 If constipation or ileus present rectal
lactulose
 Look for Hyponatremia
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50. Empirical Therapy
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51. Preventive Therapy
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52. Lactulose
 Non absorbed disaccharide
 FDA, 1977
 Most important drug
 No clear data
 It has become an ethical issue
 No difference from cheaper laxatives
 Need placebo controlled trials
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53. Rifaximine
 Minimally absorbed broad spectrum antibiotic
 No placebo controlled trials
 More useful in recurrent HE & Lactulose failure?
 No proof in shortening the overt HE episodes
 MOA: it preferentially kills small bowel bacterial over
growth, without having much effect on colonic
microbiota
 It is activated by bile salts
 Also effective against Clostridium difficile
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54. Others
 Neomycin,
 May have efficacy, but toxicity ended its use
 It is not towards anaerobic bacteria
 New found use: inhibits intestinal mucosal enzyme glutaminase
 Most useful in gene defects.
 Metronidazole, Vancomycin, Paramomycin
 Possibly by bacterial growth suppression
 Only short-term use
 Flumazenil
 ‘Awakenings’ seen in 30% of patients without ant prior BZD use
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55. Old Concepts
 Urease immunization
 Colonic resection/bypass
 Arterialisation of Portal vein stump
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56. HE with ALF
 Early ↑ICP  uncal herniation  coma, death.
 Arterial NH3, partial pressure of NH3,,ICP –
independent outcome predictors.
 HE stage 4 = 80% chance of cerebral edema.
 On EEG  subclinical epileptiform cortical activity
(d/t ↑ glutamine in Astrocytes)
 Advanced cerebral edema: hyperventilation,
systemic HTN, pupillary abnormalities,
decerebrate posture,uncal herniation and death.
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57. HE with ALF
 Lactulose  best for 1,2 stage HE
 Elevate the bed (300), minimize pt stimulation, elective
mechanical ventilation with sedation.
 acute hyperventilation  fails to ↓number of edema
attacks or onset of herniation.
 Arterial NH3 >200µg/dL correlates with cerebral edema.
 Irrevesible brain injury: ICP >20mm Hg, CPP <50mm Hg
 ICP monitors useful while OLT,but risk in coagulopathy
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58. HE with ALF
 First line: IV mannitol (0.5 g/kg body wt) [↓in Renal failure & go
for RRT to ensure multiple doses], if CPP <50 mm Hg (start
vasopressors), phenobarbital/thopental coma, phenytoin, mild to
moderate hypothermia.
 Corticosteroids have no role.
 OLT is definitve treatment.
 ICP rise continues for 24hrs after OLT  monitor till pt is awake.
 If primary graft failure/ delayed graft function  continue support
till hepatic recovery/retransplantation.
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59. Liver transplantation
 When medical therapy fails
 Priority is given now according MELD score, which
doesn’t include HE
 Even with severe HE, patient has to wait till he has the
needed MELD score.
 Modified MELD (includes Hyponatremia) may be more
useful
 In recurrent HE  muscle mass depletes rapidly 
patient becomes less fit for survival after LT
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60. Future Concepts
 Making PHES gold standard ↑Psychiatric test
usage, worldwide.
 Placebo-controlled trials are largely going on.
 In pursuit of better systems for detection &
quantification of Minimal HE.
 Overt HE is not completely reversible, as
previously thought.
 Rules to earlier Liver Transplantation.
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62. THANK YOU
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