This document provides a comprehensive review of hepatic encephalopathy (HE), including its definition, epidemiology, classifications, clinical features, diagnosis, management, and prognosis. It highlights the role of liver insufficiency and portosystemic shunt in the pathogenesis of HE, noting significant risk factors and the impact of ammonia accumulation in the brain. Additionally, the document outlines diagnostic criteria, treatment options, and preventative measures for managing HE in patients with liver disease.

1. Dr. Kwemboi Jacob
Mbale Regional Referral Hospital, Uganda
24th Aug 2021
CME

2. Content Outline
1. Definition
2. Epidemiology
3. Pathogenesis
4. Classifications
5. Clinical features
6. West Haven criteria
7. Diagnosis
8. Differential diagnosis
9. Investigations
10. Management
11. Complications
12. Prognosis
13. Prevention

3. Definition
Hepatic encephalopathy is a brain
dysfunction caused by liver insufficiency,
and/or portosystemic shunt; it manifests as a
wide spectrum of neurological or psychiatric
abnormalities ranging from subclinical
alterations to coma.
(AASLD Guidelines 2014)

4. Epidemiology of Hepatic Encephalopathy
 Among patients with cirrhosis, the prevalence of subclinical
HE (ie, Minimal hepatic encephalopathy or covert HE)
ranges between 20% and 80%.
 In cirrhosis, the 1-, 5-, and 10- year cumulative incidence of
HE ranges between 0% to 21%, 5% to 25%, and 7% to 42%,
respectively.
 Major risk factors for overt HE include MHE, prior history of
overt HE, hyponatremia, epilepsy, T2DM, higher creatinine
levels, higher bilirubin, higher Child-Pugh score.
 The development of either covert or overt HE is associated
with poor survival of cirrhotic patients.

5. Pathogenesis
1. Hepatocellular
failure – toxic
substances not
metabolised
2. Portosystemic
shunt - portal
blood directly into
systemic
circulation

6. TOXIC SUBSTANCES
 Ammonia(mainly)
 Methionine
 Mercaptans
 Short-chain fatty acids
 Gamma-amino butyric acid(GABA)
 Octopamine
 False neurotransmitter substances
 Alterations in plasma levels of aromatic & branched chain aromatic
acids.

7. Source of Ammonia
 As part of the normal physiologic process;
 Colonic bacteria and gut mucosal enzymes break down
dietary proteins, which results in the release of
ammonia from the gut into the portal circulation.
 Normally, the ammonia is converted to urea in the
liver. In many persons with liver failure or
portosystemic shunting, the ammonia released into
the portal circulation does not get adequately
eliminated by the liver and it accumulates at high
levels in the systemic circulation.

8. Raised ammonia levels in the brain
 The circulating ammonia results in substantial levels
of ammonia crossing the blood brain barrier.
 Where rapid conversion to glutamine occurs by
astrocytes; in the brain, astrocytes are the only cells
that convert ammonia to glutamine.
 Within astrocytes, glutamine levels accumulate, acting
as an osmolyte to draw water inside the cell, which
causes astrocyte swelling. The end result of the high
circulating levels of ammonia is cerebral edema and
intracranial hypertension.

9. Raised Ammonia levels

10. Inflamation
 Astrocytes and microglial cells release cytokines. Cytokines affect the
integrity of the blood-brain barrier and increase ammonia diffusion into
the brain.
Manganese
 Preferential accumulation in basal ganglia in cirrhotics with extensive
portosystemic shunts
 Has role in formation of type II Alzheimer cells, stimulating neurosteroid
synthesis and increasing GABAergic tone.
Hyperammonemia and Neurosteroids. Hyperammonemia may also be
responsible for the increase of neurosteroids concentration

11. Pathogenesis… Other factors
 Oxidative nitrosative stress: enhanced production of reactive
nitrogen species (RNS) and reactive oxygen species (ROS)
 Mercaptans (from Methionine)
 Short & medium-chain fatty acids
 Gamma-amino butyric acid(GABA)
 Octopamine
 False neurotransmitter substances

12. Causes
Chronic parenchymal liver disease:
 Chronic hepatitis.
 Cirrhosis.
Fulminating hepatic failure:
 Acute viral hepatitis.
 Drugs. E.g Paracetamol overdose
 Toxins e.g. Wilson’s Disease.
Surgical Portal-systemic anastomoses
 Portacaval shunts, or Transjugular intrahepatic portal-systemic shunting [TIPS]).

