Chapter 17．
Hepatic Failure
1
Section 1.
Concept of hepatic failure
2
1. Definition of hepatic failure
Various harmful factors
↓
parenchymal cells and Kupffer cells damadged
severely and extensively
↓
severe disturbance of liver function in
metabolism, secretion, synthesis, detoxication and immunity
↓
jaundice, bleeding, infection, renal dysfunction and
encephalopathy
↓
“Hepatic insufficiency”
↓
(late stage) “Hepatic failure”
hepatorenal syndrome and hepatic encephalopathy
3
2. Classification and causes
Severe, extensive degeneration and necrosis of hepatic cells
→ Acute (fulminant) hepatic failure
Late stage of cirrhosis or carcinoma of the liver
→ Chronic hepatic failure
4
3. Effects
Function
of of
hepatic
normal
failure
liver on the body
(1) metabolism:
Disturbance of metabolism:
carbohydrate, protein, electrolyte
(2) bile
secrete
and secrete
excrete:and excrete:
Obstacle
of bile
hyperbilirubinemia, intrahepatic cholestasis
(3) coagulation:
Disorder of coagulation:
generation↓ or consumption↑
→ clotting factor↓→ bleeding tendency
(4) bioconversion
Dysfunction of bioconversion
drug metabolism; detoxication of toxin;
inactivation of hormone
(5) immune
Dysfunction of immune (Kuppfer cells)
bacterial infection, bacteremia, intestinal endotoxemia
5
Section 2.
Hepatic Encephalopathy
6
A.
Concept and classification
Acute or chronic liver disease
A serial of
Neuropsychical symptoms
hepatic encephalopathy
Hepatic coma
ultimate clinical manifestation of HE
7
Classification:
According to the
Clinic course Acute, subacute and chronic types
Clinical neuropsychical symptoms
1st stage (prodromal period) 2nd stage (pre-coma period)
3rd stage (lethargy period)
4th stage (coma period)
Etiology
Virus infection or drug intoxication
→ extensive hepatocyte necrosis
→ acute (fulminant) hepatitis → endogenous HE
Portal or Schistosome hepatic cirrhosis → exogenous HE
( usually with obvious inducing factors)
8
B.
Pathogenesis of HE
HE is a neuropsychical disturbance.
The following features may imply
HE is mainly caused by the metabolic and functional
disturbance of the brain:
l ) Reversibility of symptoms
2) Dissemination of disease region
3) No clear evidence of morphologic alteration
4) Accompanied with biochemical abnormality
9
Several hypotheses of the pathogenesis of HE
have been proposed:
Theory of ammonia intoxication
False neurotransmitter hypothesis
Theory of amino acid imbalance
Theory of GABA(gamma-aminobutyric acid)
None of them is necessarily exclusive.
A conservative and conventional view of HE is
Almost certainly the etiology is multifactorial
10
1. Theory of ammonia intoxication
Ammonia is wildly believed to play a role
in the pathogenesis of HE.
However, a precise role for ammonia in the
pathogens of HE has yet to be clearly defined.
11
Evidences supporting ammonia intoxication
①The ammonia level in blood or CSF of patient with HE was
increased by 1~3 fold.
② HE may be induced by eating nitrogen-containing food in
patients with liver cirrhosis, and restricting intake may
alleviate HE.
③ Ammonia-lowering treatment was effective in part of patients
with HE.
④ Animal model of HE may created with ammonium chloride.
12
The metabolism of ammonia
citrulline
ATP
Enzymes
2
urea
25%
1
13
(1) Causes of increased plasma level of ammonia
l ) Decreased urea synthesis and
inadequate removal of ammonia
2) Excessive generation of ammonia
14
l ) Decreased urea synthesis
inadequate removal of NH3
Severe damaged of liver
↓
dysfunction of enzyme system, inadequate substrate
and lack of ATP
↓
disturbance of ornithine circle
↓
diminished removal of ammonia by urea synthesis.
15
2) Excessive generation
of ammonia
① Liver cirrhosis and portal vein hypertension
→ decreased bile secretion, blood stagnancy
and edema of enteric wall
→ dysfunction of digestion and absorption
bacteria propagation
→ increased generation of ammonia;
② Accompanied bleeding of alimentary tract;
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③ Accompanied renal dysfunction
→ urea excretion↓, urea diffusion into intestine↑
④ jactitation, tremor → muscle motion↑
→ ammonia generation by catabolism of adenosine.
