This document provides an overview of hepatic encephalopathy. It defines hepatic encephalopathy as a complex metabolic disorder seen in patients with liver dysfunction, characterized by disturbances in consciousness and behavior. It discusses the pathogenesis, including the ammonia and false neurotransmitter hypotheses. Precipitating factors and clinical manifestations ranging from mild cognitive changes to coma are described. Diagnosis involves ruling out other causes and elevated ammonia levels. Treatment focuses on reducing ammonia through dietary changes, lactulose, antibiotics, and other supportive measures. Prognosis depends on the severity and underlying liver disease.

1. Hepatic Encephalopathy
Dr Bikash Ranjan Praharaj
Post Graduate, Dept of Pediatrics
MKCG Medical College, Berhampur

2. • Definition
• Etiology & classification
• Pathogenesis
• Precipitating factors
• Clinical manifestation
• Management
• Outcome

3. Definition
Hepatic encephalopathy (HE) is a complex
metabolic mental state disorder with a
spectrum of potentially reversible
neuropsychiatric abnormalities seen in
patients with severe acute or chronic liver
dysfunction after exclusion of other brain
diseases

4. Characterized by
 Disturbances in consciousness & behaviour
 Personality changes
 Fluctuating neurologic signs, asterixis or
flapping tremor
 Distinctive EEG changes

5. Epidemiology
 Exact data regarding incidence and prevalence is
lacking
 60-70% of patients with liver cirrhosis, while
clinically unremarkable have pathologic changes on
EEG and psychometric tests.(MHE)
 Prevalence of minimal HE is about 53% in patients
with extra hepatic portal vein obstruction
 Approximately 50% of patients with liver cirrhosis
develop HE after surgical portosystemic bypass
procedures

6. Type Description Subcategory Subdivision
A
Encephalopathy associated with
acute liver failure, typically
associated with cerebral edema
_____ ______
B
Encephalopathy with Porto-systemic
bypass and no
intrinsic hepatocellular disease
_____ ______
C
Encephalopathy associated with
cirrhosis or portal
hypertension ⁄ Porto-systemic shunts
Episodic
Persistent
Minimal
•Percipated
•Spontaneous
•Recurrent
•Mild
•Severe
•Treatment dependent
Classification

7. Pathogenesis Theories
–Ammonia hypothesis
– False neurotransmitters & AA imbalance
– Increase permeability of BBB
–GABA hypothesis
– Others

8. The Urea Cycle Aspartate Transaminase(AST)
Alanine Transaminase (ALT)

10. Neurotoxic Action of Ammonia
• Readily crosses blood-brain barrier
• Ammonia reacts with α-ketoglutatrate to produce
glutamate and glutamine
• Consumption of α-ketoglutatrate, NADH and ATP,
inhibition of pyruvate decarboxylase decrease
TCA cycle activity which is vital for brain metabolism
• Increased glutamine formation depletes glutamate
stores which are needed by neural tissue l/t Irrepairable
cell damage and neural cell death ensue.
• Directly depress the cerebral blood flow & glucose
metabolism
• Direct toxic effect on the neuronal membrane

11. False neurotransmitters & Aminoacid imbalance
• BCAA/AAA (N= 3-3.5, In hepatic coma=0.6-
1.2)
• BCAA : hyperinsulinemia  increased
uptake & utilization by muscle & adipocytes
• AAA :
- insulin/glucagon --> catabolism of liver
proteins & muscle --> AAA
- Decrease hepatic deamination
- Decrease gluconeogenesis

12. Which ultimately l/t
Increase FNTs
Decrease normal neurotransmitters
Increase inhibitory neurotransmitters

13. False Neurotransmitter Hypothesis
 AAA are precursors to neurotransmitters and
elevated levels result in shunting to secondary
pathways

14. Increase Permeability of Blood-Brain Barrier
• Astrocyte (glial cell) volume is controlled by
intracellular organic osmolyte which is glutamine
• Increase glutamine levels in the brain result in
increase volume of fluid within astrocytes resulting in
cerebral edema (enlarged glial cells)
• Neurological impairment
“Alzheimer type II astrocytosis”
– Pale, enlarged nuclei
– characterisic of HE

16. GABA hypothesis
• Major inhibitory neurotransmitter.
• Evidence: increased GABAergic tone &
Flumazenil improves clinical outcome
• Cause
- Decrease hepatic metabolism
- Increase gut wall permeability

17. Some other theories
• Dysregulation of serotonergic system
(inversion of sleep rhythm)
• Depletion of zinc & accumulation of Mn in
globus pallidus.
• Action of cytokines and bacterial LPS on
astrocytes which are formed d/t inflmm.
elsewhere in the body.
• Neuronal NO synthase may increase c/t the
altered cerebral perfusion.