13. Classification

14. Classification
1. According to the underlying disease, HE is subdivided
into
• Type A resulting from ALF
• Type B resulting predominantly from portosystemic bypass or
shunting
• Type C resulting from cirrhosis
2. According to the severity of manifestations.
 Unimpaired (normal, no subclinical or clinical impairment of
mental state)
 Minimal (abnormal specialized tests but normal mental status)
 West Haven Grades I through IV

15. West Haven Criteria
GRADE FEATURES
0 No abnormalities detected
I Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impairment of addition or subtraction
II Lethargy or apathy
Disorientation to time
Obvious personality change
Inappropriate behavior
III Somnolence to semi-stupor
Responsive to stimuli
Confused
Gross disorientation
Bizarre behavior
IV Coma
Unable to test mental state

16. 3. 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 with relapses of overt HE.
4. According to the existence of precipitating factors, HE
is subdivided into
• Non-precipitated or
• Precipitated, and 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

17. Description of all overt HE episodes
should include the all four criteria.
 A 60 year old female with liver cirrhosis is admitted for the 3rd time in a
month with acute mental confusions. She is already on lactulose and her
caregivers maintain patient's compliance.
 Patient is disoriented to time and place, but has no focal neurological
deficits. Lab work up was notable for gross pyuria. She was treated with a
course of antibiotics and got better and was discharged home.
 Based on the current recommendations, this will be classified as:
Type C, overt Grade III, recurrent, precipitated by urinary tract
infection.

18. Clinical Features
A Disturbance in
consciousness
 Disturbances in sleep rhythm.
 Impaired memory/ apraxia.
 Mental confusion.
 Apathy.
 Drowsiness / Somnolence.
 Coma.
B. Personality Changes
 Childish behavior.
 May be aggressive out burst.
 Euphoric.

19. C Neurological signs:
 Flapping tremor / Asterixis (in pre coma).
 Exaggerated tendon reflex.
 Extensor plantar reflex.

20. West Haven Criteria
GRADE FEATURES Neurological features
0 No abnormalities detected Normal, Impaired
Psychomotor
I Trivial lack of awareness*
Euphoria or anxiety
Shortened attention span
Impairment of addition or subtraction
Mild Asterixis / tremor
II Lethargy or apathy*
Disorientation to time
Obvious personality change
Inappropriate behavior
Obvious Asterixis / tremors
III Somnolence to semi-stupor*
Responsive to stimuli
Confused
Gross disorientation
Bizarre behavior
Muscular rigidity & Clonus
Hyper-reflexia
IV Coma*
Unable to test mental state
Decerebrate posturing

21. Testing for minimal and covert HE
PHES (Psychometric Hepatic Encephalopathy Score)
evaluate cognitive and psychomotor processing speed and visuo-motor
coordination.
The PHES includes the following tests:
1. The number connection test A (NCT A),
2. Number connection test B (NCT B),
3. Digit symbol test (DST),
4. line tracing test (LTT), and.
5. Serial dotting test (SDT).

23. Other tests

24. Flapping tremor (asterixis)
 A non-rhythmic, asymmetric lapse in
voluntary sustained posture of
extremities, head and trunk.
 Due to impaired inflow of joint and
other afferent information to the
brainstem reticular formation
resulting in lapses in posture.
 Demonstrated with the patient's
arms outstretched and fingers
separated or by hyperextending the
wrists with the forearm fixed.
 Absent at rest, less marked on
movement and maximum on
sustained posture,.

25. Fetor hepaticus
 This is a sour, musty odour 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.

26. Diagnosis
Is a diagnosis of Exclusion
1. Confirm that the patient has significant liver failure
and/or portal-systemic shunting, and
2. Exclude other causes of neurological and psychiatric
dysfunction, which may explain the entire set of
abnormalities.

27. Differential Diagnosis
Intracranial bleed
Severe sepsis
Severe hyponatremia
Respiratory failure
Acute alcoholism
Wernicke's encephalopathy
Status epilepticus
Zinc deficiency
Drug overdose
Hypoglycemia
Post ictal
CNS sepsis
Delirium tremens
 (Wilson's disease)

28. Laboratory diagnosis•
 Laboratory testing adds limited value to diagnosing hepatic
encephalopathy, especially in a cirrhotic patient with prior episodes
of overt HE who presents with altered mental status...
There are four main aspects of laboratory testing.
1. To confirm the presence of chronic liver disease.
2. To rule out other causes for metabolic/toxic encephalopathy.
3. To corroborate the diagnosis of HE
4. To diagnose the cause for precipitation of HE.

