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Hepatic Encephalopathy

at a Glance
Syifa Mustika

A Patient Case
History
a 62 years old male admitted to ER with complaint of confusion since this
morning, disorientation, lethargy, abdominal pain, constipation.

Past medical history: DM ( on OHG agent), CLD (LC, Hematemesis), HCV

Home medications: Glimepiride 3 mg PO OD, Metformin 500 mg PO BID,


Furosemide 40 mg PO OD, Lactulose 30 mL PO TID

Examination:
o

General condition: Disorientation & Confusion, flapping tremors

Vital signs within normal limit

Chest: Bilateral basal crepitation

Abdomen: Distended, soft, lax, liver span 6cm , mild ascites

OUTLINE
Definition
Epidemiology

& Classification

Pathogenesis
Precipitating

factors
Clinical manifestation
Diagnosis Approach
Treatment
Outcome

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
Characterized by
Disturbances in consciousness & behavior, Personality changes,
Fluctuating neurologic signs, asterixis or flapping tremor,
Distinctive EEG changes

Epidemiology
o Exact data regarding incidence and prevalence is
lacking
o 60-70% of patients with liver cirrhosis, while clinically
unremarkable have pathologic changes on EEG and
psychometric tests.(MHE)
o Prevalence of minimal HE is about 53% in patients with
extra hepatic portal vein obstruction
o In Indonesia, the incidens are 30-88% range from
subclinical to overt HE

Classification
Type

Description

Subcategory

Encephalopathy associated with acute


liver failure, typically associated with
_____
cerebral edema

Encephalopathy with Porto-systemic


bypass and no
intrinsic hepatocellular disease

Encephalopathy associated with cirrhosis


or portal
hypertension Porto-systemic shunts

Subdivision

______

_____

______

Episodic

Percipated
Spontaneous
Recurrent
Mild
Severe
Treatment dependent

Persistent
Minimal

Pathogenesis Theories

Ammonia

hypothesis
False neurotransmitters & AA imbalance
Increase permeability of BBB
GABA hypothesis
Others

Neurotoxic Action of Ammonia

Readily crosses blood-brain barrier

Ammonia reacts with -ketoglutatrate to produce glutamate and


glutamine

Consumption of -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 results in Irrepairable cell damage and neural
cell death ensue.

Directly depress the cerebral blood flow & glucose metabolism

Direct toxic effect on the neuronal membrane

False neurotransmitters & Aminoacid imbalance

Decrease Rasio BCAA/AAA (N= 3-3.5, In hepatic coma=0.6-1.2)

Decreased BCAA

Increased AAA

Decreased Rasio insulin/glucagon --> increased catabolism of liver proteins & muscle
increased AAA

Decrease hepatic deamination

Decrease gluconeogenesis

: hyperinsulinemia increased uptake & utilization by muscle & adipocytes


:

Which results in

Increase FNTs

Decrease normal neurotransmitters

Increase inhibitory neurotransmitters

-->

False Neurotransmitter Hypothesis


AAA are precursors to neurotransmitters and
elevated levels result in shunting to secondary
pathways

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

GABA hypothesis

Major inhibitory neurotransmitter.

Evidence: increased GABAergic tone &


Flumazenil improves clinical outcome

Cause

Decrease hepatic metabolism

Increase gut wall permeability

PRECIPITATING FACTORS

CLINICAL MANIFESTATIONS

Variable & fluctuating


Mild disturbance of consciousness & altered
behavior to deep coma
Psychiatric changes of varying degrees
Signs of liver cell failure like flapping tremor &
fetor hepaticus

Stages of Hepatic Encephalopathy

Signs of CLD

CLINICAL MANIFESTATIONS
In MHE :

have normal standard mental status testing & abnormal


psychometric testing.

Mild to moderate HE:

Decreased short term memory or forgetfulness

Loss of concentration & irritability

Asterixis, hyperventilation & hypothermia

Relative bradycardia (if ass. with increase ICP)

CLINICAL MANIFESTATIONS

Clinical Grading
West

Haven Classification system


ISHEN Criteria
Prognostic significance
Better in grade I & worse in grade IV

Diagnosis Approach
No

single laboratory test is sufficient to


establish the diagnosis
No Gold Standard
Diagnosis is mainly clinical on basis of
history, clinical exam (including mental
status) & raised blood ammonia level

Recommendation on Diagnosis HE

The diagnosis of HE is through exclusion of other causes of brain dysfunction

HE should be divided into various stages of severity

Overt hepatic encephalopathy is diagnosed by clinical criteria and can be


graded according the WHC and the GCS

The diagnosis and grading of MHE and CHE can be made using several
neurophysiological and psychometric tests that should be performed by
experienced examiners

