PowerPoint Template

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Pathophysiology
Department of Pathophysiology Shanghai Jiao-Tong
University School of Medicine
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Chapter ??Hepatic Dysfunction
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Contents

• Overview
• Hepatic Encephalopathy, HE
• Definition,Clinical features and
  classification
• Pathogenesis
• Precipitating factors of HE
• Principles of treatment for HE
•  Hepatorenal Syndrome, HRS
• Concept Pathogenesis

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Overview

• Normal function of liver
• Etiology of liver disease and liver dysfunction
• Pathogenesis of liver disease

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Overview
Enviromental causes
Herritage/Genetic causes
Hepatitis virus Alcohol Drugs and toxins
Hepatic Injury
Fulminant hepatic failure
Chronic persistent hepatitis
Recovery
cirrhosis
Necrosis
Triggers
hepatic insufficiency
Hepatic Failure
Hepatic Encephalopathy
Hepatorenal syndrome
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• Hepatic Encephalopathy

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Definition of Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a complex,
potentially reversible disturbance in CNS that
occurs as a consequence of severe liver diseases.
It is characterized by neuropsychical
manifestations ranging from a slightly altered
mental status to coma.
2010?10?22?
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Staging
The West Haven criteria of altered mental state
in HE (In patients with cirrhosis and overt
encephalopathy) Stage 0. Lack of detectable
changes in personality or behavior. Asterixis
absent. Stage 1. Trivial lack of awareness.
Shortened attention span. Impaired addition or
subtraction. Hypersomnia, insomnia, or inversion
of sleep pattern. Euphoria or depression.
Asterixis can be detected. Stage 2. Lethargy or
apathy. Disorientation. Inappropriate behavior.
Slurred speech. Obvious asterixis. Stage 3. Gross
disorientation. Bizarre behavior. Semistupor to
stupor. Asterixis generally absent. Stage 4.
Coma.
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96,
No. 7, 2001
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Types
A classification of hepatic encephalopathy was
introduced at the World Congress of
Gastroenterology 1998 in Vienna. According to
this classification, hepatic encephalopathy is
subdivided in type A, B and C depending on the
underlying cause.
Type A (acute) describes hepatic encephalopathy
associated with acute failure Type B
(bypass) is caused by portal-systemic shunting
without associated intrinsic liver disease Type
C (cirrhosis) occurs in patients with cirrhosis
this type is subdivided in episodic, persistent
and minimal ncephalopathy
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Pathogenesis of HE

• HE may be due to primarily to a failure of the
  liver to remove adequately vertain substances in
  plasma that have the ability,directly or
  indirectly to modulate the function of the
  central nervous systerm. Several hypotheses have
  been proposed

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Pathogenesis

• Ammonia intoxincation hypothesis
• False neurotransmitters hypothesis
• Amono acid imbalance hypothesis
• The Gamma-aminobutyric acid hypothesis
• Synergistic actions of multiple toxins

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Ammonia intoxincation

• Causes of elevated ammonia in hepatic
  inssufficiency
• 1)Decreased clearance of ammonia
• 2)Increase production of ammonia in
  gstrointestinal tract
• Intoxicaton of ammonia on the brain
• 1)Impairment of energy metabolism in brain
• 2)Alteration of neurotransmitters
• 3)Inhibiting action of nerve cells membrane

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False neurotransmisson hypothesis
In hepatic dysfunction or formation of
portal-systemic shunt, some kind of amine
elevated due to failure of hepatic deamination,
and then filter into central nervous system
interferes with physiologic functions by
competitively inhibiting normal neurotransmitters
(dopamine, norepinephrine) and favoring
formation of false neurotransmitters (octopamine,
phenylethanolamine) ,which have similar structure
but much weaker activity than true
neurotransmitters. The net physiologic result of
such changes is reduced neural excitation an
hence increased neural inhibition.
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Amino acid imbalance hypothesis

• The aromatic amino acids (AAA),
  tyrosine,phenylalanine and tryptophan are
  increased in liver disease whiletge branched
  amino acids (BCAA), valine,leucine and isoleucine
  are decreased. The AAA are the precursors of
  false neurotransmitters.

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Gamma-amino butyric acid hypothesis

• Plasma level of GABA
• In liver failure, a major resource of the
  increased plama GABA is considered to be the
  intestinal bacteria and the intestinal wall. The
  permeability of the blood-brain to GABA is
  increased in liver failure,if some of the GABAis
  not catabolized or taken up by neurons,it may
  reach GABA receptors and augment GABA-ergic
  neurotransmission. Activation of the GABA
  receptor increase neuronal membrane permeability
  to Cl- BY OPENING Cl- ionophore, and Cl- enters
  the neuron causing membrane hyperpolarization.
  Benzodizepines(BZ) recepter agonists increase the
  frequency of GABA-gate Cl- channel openings.
• GABA and/or BZ receptor density increased
• Ammonia can augment the activity of GABA-ergic
  neurons.

