Understanding

Cerebral Dysfunction
in
Hepatic
Encephalopathy
By
Dr Junaid Saleem
Consultant Physician
Special Interest: Liver Disorders
Hearts International Hospital
Rawalpindi
Presentation At A Glance
Definition(s)
Preconditions to be met for
Development of Hepatic
Encephalopathy (HE)
Precipitating Factors
Cerebral and Neuronal Dysfunctions
Biochemical Abnormalities and
Advances in Diagnostic Imaging
Techniques
Definition ( s )
Definition
Hepatic Encephalopathy reflects a
spectrum of neuropsychiatric
abnormalities seen in patients with
liver dysfunction after exclusion of
other known brain diseases.

Working Group of WCOG Final Report. Hepatology, Vol. 35, No. 3, 2002
Definition
Hepatic encephalopathy is a
potentially reversible syndrome of
global cerebral dysfunction observed
in patients with liver diseases
(reduced liver mass) or porto-
systemic shunting, characterized by:
Personality changes
Intellectual impairment
Depressed level of consciousness

Preconditions to
be met for
Development of
Hepatic
Encephalopathy
Preconditions to be met
for Development of
Hepatic Encephalopathy
1.Reduced Liver Mass
< 25 – 30 % of Functional Liver
Unable to deal with the Gut derived
Nitrogen Load
Passes through, but is not Detoxified /
Metabolized
2.Porto-Systemic Shunts
Bypassing Liver
Liver Diseases
Acute
Acute Liver Failure (ALF)  Fulminant
Hepatic Failure (FHF)
Chronic
Chronic Hepatitis
Cirrhosis
Cholestatic liver Disease
Wilson’s Disease
Porto-Systemic Shunts
(PSSs)
Congenital or acquired vascular
abnormalities
Single or multiple vascular bypass
channels
Permit portal blood flow to bypass the
liver and enter the systemic circulation
directly.
Neurotoxic substances get a direct access
to the CNS
Hepatic Encephalopathy
A n a to m y o f
P o te n tia l
P o rto -
S y ste m ic
S h u n ts

1.Under the
Diaphragm
2.Lower
Esophagus
3.Abdominal
Wall
4.Colon and
Rectum
 Liver Shunt

Portal Vein Spleen

( http :// maxshouse . com / portosystemic_shunts

_pathogenesis_and_pathophysiology . htm )
Iatrogenic Shunts
 TIPS Surgical Shunts

Hepatic
Encephalopat
hy Mechanism
Gut Derived


Nitrogenous
Material
Bypasses Liver
Via Shunts and
Reaches the
Brain Directly
Precipitating
Factors
 Precipitants of Hepatic
Encephalopathy
ncreased Ammonia Production , Dehydration
•Vomiting
bsorption or Entry Into the Brain
xcess Dietary Intake of Protein •Diarrhea
I Bleeding •Hemorrhage
nfection •Diuretics
lectrolyte Disturbances (ie., hypokalemia) •Large volume
onstipation paracentesis
etabolic alkalosis
D ru g s
•Benzodiazepines
Portosystemic Shunting •Narcotics
•Radiographic or surgically placed •Alcohol
shunts
•Spontaneous shunts Primary
•Vascular Occlusion Hepatocellular
•Portal or Hepatic Vein Thrombosis Carcinoma
Hepatic Encephalopathy
Exacerbating factors
Cerebral and
Neuronal
Dysfunctions
 Pathogenesis

Multifarious toxins → Dysfunction of CNS

(No obvious morphological change)

Several hypotheses to
uncover the mystery
Cerebral and Neuronal
Dysfunctions
Astro-glial edema and resultant:
Selective alterations of blood-brain barrier
permeability
Changes in cerebral energy metabolism
Alterations of gene expression. e.g.
Mono-amine oxidase
Peripheral-type benzodiazepine receptor
(PTBR)
Neuronal NO synthetase
Changes in neurotransmitter systems (False
neurotransmitters)
Butterworth RF. Complications of cirrhosis III. Hepat
encephalopathy. J Hepatol, 2000;32:171-180
Neuronal Dysfunctions –
Role of Astrocytes
Important constituents of the blood-brain
barrier –
 Transastrocytic transport.
Communicate directly with neurons
Regulate neurotransmitter processing
Regulate ionic milieu
Provide substrates for neurons
Only cells in brain containing glutamine
synthetase
Major site of cerebral ammonia detoxification
Upon exposure
Stephan vom to
Dahlammonia, cultured as a complicatio
et L. Hepatic encephalopathy
astrocytes develop
of liver Alzheimer
Disease. World type
J Gastroentero, 2001;II7(2):152 - 156
Neuronal Dysfunctions
–
Role of Astrocytes
Pathophysiology of both acute or chronic
liver failure is similar, but different kinetics.