Besides, decreased H+ in renal tubule caused by respiratory
alkalosis or carbonic anhydrase inhibiter may increase NH3
diffuse from kidney into blood. Elevation of pH in bowel
lumen may increase absorption of NH3 into blood.
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(2) Toxic role of ammonia on brain
l ) Interfering cerebral energy metabolism.
2) Changing neurotransmitter in the brain
3) Direct inhibitory effect on neural cell membrane
18
l ) Interfering cerebral
energy metabolism
Glycose
③Inhibiting activity of pyruvic acid
decarboxylase → generation of acetyl
coenzyme A↓ →impairing TA cycle
Glucose-6-phosphate
NH
② Excessive consumption
3
reduced coenzyme I →
Pyruvic 
acetyl COA 
hindering delivery ofLactic
H+ acid
acid
in respiratory chain
Acetylcholine 
Oxaloacetic
Choline
acid
→ATP generation↓
Succinic
acid ATP  Citric acid
①Excessive consumption of
a- ketoglutaric acid
→ hindering tricarboxylic
acid cycle
a-Ketoglutaric acid
g-aminobutyric acid
Glutamic
acid 
ATP 
glutamine
④
Excessive
consumption
of ATP
Krebs
citric
acid cycle
by synthesis of glutamine
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2) Changing neurotransmitter in the brain
Inhibition of pyruvic acid
decarboxylase by NH3
① Excitative neurotransmitter↓
Glycose
Glucose-6-phosphate
NH
3
Pyruvic 
acetyl COA 
acid
Acetylcholine 
Oxaloacetic
Choline
acid
Succinic
acid
Citric acid
Lactic acid
a-Ketoglutaric acid
g-aminobutyric acid
Glutamic
acid 
ATP
glutamine
Glutamic acid consumed
by combination with NH3
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2) Changing neurotransmitter in the brain
① Excitative neurotransmitter↓
Glycose
Glucose-6-phosphate
NH
3
Pyruvic 
acetyl COA 
acid
Acetylcholine 
Oxaloacetic
Choline
acid
Succinic
acid
Citric acid
Lactic acid
a-Ketoglutaric acid
g-aminobutyric acid
Glutamic
acid 
ATP
glutamine
② Inhibitive neurotransmitter ↑
21
.
3) Direct inhibitory effect on neural cell membrane
Interfere membrane potential and excitation of neuron
by inhibiting Na+-K+-ATPase and competitively inhibit K+
enter cells.
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2. False neurotransmitter hypothesis
(1) Reticular activating system (RAS) and conscious state
Consciousness
neurotransmitter
noradrenalin
dopamine
Nonspecific ascending
project system
Various
impulses
23
(2) True and false neurotransmitter
True neurotransmitter
HO
—
HO
—
—CHOHCH2 NH2
noradrenalin
HO
—
HO
—
False neurotransmitter
—CHOHCH2 NH2
phenylethanolamine
—CHCH2 NH2
dopamine
—CHOHCH2 NH2
HO
—
Octopamine
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(3) Mechanisms of false neurotransmitter formation
LIVER
(MAO) Catabolism
.
Phenylalanine Phenylethylamine
(bacterial decorboxylase )
Tyrosine - - -  Tyramine
INTESTINE
.
phenylethanolamine
(b -hydroxylase)
Octopamine
BRAIN
Accumulation of false neurotransmitter in reticular formation
→ obstacle in transfer of neural impulse
→ CNS dysfunction → COMA
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3. Theory of amino acid imbalance
Aromatic amino acid (AAA):
Phenylalanine, Tyrosine and tryptophan
Branched chain amino acid (BCAA):
Valine, leucine, isoleucine
Normal: BCAA/AAA 3~3.5
In hepatic coma: BCAA↓, AAA↑, BCAA/AAA 0.6~1.2
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(1) Cause of amino acids imbalance
AAA
Insulin
catabolism
inactivate
LIVER
BCAA
NORMAL
MUSCLE
ADIPOSE CELL
AAA
DISEASED
BCAA 
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Dysfunction of the liver
Ratio of insulin / (HGF) 
 AAA generation from the catabolism
of proteins of muscle and liver 
Catabolism of AAA 
AAA 
AAA to be converted into glucose 
Inactivation of insulin   hyperinsulinemia
 BCAA uptake and degradation
in skeletal muscle and fat 
BCAA
(HGF = hyperglycemic-glycogenolytic factor, glucagon )
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(2) Effects of amino acids imbalance
Phenylalanine
(A-decarboxylase)
(P-hydoxylase)
Tyrosine
(A-decarboxylase)
Tryptophan
(T-hydoxylase)
Dopa
Phenylethylamine
(Tr-hydroxylase)
(b-hydroxylase)
Tyramine
(b-hydroxylase)
(D-decarboxylase)
Dopamine
(D-b-hydoxylase)
Phenylethanolamin 5-HT
NE
Octopamine
( →↓normal conversion pathway;
→↓abnormal conversion pathway;
inhibition)
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BCAA, AAA
excessive AAA enter brain
false neurotransmitter
true neurotransmitter 
(octopamine and
phenylethanolamin)
(noradrenalin
and dopamine)
Disturbed brain function
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4. Theory of GABA(gamma-aminobutyric acid)
GABA → permeability of cellular membrane to Cl－
→ neuron ultra-polarization or depolarization
（inhibitive neurotransmitter）
Hepatic encephlopathy has been reported to be associated with
increased plasma levels of GABA.