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Synergistic actions of multiple toxins

• Manganese induce pathologicalchanges of
  astrocyte
• Mercaptans inhibit the production of urea and
  Na-k-ATPase on neuron membrane,disturbe the
  electron transport on mitochondria
• Short-chain fatty acids inhibit energy
  metabolismof the brain, disturbe the post neuron
  potential
• Phenols inhibite the activit of many enzymes

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• precipitating factors of HE

• Gastrointestinal hemorrhage
• Unadvisable dietary protein
• Excessive diuresis
• Abuse of sedatives, tranquilizers and narcotic
  analgesic
• Renal failure
• Severe infections
• Constipation
• Others

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Hepatorenal syndrome

• Hepatorenal syndrome is the development of a
  reversible and functional renal failure in
  patients with severe liver diseases in absence of
  any other identified cause of renal pathology. It
  is characterized by a marked decrease in GFR and
  renal plasma flow.

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Pathogenesis of HRS
decompensated cirrhosis
Hepatic dysfunction
portal hypertension
hydroperitoneum Gastrointestinal hemorrhage
Abdominal organs congestion
Kallikrein kinin ?
PGE2? TXA2? LTs?
Andotoxemia
effective circulating blood volume ?
Aympathetic nervous systerm? Renin-angiotensin
aldosterone systerm?
Vasoconstriction of kidney
GFR?
HRS
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The End
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1)Impairment of energy metabolism in brain
2)Alteration of neurotransmitters 3)Inhibiting
action of nerve cells membrane
NH3 ?
Brain
Systemic circulation
NH3?
Protal-systemic shunts
Ornithine
Kidney
NH3
Urea
Liver
?
?
Citrulline
Argininosuccinate
Other tissues to produce NH3
Intestine
AA
Urea
NH3
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NH3
Glutamate
L-glutamine
ATP
ADP
NAD
NH3
GABA
NADH
Pyruvic acid
??Glutatrate
?
NAD
NH3
?
Acetyl-CoA
NADH
Succinate
Citric acid
?
Choline
?
Acetylcholine
Oxaloacetate
Toxicaton effect of ammonia on brain tissue
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Phenolethanolamine
Octopamine
Tyramine ?
Phenylethylamine ?
Phenylethylamine
?
MAO
Tyramine
Phenylalanine
Tyrosine
Phenylethylamine
Tyramine
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NH2
HO
CH2CHCOOH
Dopamine
HO
True neurotransmitter
Tyrosine
Dolbar
Norepinephrine
NH2
NH2
CH2CHCOOH
CH2CH2
HO
HO
Tyrosine
Octopamine
Tyramine
False neurotransmitter
Phenylalanine
Phenolethanolamine
Phenylethylamine
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Phenolethanolamine
Octopamine
Serotonin
BRAA?
AAA?
AAA
BCAA
?
AAA
Metabolism
?
Insulin Glucagon
AAA from other tissue
Aromatic amino acid
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Inhibit brain function
GABA ?
GABA ?
?
GABA
Metabolism
Glutamic acid
GABA
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Hepatic funtion Clinical manifestations

• Bodys metabolism
• 1.Carbohydrate metabolism
• 2. Protein metabolism
• 3.Lipid metabolism
• 4. Water and Electrolyte metabolism
• 5.Hormone metabolism
• Blood coagulation
• Biotransformation and detoxifcation
• Immunity
• Secretion and excretory function

• Metabolism dysfunction
• 1.Hypoglycemia
• 2.Hypoalbuminemia ?high ammonia? increased
  transaminase
• 3.Fatty liver?decreased plasma cholesteryl ester
• 4. Disorders Water and Electrolyte metabolism
• 5. High estrogen,spider angioma ?
• liver palms etc.
• Bleeding tendency
• Intoxication
• Infection
• Jaundice

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Hepatic insufficiency

• Conditions in which the liver functions fall
  below the normal ranges. The symptom include
  jaundice, bleeding, secondary infection, renal
  dysfunction and hepatic encephalopathy .Severe
  hepatic insufficiency may cause liver failure or
  death.

Hepatic failure
Hepatic failure is a terminal stage of hepatic
insufficiency. Hepatic encephalopathy and
hepatorenal syndrom are the primary clinical
manifestations.
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Spider angiomas
Palmar erythema
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