18. Other neurotoxins
• Mercaptans: Inhibit Na+-K+ ATPase
• Short & medium chain fatty acids:
inhibit Na+-K+ ATPase & Urea synthase
• Phenol: a neurotoxin

19. Precipitating factors

20. CLINICAL MANIFESTATIONS

21. • Variable & fluctuating
• Mild disturbance of consciousness &
altered behavior to deep coma
• Psychiatric changes of varying degrees
• F/o liver cell failure like flapping tremor
& fetor hepaticus

22. In MHE :
• children have normal abilities of memory,
language, construction & pure motor
skills.
• have normal standard mental status
testing & abnormal psychometric testing.

23. Mild to moderate HE:
• Decreased short term memory or
forgetfulness
• Loss of concentration & irritability
• Asterixis, hyperventilation &
hypothermia
• Relative bradycardia (if ass. with increase
ICP)

25. Clinical grading
• West Haven classification system
• Prognostic significance
• Better in grade I & worse in grade IV

27. Minimal encephalopathy
• Defined as encephalopathy that does not lead
to clinically overt cognitive dysfunction but
can be demonstrated with neuropsychological
studies.
• May account for 60% of patients with
portosystemic shunts.

28. Clinical Manifestations & Diagnosis :MHE
• Clinically normal
• No mental deficit
• Normal verbal ability
• Deficit in attention ,visual perception, memory
function, and learning
• Impaired daily activities / driving
• Only sophisticated tests such as
EEG,CFF,ICT,NCT,DST, RBANS & PSE Syndrome
test.
• Neuroimaging : SPECT ,MRI,MRS.DWI

29. Manifestations & Diagnosis :MHE
Number Connection Test (NCT)
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Time to
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Draw a star
SAMPLE HANDWRITING

30. Diagnosis of HE
• No single laboratory test is sufficient to
establish the diagnosis
– No Gold Standard
• Dx is mainly clinical on basis of history, clinical
exam (includ mental status) & raised blood
ammonia level

31. Diagnostic Criteria
• Asterixis (“flapping tremor”)
• Hx liver disease
• Impaired performance on neuropsychological tests
– Visual, sensory, brainstem auditory evoked potentials
• Sleep disturbances
• Fetor Hepaticus
• EEG
• PET scan
– Changes of neurotransmission, astrocyte function
• Elevated serum NH3
– Stored blood contains ~30ug/L ammonia
– Elevated levels seen in 90% pts with HE
– Not needed for diagnosis

32. Investigations

33. Confirmation of liver
disease/portosystemic shunt
1. LFT: increase in the following
- Sr bilirubin/AST/ALT/ALP/GGT
- PT(INR) > 1.5 with encephalopathy or >2
without encephalopathy
- Sr protein, A:G ratio
2. Sr ammonia level is increased in most cases
3. USG

34. Detection of causative factors
• Viral serologic markers: HBs Ag, HBe Ag, anti-HBc,
HBV DNA increased in Hepatitis
• TORCH screening
• Autoimmune ab: ANA, ASMA, LKM1
• Sr Cu, ceruloplasmin, urinary Cu : wilson’s disease
• Urine for metabolic disorders
• Sweat chloride & cystic fibrosis mutation studies
• Alfa 1 antitrypsin levels : Alfa 1 antitrypsin def
• Alfa feto protein : tyrosinemia type 1
• Sr lactate & pyruvate : GSD & resp chain defects
• Liver biopsy: cirrhosis

35. R/o other diseases with similar presentation
• CT Scan: to r/o cerebral hemorrhage
• EEG: r/o seizure disorder
• CSF study: meningitis or encephalitis
• Blood tests: metabolic causes of
encephalopathy including hypoglycemia &
uremia
• Serum urea, Cr & electrolytes: renal failure

36. Detection of complications
• ABG- hypoxia is common
• CBC: to r/o infection
• Hb,PCV,CPS
• PT, aPTT
• Pt count decreased in advanced cases &
coagulopathy
• Blood glucose: hypoglycemia
• Sr ammonia
• RFT

37. Differential Diagnosis
Metabolic
encephalopathies
- Diabetes (hypoglycemia,
ketoacidosis)
- Hypoxia
- Carbon dioxide narcosis
Toxic
encephalopathies
- Alcohol (acute alcohol
intoxication, delirium
tremens, Wernicke-
Korsakoff syndrome)
- Drugs
Intracranial events
- Intracerebral
bleeding or
infarction
-Tumor
- Infections
(abscess,
meningitis)
- Encephalitis
Psychiatric diseases

38. Treatment of Hepatic Encephalopathy
• Various measures in current treatment of HE
– Strategies to lower ammonia production/absorption
• Nutritional management
– Protein restriction
– BCAA supplementation
• Medical management
– Medications to counteract ammonia’s effect on brain cell
function
• Lactulose
• Antibiotics
– Devices to compensate for liver dysfunction
– Liver transplantation

39. Proposed
Complex
Feedback
Mechanisms
In Treatment
Of HE

40. Diet
• Decreased protein intake with high
carbohydrates
• Calorie in the form of 10%D infusion
• Protein restricted to 0.5-1 g/kg/day
• Veg protein preferred as they are less
amminogenic , contain less amount of
methionine & AAA and more fibres
• Dietary supplementation of BAA
• 50% of non-protein calories should come from
MCT

