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Pathophysiology
Department of Pathophysiology
Shanghai Jiao-Tong University School of Medicine
Chapter ⅩⅤ
Hepatic Dysfunction
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
Overview
 Normal function of liver
 Etiology of liver disease and liver
dysfunction
 Pathogenesis of liver disease
Overview
Enviromental causes
Hepatitis virus
Alcohol
Drugs and toxins
Recovery
Herritage/Genetic causes
Hepatic Injury
Fulminant hepatic
failure
Chronic persistent
hepatitis
Necrosis
cirrhosis
Triggers
Hepatic Failure
Hepatic
Encephalopathy
hepatic insufficiency
Hepatorenal
syndrome
Hepatic Encephalopathy
Definition of Hepatic Encephalopathy
Hepatic encephalopathy (HE) is a complex,
potentially reversible disturbance in CNS
that occurs as a2010年10月22日
consequence of severe
liver diseases. It is characterized by
neuropsychical manifestations ranging
from a slightly altered mental status to
coma.
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
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
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:
Pathogenesis
Ammonia intoxincation hypothesis
False neurotransmitters hypothesis
Amono acid imbalance hypothesis
The Gamma-aminobutyric acid hypothesis
Synergistic actions of multiple toxins
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
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.
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.
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.
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
precipitating factors of HE
Gastrointestinal hemorrhage
Unadvisable dietary protein
Excessive diuresis
Abuse of sedatives, tranquilizers and
narcotic analgesic
Renal failure
Severe infections
Constipation
Others
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.
Pathogenesis of HRS
decompensated
cirrhosis Hepatic
portal hypertension
dysfunction
hydroperitoneum
Abdominal organs
Gastrointestinal
congestion
Andotoxemia Kallikrein PGE2 TXA2
hemorrhage
—kinin  LTs
effective
circulating
blood volume 
Aympathetic nervous
systerm
Renin-angiotensin
aldosterone systerm
Vasoconstriction
of kidney
GFR
HRS
The End
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