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