Increased blood ammonia alone does not add any diagnostic, staging, or
prognostic value for HE in patients with CLD. A normal value calls for diagnostic
reevaluation

Diagnostic Criteria
Asterixis (flapping tremor)
History of 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

Psychometric test
Number Connection Test (NCT)

Draw a star

Time to complete____________________
End

10

4
7
5

25

9
Begin

11

14
3

23

24

2
13
17
16

15
19

18

SAMPLE HANDWRITING

12
22

20

21

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

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 : wilsons disease

Urine for metabolic disorders

Alfa 1 antitrypsin levels : Alfa 1 antitrypsin def

Alfa feto protein : tyrosinemia type 1

Sr lactate & pyruvate : GSD & resp chain defects

Liver biopsy: cirrhosis

Rule Out 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

Detection of complications

ABG- hypoxia is common

CBC: to r/o infection

Hb,PCV

PT, aPTT

Pt count decreased in advanced cases & coagulopathy

Blood glucose: hypoglycemia

Sr ammonia

RFT

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

Guidelines and Recommendation

Treatment of Hepatic Encephalopathy

Various measures in current treatment of HE

Strategies to lower ammonia production/absorption


Nutritional

management

Protein
BCAA
Medical

restriction

supplementation

management

Medications to counteract ammonias effect on brain cell function


Lactulose

Antibiotics

Liver transplantation

Proposed
Complex
Feedback
Mechanisms
In Treatment
Of HE

Diet

Decreased protein intake with high carbohydrates

Calorie in the form of 10% Dextrose 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 BCAA

Lactulose

Non absorbable synthetic diasachharide

Degraded by colonic bacteria to form lactic acid & acetic acid

Fecal acidity increase so there will be 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

Actions Of Lactulose

Bowel sterilization
Rifaximin

:550mg twice daily


Neomycin : orally through NGT dose: 50100mg/kg QID
Metronidazole 250mg orally TID

Other treatment options

Oral BCAA

IV LOLA

Metabolic Ammonia Scavenger: Gliceryl Phenyl Buthirate

Probiotics

Glutaminase Inhibitors

Laxative

Flumazenil

Supportive care

Fluid & electrolyte balance:

Should contain 1meq/kg/d of glucose

Met acidosis: NaHco3

Hypokalemia: pot. Chloride

Early identification & treatmen of GI bleeding, septicemia &


hypoxia

Avoidance of precipitating factors: drugs/paracentesis

Drugs: To improve sensorium e.g Flumazenil, l-dopa,


bromocriptine

Treatment 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

Treatment of complications
4. Respiratory failure:
-

In Stage III & IV

Endotracheal Intubation and Mechanical Ventilation

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

Minimal HE: Special Considerations

1.

No established indication for treatment

2.

Consider changes in daily activities (avoid driving)

3.

In selected patients

Lactulose

Dietary intervention vegetable based diet

Probiotics

Prophylaxis Of New Episodes

1. Control

of precipitating factors

2. Nutritional

3. Adequate

support

protein intake with dairy and vegetable


based diets

4. Lactulose

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 Trasplantation can reverse all changes

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

PT

LIVER ENZYMES: AST/ALT

PROLONGED

AFP
ASS. COMPLICATIONS

ABSENT

PRESENT

IMPROVEMENT OF
SENSORIUM WITH T/t

RAPID

NO IMPROVEMENT AFTER
48 HRS OF T/t

Take Home Messages

Ammonia is the main culprit

Diagnosis mainly by clinical exclusion

Bad prognostic indicators:


- decreased Liver span

- increased Bilirubin level


- alteration Liver enzyme levels

- prolonged Prothrombin time

Managing of precipitating causes & supportive care is the


mainstay of treatment

Comprehensive Approach in Hepatic Encephalopathy


Rule Out Other Cause

Identify Precipitating Factor

Initiate Empiric Treatment

Hypoxia

Sepsis

Lactulose od 15-30 ml 2-3 times daily

Hypercapnea

GI Bleeding

Rifaximin od 550mg twice daily

Acidosis

Constipation

Neomycin od 500mg four times daily

Uremia

Dietary protein overload

Metronidazol od 250mg four times

CNS drugs

Dehydration

Flumazenil iv 1-3mg

Electrolyte changes

CNS active drugs

BCAA oral

Prior seizure or stroke

Hypokalemia

LOLA iv

Delirium ttremenz

Poor compliance

Wernicke-korsakoff
syndrome

Prior anesthesia

Intracerebral
hemorrhage

Bowel obstruction

CNS sepsis

Uremia

Cerebral edema

Development of HCC

Hypoglycemia

Minimal Hepatic Encephalopathy


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 perhaps normal