In ALF/ FHF and High Grade HE associate with
CLD astrocytes swell  cerebral edema

In Low Grade HE (0-I) no clinical signs of
cerebral edema, but evidence of increased
cell hydration

A disturbance of astrocyte hydration is
apparently a major pathophysiologic event
Stephan vom Dahl et L. Hepatic encephalopathy as a
in both forms.
complication
Increase Permeability of
Blood-BrainAstrocytes
Barrier
Alz = Alzheimer type II
 Pale enlarged nuclei
Astrocyte (glial  Prominent nucleoli
 Margination of chromatin
cell) volume is
controlled by
intracellular
organic osmolyte
-glutamine.

Glutamine levels
in the brain result
in  volume of
fluid within
astrocytes
 cerebral edema

Neurological N = Normal Astrocytes
Neuronal Dysfunctions
–
Role of Astrocytes
Multiple factors could result in a common
pathogenetic end path, i.e. glial swelling
with its functional consequences
Increase of astrocyte hydration is induced
by:
Hyperammonemia
Hyponatremia
Benzodiazepines
Cytokines (TNF-α, IL-1β, IL-6)

Stephan vom Dahl et L. Hepatic encephalopathy as a

complication
Effects of Increased Astrocytic
Hydration
Biochemical
Abnormalities
Pathogenesis Theories
Endogenous Neurotoxins
 Ammonia
 Mercaptans
 Phenols
 Short-medium fatty acids
Change in Neurotransmitters and
Receptors
 An increased GABA-ergic tone
 Altered BCAA/AAA ratio
 False Neurotransmitters
Other
 Zinc deficiency
 Manganese deposits

Pathogenesis Theories:
Ammonia Hypothesis
Ammonia enters the bloodstream as a
result of its absorption from the GI tract
and its liberation from kidney and
muscle cells.

Ammonia accumulates because damaged
liver cells fail to detoxify and convert to
urea the ammonia that is constantly
entering the bloodstream.

The increased ammonia concentration in
the blood causes brain dysfunction and
damage, resulting in hepatic
encephalopathy.
Neurotoxic Action of
Ammonia
Readily crosses blood-brain barrier
Increased NH3  increased glutamate
α-ketoglutarate + NH3 + NADH →
glutamate + NAD
glutamate + NH3 + ATP → glutamine +
ADP + Pi
As α-ketoglutarate is depleted TCA cycle
activity halted decreased cellular energy
production
Increased glutamine formation depletes
glutamate stores which are needed by
neural tissue
Irrepairable cell damage and neural cell
Pathogenesis Theories:
Ammonia Hypothesis
The largest source of ammonia is
the enzymatic and bacterial
digestion of dietary and blood
proteins in the GI tract as a
result of:
GI bleeding
High-protein diet
Bacterial infections
Uremia
Pathogenesis Theories:
Ammonia Hypothesis
The ingestion of ammonium salts
also increases the blood
ammonia level.

Increased ammonia absorption
from the GI tract and from the
renal tubular fluid in:
Alkalosis
Hypokalemia
 Pathogenesis Theories:
Ammonia Hypothesis
Conversely, serum ammonia is decreased
by:
elimination of protein from the diet
administration of antibiotic agents that
reduce the number of intestinal
bacteria capable of converting urea to
ammonia, such as:
 Neomycin sulfate
 Metronidazole

 Rifaximin

Nathan M, et al. Rifaximin Treatment in Hepatic Encephalopathy. N Engl J Med 362

Neurotoxic Action of
Ammonia
Readily crosses blood-brain barrier
Increased NH3  increased glutamate
α-ketoglutarate + NH3 + NADH →
glutamate + NAD
glutamate + NH3 + ATP → glutamine +
ADP + Pi
As α-ketoglutarate is depleted TCA cycle
activity halted decreased cellular energy
production
Increased glutamine formation depletes
glutamate stores which are needed by
neural tissue
Irrepairable cell damage and neural cell
Pathogenesis Theories:
Change In Neurotransmitters and Receptors
BCAA-Ammonia