29. Investigations
• Routine Investigations –
CBC
LFTS
Electolytes
Urea
Creatinine
Prothrombin time
Elevation of blood ammonia.
EEG (Electroencephalogram)
CSF & CT Scan – Normal/cerebral edema.

30. Precipitating / Aggravating factors
 excessive protein intake;
 constipation;
 gastrointestinal bleeding;
 hypokalemia;
 hyponatremia;
 infections (e.g. UTI, spontaneous
bacterial peritonitis, sepsis);
 anemia.
 sedative drugs: benzodiazepines,
morphine;
 dehydration;
 fluid restriction;
 diuretics;
 diarrhea;
 vomiting;
 arterial hypotension/hypovolemia;
 peripheral vasodilatation;
 shock, operation;
 hypoxia;
 azotemia;
 alkalosis;

31. Management
Broadly classified into four
1. Supportive care to patients with altered mental
status
2. Identification and treatment of Precipitating
factors
3. Interventions to reduce production of and
absorption of gut derived ammonia and other
toxins
4. Prescription of agents to modify neurotransmitters

32. Management
 A)Maintain ABC
 B)Elimination or correction of precipitating causes
 C)Decrease ammonia levels –
 Non absorbable Disaccharides - lactulose
 Antibiotics, such as rifaximin.
 Oral branched-chain amino acids (BCAAs)
 Intravenous L-ornithine L-aspartate (LOLA)
 Probiotics
 Other antibiotics..
 D) Nutrition
 E)Liver Transplantation

33. Drug Therapies

35. Mechanism of action of Lactulose
 A non-absorbable disaccharide.
 It produces osmosis of water-
Diarrhea.
 It reduces pH of colonic content &
thereby prevents absorption of
NH3.
 It converts NH3- to NH4 that can
be excreted.
 Aim 2-4 stool/day

36. Antibiotics:
Rifaximin
 Broad spectrum antibiotic,
Negligible systemic absorption.
 Shown to decrease
hospitalizations and length of stay
as compared to lactulose in
humans.
 DOSE: 550 mg orally B.I.D
 Metronidazole
 Neomycin
Side effects: Ototoxicity,
nephrotoxicity.
 Vancomycin

37. Diet
 With held dietary protein during acute episode if patient cannot eat.
 Oral intake should be 60 - 80 g/day as tolerated.
 Vegetable protein is better tolerated than meat protein.
 G.I.T bleeding should be controlled
 120ml of magnesium citrate by mouth or NG tube every 3 - 4 hours until
stool free of blood

38. Stimulation of metabolic ammonia metabolism
 Sodium benzoate 5 g orally twice a day.
 LOLA (L-ornithine-L-aspartate) 9 g orally thrice a day.
 L-acyl-carnitine aspartate 4 g orally daily.
 Zinc sulphate 600mg/day in divided doses.

39. COMPLICATIONS
 Cerebral Edema
 Brain herniation
 Increased risk of:
 Cardiovascular collapse
 Kidney failure, Respiratory failure
 Sepsis
 Permanent nervous system damage (to movement, sensation, or mental
state)
 Progressive, irreversible coma
 Side effects of medications

40. PROGNOSIS
Acute hepatic encephalopathy may be treatable.
Patients with a previous episode of overt HE have a 42%
risk of recurrence at 1 year, and those with recurrent
overt HE have a 46% risk of another episode within 6
months, despite receiving standard care
Both forms may result in irreversible coma and death.
Approximately 80% (8 out of 10 patients) die if they go
into a coma.
Recovery & the risk of the condition returning vary
from patient to patient

41. PREVENTION
 Treating liver disorders may prevent some cases of hepatic
encephalopathy.
 Avoiding heavy drinking and intravenous drug use can prevent many liver
disorders.

44. Referencess
 Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline
by © 2014 The American Association for the Study of Liver Diseases and EASL
 Articles
 Rudler, M., Weiss, (2021). Diagnosis and Management of Hepatic Encephalopathy.
Clinics in Liver Disease, 25(2), 393–417.
 Rose, C. F., Amodio. (2020). Hepatic encephalopathy: Novel insights into
classification, pathophysiology and therapy. Journal of Hepatology
 Dharel, N., & Bajaj, J. S. (2015). Definition and Nomenclature of Hepatic
Encephalopathy. Journal of Clinical and Experimental Hepatology
 Elsaid, M. I., & Rustgi, V. K. (2020). Epidemiology of Hepatic Encephalopathy.
Clinics in Liver Disease, 24(2), 157–174

45. THANK YOU