Hepatic encephalopathy is a brain dysfunction caused by liver disease or portosystemic shunts. Gut-derived toxins such as ammonia cross the blood-brain barrier and cause neurological or psychiatric abnormalities. Treatment involves removing precipitating causes, lowering ammonia levels through antibiotics, lactulose, and BCAA supplementation, and correcting nutritional deficiencies. For refractory or recurrent cases, transplantation may be required.

1. HEPATIC
ENCEPHALOPATHY
Presentor – Dr. Nikhil Bhangale
General Medicine

2. Hepatic encephalopathy
 Definition –
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)

3. Pathophysiology
1) Hepatocellular failure
2) Portosystemic shunt
Gut derived neurotoxins
Brain water homeostasis
Oxidative nitrosative stress
Astrocyte dysfunction
Neurotransmitter dysfunction

6. Gut derived neurotoxins
 Ammonia(mainly)
 Mercaptans (from Methionine)
 Short & medium-chain fatty acids
 Gamma-amino butyric acid(GABA)
 Octopamine
 False neurotransmitter substances
 Alterations in plasma levels of ↑ aromatic &
↓branched chain amino acids
 Indoles (from tryptophan)

7. Brain water homeostasis
 ↑ NH3 + Glutamate Glutamine
↑ Efflux of Myoinositol
Astrocyte
swelling
(Alzeimer type 2
Astrocytosis)

8. 8

9. Oxidative nitrosative stress
 Ammonia , hypo-osmotic
swelling,inflammatory cytokines, BZD induce
oxidative and nitrosative stress response in
astrocytes.
 Response mediated by NMDA receptors

10. Astrocyte dysfunction
 Oxidative / nitrosative stress can promote
covalent modification of tyrosine residues in
astrocyte proteins.
 This protein tyrosine nitration ,interfere with
protein function and intracellular signal
transduction.

11. Neurotransmitter dysfunction
 Shift of balance between inhibitiry and
excitatory neurotransmission towards
inhibitory.
 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-
A
 Acetyl choline(Ach) levels decresed

12. Precipitating Factors
 GI bleeding
 Infections(sepsis)
 Excess protein in diet
 Electrolyte disorder- Hyponatremia,hypokalemia
 Constipation
 Dehydration-
Fluid restriction
Excessive diuresis
Paracentesis abdominis(large volume >3-5 Lt )
Diarrhoea/vomitting
 Alcohol misuse/bout
 TIPS insertion
 Surgery

13.  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
Encephalopathy

15.  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.

16. West haven criteria

17. Clinical features
 Minimal HE
 Affection of
1) Attention span
2) Working memory(WM)
3) psychomotor speed
4) visuospatial ability

18. Asterixis/Flapping tremors
 often present in the early to middle stages of HE that precede stupor
or coma
 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
sustained posture
 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
other diseases

19. CoAsterixis is also seen in
 uraemia
 ventilatory failure (CO2 narcosis)
 drug intoxication-barbiturates,
phenytoin
alcoholism
 Electrolyte imbalance-hypokalaemia
hypomagnesaemia
hypoglycemia
19

20. Asterixis (Flap
Test))

21. Fetor hepaticus
 It is a sour , musty, feculent smell detected on
breath of some patients
 Due to presence of mercaptans(byproduct of
methionine metabolism)
 Its presence does not correlate with degree or
duration of encephalopathy and its absence
does not exclude hepatic encephalopathy.

22. Personality changes
 Apathy
 Irritability
 Euphoria
 Disinhibition
 Childishness
 Loss of concern for family and friends

23. Intellectual deterioration-
 Slight impairment of mental function to gross
confusion
 Constuctional apraxia (inability to make
designs from match or blocks)
 Changes in handwriting

25. Disturbed consciousness
Day time sleepiness - Early sign
 Disturbed night sleep
Speech
slow
slurred
voice – monotonus

26. Motor system
 Hypertonia
 Hyper-reflexia
 Positive Babinski sign
 Transient focal symptoms

27. Extrapyramidal dysfunction
 Hypomimia (masked facies, masking of
facies)
 muscular rigidity
 bradykinesia, hypokinesia
 monotony and slowness of speech
 parkinsonian-like tremor
 dyskinesia with diminished voluntary
movements

28.  Hepatic myelopathy (HM)
Mainly with surgically created long-standing portocaval
shunts.
Demyelination of pyramidal tracts →
1) paraplegia with progressive spasticity
2) hyper-reflexia
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).

29. 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)

30. Diagnosis
 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
for diagnosis.
 According to AASLD guidelines –
The diagnosis of HE is through exclusion of
other causes of brain dysfunction.

