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Chapter 17 .
Hepatic Failure
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Section 1.
Concept of hepatic failure
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1. Definition of hepatic failure
Various harmful factors ↓
parenchymal cells and Kupffer cells damadgedseverely 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
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Severe, extensive degeneration and necrosis of hepatic cells
→ Acute (fulminant) hepatic failure
Late stage of cirrhosis or carcinoma of the liver
→ Chronic hepatic failure
2. Classification and causes
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(1) metabolism: (2) bile secrete and excrete: (3) coagulation:
(4) bioconversion
(5) immune
Disturbance of metabolism: carbohydrate, protein, electrolyteObstacle of bile secrete and excrete: hyperbilirubinemia, intrahepatic cholestasis
Disorder of coagulation: generation↓ or consumption↑ → clotting factor↓→ bleeding tendency Dysfunction of bioconversion drug metabolism; detoxication of toxin; inactivation of hormoneDysfunction of immune (Kuppfer cells) bacterial infection, bacteremia, intestinal endotoxemia
3. Function of normal liver 3. Effects of hepatic failure on the body
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Section 2.
Hepatic Encephalopathy
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A serial ofNeuropsychical symptoms
hepatic encephalopathy
A. Concept and classification
Acute or chronic liver disease
Hepatic coma
ultimate clinical manifestation of HE
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Classification:
According to the
Clinic course
Clinical neuropsychical symptoms
Etiology
Acute, subacute and chronic types
1st stage (prodromal period) 2nd stage (pre-coma period)
3rd stage (lethargy period) 4th stage (coma period)
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)
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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
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Theory of ammonia intoxication False neurotransmitter hypothesis Theory of amino acid imbalance Theory of GABA(gamma-aminobutyric acid)
Several hypotheses of the pathogenesis of HE have been proposed:
None of them is necessarily exclusive.
A conservative and conventional view of HE is
Almost certainly the etiology is multifactorial
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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.
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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.
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citrulline
The metabolism of ammonia
1
2
3
urea25%
ATP
Enzymes
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(1) Causes of increased plasma level of ammonia
l ) Decreased urea synthesis and
inadequate removal of ammonia
2) Excessive generation of ammonia
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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.
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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
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Krebs citric acid cycle
glutamine
-aminobutyric acid
acetyl COA
NH3
Glutamic acid
Glycose Glucose-6-phosphate
Pyruvicacid
Lactic acid
Oxaloaceticacid
Citric acid
Succinicacid
-Ketoglu-taric acid
ATP
Choline Acetylcholine
①Excessive consumption of - ketoglutaric acid → hindering tricarboxylic acid cycle
③Inhibiting activity of pyruvic acid decarboxylase → generation of acetyl coenzyme A↓ →impairing TA cycle
Krebs citric acid cycle ④ Excessive consumption of ATP by synthesis of glutamine
② Excessive consumption reduced coenzyme I → hindering delivery of H+ in respiratory chain →ATP generation↓
l ) Interfering cerebral energy metabolism
ATP
ATP
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2) Changing neurotransmitter in the brain
① Excitative neurotransmitter↓
Glutamic acid consumed
by combination with NH3
Inhibition of pyruvic acid
decarboxylase by NH3
glutamine
-aminobutyric acid
acetyl COA
NH3
Glutamic acid
Glycose Glucose-6-phosphate
Pyruvicacid
Lactic acid
Oxaloaceticacid
Citric acid
Succinicacid
-Ketoglu-taric acid
ATP
Choline Acetylcholine
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② Inhibitive neurotransmitter ↑
① Excitative neurotransmitter↓
2) Changing neurotransmitter in the brain
glutamine
-aminobutyric acid
acetyl COA
NH3
Glutamic acid
Glycose Glucose-6-phosphate
Pyruvicacid
Lactic acid
Oxaloaceticacid
Citric acid
Succinicacid
-Ketoglu-taric acid
ATP
Choline Acetylcholine
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.
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
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(2) True and false neurotransmitter
phenylethanolamine
Octopamine
—CHOHCH2 NH2
HO —
—CHOHCH2 NH2
True neurotransmitter False neurotransmitter
noradrenalin
HO —HO —
—CHOHCH2 NH2
HO —HO —
—CHCH2 NH2
dopamine
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LIVER . Phenylalanine Phenylethylamine (bacterial decorboxylase ) Tyrosine - - - Tyramine INTESTINE. BRAIN
phenylethanolamine ( -hydroxylase) Octopamine
(MAO) Catabolism
CNS dysfunction → COMA
obstacle in transfer of neural impulse→
→
Accumulation of false neurotransmitter in reticular formation
(3) Mechanisms of false neurotransmitter formation
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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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AAA
(1) Cause of amino acids imbalance
AAA
BCAA
MUSCLE
ADIPOSE CELLLIVER
DISEASED
inactivateInsulinBCAANORMAL
catabolism
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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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Phenylalanine Tyrosine (P-hydoxylase) (A-decarboxylase)
(A-decarboxylase) (T-hydoxylase)
Dopa (-hydroxylase)
(Tr-hydroxylase) (D-decarboxylase)
-hydroxylase) Dopamine
(D--hydoxylase)
Phenylethanolamin 5-HT NE Octopamine
( →↓normal conversion pathway;
→↓abnormal conversion pathway; inhibition)
(2) Effects of amino acids imbalance
Tryptophan
Tyramine
Phenylethylamine
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BCAA, AAA
excessive AAA enter brain
false neurotransmitter true neurotransmitter (octopamine and (noradrenalin phenylethanolamin) 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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Excitation ↓ GABA synthesisGABA release from vesicle by enteric bacteria of presynaptic neurons Removal of GABA by liver ↓ Combined to GABA-R on postsynaptic neurons ↓ Inflow of extracellular Cl -
into postsynaptic neurons ↓ Hyperpolarization of postsynaptic neurons Hepatic failure ↓ CNS inhibition BBB permeability↑
The mechanism of GABA in HE
Normal Liver
Removal of GABA↓
GABA synthesis by enteric bacteria
BBB normal
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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
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Inhibition GABA trnsaminase Accumulation of GABA in brain
Hepatic Encephlopathy
Comprehensive hypothesis
dysfunction of the liver
Hyperammonemia
Toxic effects on brain
true neurotransmitter AAA enter brain 5HT false neurotransmitter
GlutamineAAA BCAA
Insulin HGF
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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-, IL-6↑
3. Increased sensitivity of brain
Neurotoxin, drugs, infection, hypoxia, electrolyte disturbance
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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
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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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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 , ,
and .
Summary
ammonia intoxication false neurotransmitteramino acid imbalance increased GABA formation
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disturbance of the brain, the etiology is multifactorial,
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
Summary
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