41. Lactulose/lactitol
• Non absorbable synthetic diasachharide
• Degraded by colonic bacteria to form lactic acid & acetic
acid
• Fecal acidity increase l/t decrease absorption of NH3
• Favours growth of lactose fermenting bacteria &
diminished growth of ammo producing bacteria like
bacteroides
• Detoxify short chain FAs produced in presence of blood
& proteins
Dose: 1-2 ml/kg per orally or as enema in higher doses
N:B:- Alternatively, phosphate enema can be used

42. Actions Of Lactulose

43. Bowel sterilization
• Neomycin : orally through NGT dose: 50-
100mg/kg
• Ampicillin
• Rifaximin
• metronidazole

44. Other measures
• NGT aspiration
• High colonic wash
• Zn
• L-Ornithine-L-Aspartate : oral/iv
• Sodium Benzoate: 5g PO BD
• H.Pylori eradication

45. Supportive care
• Fluid & electrolyte balance:
- Should contain 1meq/kg/d of glucose
- Met acidosis: NaHco3
- Hypokalemia: pot. Chloride
• Early identification & T/t of GI bleeding,
septicemia & hypoxia
• Avoidance of ppt factors: drugs/paracentesis
• Drugs: To improve sensorium e.g Flumazenil, l-dopa,
bromocriptine

46. T/t in Resistant cases
• Plasmapheresis/hemodialysis
• exchange transfusion
• Surgical shunt occlusion
• Temporary hepatic support:
- ELAD (Extracorporeal Liver Assist Devices)
- MARS (Molecular Adsorbent Recirculating
System)
• Liver transplantation

47. T/t of complications
1. CNS complications:
• Cerebral edema:
- Elevation of bed by 30 “,mannitol,
hyperventilation & fluid restriction
- Hypothermia & phenobarbitone
• Seizures: phenytoin & gabapentin
• Cerebral hypoxia: O2, N-acetylcysteine
2. Hypotension: colloids/albumin infusion
3. Bleeding: Inj Vit-k/ FFP/ Inj Ranitidine

48. 4. Respiratory failure:
- In Stage III & IV
- Endotracheal Intubation
5. Renal Failure:
- Furosemide in a dose of 1-2 mg/kg in early
stages if CVP > 8-10 cm of H2O
- Hemodialysis in established cases
- Urine output should be maintained
- Dopamine: Improve renal perfusion
6. Ascites: 5% albumin, bile acid binders

49. Monitoring Protocol
Daily Once in 3 days Weekly
•Blood glucose (2 hrly)
•Sr electrolytes: Na, K, HCO3-
•Hb, PCV, CPS
-Renal function
tests
-PT
-NEC
-Sr amino acids
-EEG

50. Minimal HE
1.No established indication for treatment
2.Consider changes in daily activities (avoid
driving)
3.In selected patients
• Lactulose /lactitol
• Dietary intervention vegetable based diet
• Probiotics

51. Prophylaxis Of New Episodes
1.Control of precipitating factors
2.Nutritional support
3.Adequate protein intake with dairy and
vegetable based diets
4.Vitamins
5.Zinc supplementation
6.Lactulose /lactitol as needed
7. OLT evaluation

52. Course And Prognosis
•Develops rapidly few hours – 1-2 days
•Mortality in grade IV is 80%
•Death usually due to brain herniation / edema ICH
•Type C develops slowly – undulating course /
recurrence
•Neuropsychiatric manifestations are reversible
•Can lead to permanent damage with dementia, extra
pyramidal signs, cerebellar degeneration,myelopathy
with spastic paraplegia, peripheral polyneuropthy
•Liver TX can reverse all changes

53. Prognostic indicators
FEATURES GOOD PROGNOSIS BAD PROGNOSIS
AGE CHILDREN ADOLESCENTS
ETIOLOGY PCM POISONING, HEP A HEP C
DURATION OF
ENCEPHALOPATHY
< 7 DAYS > 7 DAYS
COMA GRADE I & II III & IV
LIVER SIZE ENLARGED SHRINKING/NON PALPABLE
BLEEDING TENDENCY ABSENT PRESENT
FLUID RETENTION ---- +++
SR ALBUMIN N
PT N PROLONGED
LIVER ENZYMES: AST/ALT N
AFP
ASS. COMPLICATIONS ABSENT PRESENT
IMPROVEMENT OF
RAPID
SENSORIUM WITH T/t
NO IMPROVEMENT AFTER
48 HRS OF T/t

54. Take home points
• Ammonia is the main culprit
• Dx mainly by clinical exclusion
• Bad prognostic indicators:
- Liver span
- Bilirubin level
- Liver enzyme levels
- Prothrombin time
• T/t of precipitating causes & supportive care is
the mainstay of t/t
• Prognosis bad in type A & better in other types

55. Thanks