31. Differential diagnosis
Metabolic CNS Toxins Infection
Hypo-natremia stroke CNS
depressants
sepsis
Hypokalemia subdural
hematoma
alcohol
(abuse/withdrawal)
Meningitis
Hypoxia /
Hypercapnea
Intracranial bleed Wernicke-Korsakoff
syndrome
Encephalitis
Hypoglycemia /
Ketoacidosis
abscess
Uremia CNS neoplasm
Seizure / Postictal

32.  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
cycle disorders.

33. 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)

34. 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

35. Portosystemic encephalopathy (PSE) syndrome test
five paper-pencil tests

36. EEG findings-
 Progressive slowing of normal alpha(8-13Hz)
frequency
 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
induced (lithium,valproate,baclofen).

37. Radiological tests
 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
processes,neuronal activity.

38.  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.

39. TREATMENT
 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)
V. probiotics
VI. other antibiotics.
 C) Nutrition
 D)LiverTransplantation

40. Non-absorbable Disaccharides
 Like lactulose / lactitol -is the first choice for treatment of
episodic OHE
 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
ammonia production.
3) NH3 converted to NH4 ions , which are less readily absorbed

41.  Acts as probiotic – helps in growth of good
bacteria like bifidobacterium,lactobacillus
and supresses NH3 forming bacteria
(bacteroids)
 Reduction of intestinal NH3 production –
through inhibition of glutaminase activity

42.  Dosage – 15-30 ml ,two – four times/day,
Dose needs to be titrated ,so as to pass 2-3
bowel movements/day.
 Can be given as rectal enema
 Overuse has its risks like
Aspiration, dehydration,
hypernatremia, and severe perianal skin
irritation. overuse can even precipitate HE.

43. Antibiotics - Rifaximin
 aim of modifying the intestinal flora
(selectively eliminate urease producing
bacteria).
 Rifaximin is an effective add-on therapy to
lactulose for prevention of OHE recurrence
 Other antibiotics – metronidazole, Neomycin
(also a known glutaminase inhibitor)

44. oral branched-chain amino
acids (BCAAs)
 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.
 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
immune function

45. L-ornithine L-aspartate (LOLA)
 Can be given Intravenously (preferred) or Oral
use
 salt of the amino acids ornithine and aspartic
acid and provides key substrates to &
promotes metabolic pathway,urea
cycle,resulting in detoxification of ammonia.

47. L-ornithine phenylacetate - would participate in
the clearance of ammonia in muscles and the
liver through glutamine synthesis
ammonia
 L-ornithine Glutamine
 Glutamine + phenylacetate
phenylacetylglutamine
Excreted by kidney

48. Acarbose
 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.

49. Drugs which increase ammonia
clearance
 Sodium benzoate,sodium
phenylbutyrate,sodium phenylacetate,
GPB(Glyceryl phenylbutyrate)
 Conjugate with glycine, excess nitrogen
excreted in urine as hippurate
 high sodium load,so cautious use is advised.
 Efficacy is not clearly established yet.

50. Zinc supplementation
 zinc deficiency is common in patients with
cirrhosis.
 Poor zinc levels → impaired activity of urea
cycle enzymes in liver & glutamine
synthetase
 zinc increases the activity of ornithine
transcarbamylase, an enzyme in the urea
cycle, may also improve HE

51. Probiotics
 promote nonammoniagenic(non-urease
producing) bacteria in the gut
 Like Lactobacillus
acidophilus,bifidobacterium

52.  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
postdischarge survival.

53.  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
embolisation,baloon occlusion,vascular
plugging

54.  Nasogastric intubation – for patients unable
to take orally & also for those who are at risk
of aspiration due to depressed sensorium.

55. Liver transplantation
 only treatment option for HE that does not
improve on any other treatment.
 Artificial liver support system
(MARS, molecular adsorption recirculating
system)
Purifies blood by removal of albumin
bound and water soluble molecules. It removes
NH3,endotoxin, inflammatory mediators.

56. Nutrition
 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
energy depots.
 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
of HE.

57.  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
ammonia excretion

58. 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.

59. Other drugs
 Rivastigmine – Ach levels are decreased , so
rivastigmine improves psychometric
performance
 Sildenafil - ↓ function of NO-cGMP pathway,
so , ↓ extracellular cGMP levels. Sildenafil
improves cGMP levels & restore learning
ability & intellectual function.

60. AST-120 (cremezin) –
 oral adsorbent used in Japan to delay
initiation of dialysis in patients with ESRD.
Binds ammonia, bile acids, inflammatory
mediators.
 NMDA-receptor antagonists
ammonia leads to overstimulation of
NMDA receptors