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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