A major source of GABA is considered to be the gut (intestinal
bacteria and the intestinal wall).
In hepatic failure, GABA is not catabolized effectively by the
liver and the permeability of the blood-brain barrier to GABA
is increased, it may enter into brain and exert inhibitive effect
on axons of the neuron through the GABA receptors.
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The mechanism of GABA in HE
Excitation
↓
GABA release from vesicle
of presynaptic neurons
↓
Combined to GABA-R
on postsynaptic neurons
↓
Inflow of extracellular Cl－
into postsynaptic neurons
↓
Hyperpolarization of
postsynaptic neurons
↓
CNS inhibition
GABA synthesis
by enteric bacteria
Removal of GABA by liver
Normal Liver
BBB normal
GABA synthesis
by enteric bacteria
Removal of GABA↓
Hepatic failure
BBB permeability↑
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5. Other neurotoxins
Mercaptan (derived fron methionine)
 inhibit urea synthesis, mitochondria respiration and
Na+-K+ -ATPase activity
Short-chain fatty acid (obstacle of fat metabolism)
 inhibit Na+-K+ -ATPase activity, interfere membrane
ion and neural impulse transference
Phenol (derived fron tyrosine)
 toxic action to brain
33
Comprehensive hypothesis
dysfunction of the liver
HGF
AAA 
BCAA 
Glutamine
AAA enter brain 
Insulin 
true neurotransmitter 
5HT 
false neurotransmitter 
Inhibition GABA trnsaminase   Accumulation of GABA in brain
Toxic effects on brain
Hyperammonemia
Hepatic Encephlopathy
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C. Inducing factors of HE
1. Increased nitrogen load
Exogenous: bleeding of alimental tract,
excessive intake of protein, blood transfusion.
Endogenous: azotemia caused by hepatorenal syndrome,
hypokalemic alkalosis,
constipation and infection
2. Increased permeability of the blood-brain barrier
Infection → TNF-a, IL-6↑
3. Increased sensitivity of brain
Neurotoxin, drugs, infection, hypoxia, electrolyte disturbance
35
D.
Pathophysiological basis of
prevention and treatment
l. Preventing inducing factors
2. Decreasing blood ammonia
3. Artificial liver, liver transplantation
4. Other measures: supplement of BCAA-rich amino acid
mixture to correct amino acid unbalance; administration
of L-dopa to regain consciousness, etc.
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Section 4.
Hepatic Renal Failure
37
1. Conception
Severe liver disease (acute or chronic )
absence of any other identifiable cause of renal failure
（hypovolaemia, drug nephrotoxicity,
sepsis or glomerulonephritis）
Renal failure
Hepatic renal failure or hepatorenal syndrome (HRS).
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2. pathogenesis
Liver cirrhosis
Decreased effective renal blood flow
Excitation of sympathetic nerve system
Activation of Renin-angiotensin system
Deficiency of kallikrein-kinin system
Increase of ET and TXA2
Renal vasoconstriction
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Summary
1. A serial of neuropsychical symptoms caused by acute or
chronic liver disease are called hepatic encephalopathy
2. HE is mainly caused by the metabolic and functional
disturbance of the brain, the etiology is multifactorial,
including ammonia intoxication, false neurotransmitter,
amino acid imbalance and increased GABA formation .
40
disturbance of the
brain, the etiology is multifactorial,
Summary
including ammonia intoxication, false neurotransmitter,
amino acid imbalance and increased GABA formation
3. Inducing factors of HE include increased nitrogen load
increased permeability of the blood-brain barrier and
increased sensitivity of brain
4. Hepatic renal failure or hepatorenal syndrome is defined
as the renal failure occurred in patients with severe liver
disease who absence of any other identifiable cause of
renal failure
41