Connection


Pathogenesis Theories:
False Neurotransmitter
Hypothesis
Liver cirrhosis characterized by altered
amino acid metabolism
 IncreasedAromatic Amino Acids
(AAA) in plasma and influx in brain

 Decrease in plasma Branched Chain

Amino Acids (BCAA)
 Share a common carrier at blood-
brain barrier
  BCAAs in blood may result in  AAA
transport to brain
 Pathogenesis Theories:
False Neurotransmitter Hypothesis
AAA are precursors to neurotransmitters and
elevated levels result in shunting to
secondary pathways
Normal Transmitter / Amino Acid Precursor False Neurotransmitter /
Modulator Modulator

Dopamine Tyrosine Tyramine

Norepinephrine Tyrosine Octopamine
? Phenylalanine Phenethyamine
? Phenylalanine Phenylthanolamnine
Serotonin (5- Tryptophan ? Tryptamine
Hydroxytrptamine)

Histamine Histidine ?
 Abnormal plasma amino acids :
chronic liver disease
400 Glu
350 Phe Asp
300 Meth
% of Normal

250 Tyr
200
Try
150
Gly
100 Orn
Thr Lys Tau Ser His
50 Val Leu Arg
Pro Ala
Ileu
Essential Non-Essential
Cerra, et al; JPEN, 1985 J. Y. Pang
Increased GABA - ergic
Activity
Astrocyte áPeripheral Type
Edema Benzodiazepine
Receptors ( PTBRs )

Synthesis of
áGABA neuro - steroids ( eg
Activit Allopregnenolone )
y
Pathogenesis Theories:
False Neurotransmitter
Hypothesis
Other theories exist about the causes of
encephalopathy, including excess
tryptophan and its metabolites, and
endogenous benzodiazepines or opiates.


Benzodiazepine-like chemicals
(compounds) have been detected in the
plasma and cerebrospinal fluid of
patients with hepatic encephalopathy
due to cirrhosis

Advances in
Diagnostic
Techniques
Neuro Imaging
Techniques –
CT Scan
Controversial
Information in
patients with
cirrhosis without
encephalopathy.

Anatomic
abnormalities
attributed to
atrophy and edema,
correlate with
neuro- psychologic
test performance
 Neuro Imaging
Techniques –
MR Imaging
Symmetrical high-signal
abnormalities in the
globus pallidus on T1-
weighted images due to
accumulation of
Manganese (Mn)

Generalized increase in
white matter, limbic, and
other extrapyramidal
areas.

These abnormalities
correlate well with liver
 Neuro Imaging
Techniques –
MR Spectroscopy
This technique can
produce measures of
common chemicals in
the brain.

1H-Spectra have shown
a characteristic
pattern: an increase
in the glutamine /
glutamate peak
coupled with a
decrease in the myo-
benberger J, et al. Proton magnetic resonance spectroscopy of the brain in symptom
inositol
asymptomatic andwith
patients choline
liver cirrhosis. Gastroenterology 1997;112:1610-1616.
Parietal
1H - MNR
spectra
 (A) From a healthy
person
 (B) Patients with
post hepatitic
cirrhosis and
latent (subclinical)
HE
 (C) Manifest grade
I-II HE.
 An increase in the
glutamine/glutam
ate signal (Glx)
and a decrease of
the inositol signal
(Ino) is observed.
Further
abbreviations:
Parietal 1H-
MNR spectra
from a 47-year-
old patient
with alcoholic

cirrhosis 3 days
before and 7
days after
implantation
of TIPS, showing

an increased Glx
signal and a
decreased Ino
 Neuro Imaging
Techniques –
PET Scan
This technique can
provide images of
the brain that reflect
a specific
biochemical or
physiologic process.
The exact nature of
the image depends
on the tracer used.
PET measures of
cerebral blood flow
(using 15 O-water)
Using 13 N Ammonia
metabolic ate can be
determined
Neuro Imaging
Techniques
Preliminary results show that hepatic
retinopathy, as detected by neuro-
physiological testing, very sensitively
reflects the degree of HE, and responds
to HE therapy.
Routine Labs
Do Not Forget The
Good Old
Prothrombin Time (PT)
International Normalized Ratio (INR)
Albumen
Alanine Transaminase 
Bilirubin
Conjugated 
Unconjugated
Urea 
Creatinine
Fibrinogen
Thank you