Transcript PowerPoint 演示文稿

"With ordinary talent and
extraordinary perseverance, all
things are attainable."
- Thomas E. Buxton
"Achievement is connected
with action…..!”
- Conrad Hilton
1
Pathophysiology of
Liver
Guo xiaosun
Shandong University
2
Liver anatomy:
• Four Lobes
3
Anatomy
•
•
•
•
•
•
Lungs
Heart
Liver
Omentum
Diaphragm
Gall bladder
4
Structure of Liver Lobule
5
Structure of Liver Lobule
6
Normal Liver Histology
Liver Functions:
• Metabolism – Carbohydrate, Fat &
Protein
• Secretory – bile, Bile acids, salts &
pigments
• Excretory – Bilirubin, drugs, toxins
• Synthesis – Albumin, coagulation factors
• Storage – Vitamins, carbohydrates etc.
• Detoxification – toxins, ammonia, etc.
8
Causes and mechanisms of Liver Disease
– Biological Factors: virus(HBV)
– Physical and Chemic Factors(Alcohol ，
Tetrachloride)
– Genetic Factors（Hemochromatosis）
– Immunity Factors: （chronic hepatitis -activated T cell ）
– Nutritional Factors: (nutritional deficiency –
worsen the condition)
9
Alcoholic Fatty Liver
10
Jaundice
• A yellowing of the skin, sclerae, and
other tissues caused by excess
circulating bilirubin.
11
Jaundice
12
Jaundice
13
Bilirubin Metabolism
•
•
•
•
•
Formation
Plasma transport
Liver uptake
Conjugation
Biliary excretion
14
15
CHOLESTASIS
• A clinical and biochemical syndrome
that results when bile flow is impaired.
16
Etiology
• intrahepatic causes
– hepatitis, drug toxicity, and alcoholic
liver disease.
• intrahepatic and extrahepatic causes
– duct stone and pancreatic cancer
17
Contributing factors
• interference with microsomal hydroxylating
enzymes
• impaired activity of Na+,K+-ATPase
• altered membrane lipid composition and
fluidity
• interference with the function of
microfilaments
• enhanced ductular reabsorption of bile
constituents
18
The pathophysiologic effects
• mixed hyperbilirubinemia
• pruritus
• steatorrhea and hypoprothrombinemia
• osteoporosis or osteomalacia
• hyperlipidemia
19
Portal Hypertension
• Increased pressure in the portal venous
system.
20
21
22
Mechanism
• vascular compression and distortion by the
fibrosis and regenerating nodules enhance
resistance in the sinusoids and terminal portal
venules.
• contractility of sinusoidal lining cells,
production of vasoactive substances (eg,
endothelins, nitric oxide), various systemic
neurohumoral factors that affect splanchnic
arterioles, and Swelling of hepatocytes.
23
Cirrhosis
24
Cirrhosis
Fibrosis
Regenerating Nodule
25
Complications
• portal-systemic venous collaterals
develop (caput medusae , rectal varices ,
esophageal varices )
• hepatic encephalopathy
• ascites
• hypersplenism
26
• The principal consequences of portal
hypertension are the result of reduced blood
flow though the liver and the effects of
elevated pressure in the hepatic portal
system.
27
• With less blood flowing through the
cirrhotic liver,its remaining functional
cells have reduced access to the blood,
compromising their detoxification
activities. It's as if the blood is bypassing the liver (shunting) . As a
result,toxins are more concentrated in
the blood and are more likely to produce
damaging effects.
28
Massive ascites in an elderly woman.
29
30
31
32
Ascites
• Free fluid in the peritoneal cavity
33
Etiology
• cirrhosis
• chronic hepatitis, severe alcoholic
hepatitis without cirrhosis, and hepatic
vein obstruction
34
review:Pathogenesis of edema
• 1. imbalance of exchange between intraand extra-vascular fluid
–
–
–
–
increased capillary blood presure
decreased plasma colloid osmotic presure
increased capillary permeability
obstruction of lymphatic flow;
• 2. imbalance of exchange between intraand extra- body fluid:
– decreased filtration rate of glomeruli
– increased water and sodium reabsorption in
renal.
35
Pathophysiology
(1)Low serum osmotic pressure
Synthesized by the liver, albumin is the
major contributor to oncotic pressure in the
serum. Decreased levels usually develop
only in severe hepatic dysfunction. osmotic
pressure tends to retain fluid in capillaries
(2) High portal venous pressure
36
(3) Hepatic lymphatic obstruction may
also be involved.
plasma proteins leaking into interstitial space
rely on the lymphatics for movement back
into the circulatory system with the
interstitial fluid. If lymph flow is obstructed,
not only is backflow of interstitial fluid
blocked but also colloid pressure in
interstitial fluid increases.
37
• (4) Na retention
– In cirrhosis, arterial vasodilation leads to a
decrease in splanchnic and systemic vascular
resistance with pooling of blood in the splanchnic
circulation, leading to a reduction in the effective
arterial blood volume. This in turn leads to
stimulation of the sympathetic nervous and reninangiotensin-aldosterone systems, promoting renal
sodium and water retention in an attempt to
restore the effective arterial blood volume and
maintain blood pressure.
38
patient with alcoholic cirrhosis and portal hypertension.
Note the parotid hypertrophy, distended abdomen from
ascites, and scrotal and pedal edema.
39
40
41
SYSTEMIC ABNORMALITIES
• Depression of the liver’s chemical
and drug detoxification function
• Skin and endocrine changes
– Spider nevi, palmar erythema
– Complex derangements in the
metabolism of sex hormones
– Other endocrine derangements
42
• Hematologic abnormalities
• Renal and electrolyte abnormalities
– Hypokalemia
– Hyponatremia
– Renal failure
43
Close-up view of a spider angioma of the skin
in a patient with liver disease. Note the central,
punctate filling vessel and the "spider-like"
vessels emanating from it.
44
Liver palms: thenar and hypothenar erythema
in a patient with chronic liver disease.
45
46
Hepatic Encephalopathy
• A neuropsychiatric syndrome caused by
liver disease and usually associated
with portal-systemic shunting of venous
blood.
47
Etiology
• fulminant hepatitis ( viruses, drugs, or
toxins)
• cirrhosis or other chronic disorders
48
• Grade 0 - Clinically normal mental
status but minimal changes in memory,
concentration, intellectual function, and
coordination , Asterixis absent
• Grade 1 - Mild confusion, euphoria, or
depression; decreased attention;
slowing of ability to perform mental
tasks; irritability; and disordered sleep
pattern, such as inverted sleep cycle,
Asterixis can be detected
49
• Grade 2 - Drowsiness, lethargy, gross deficits
in ability to perform mental tasks, obvious
personality changes, inappropriate behavior,
and intermittent disorientation, usually
regarding time, Obvious asterixis
• Grade 3 - Somnolent but can be aroused,
unable to perform mental tasks, disorientation
about time and place, marked confusion,
amnesia, occasional fits of rage, present but
incomprehensible speech, Asterixis generally
absent
• Grade 4 - Coma with or without response to
painful stimuli
50
51
Pathogenesis of HE
• 1. The causative metabolic toxins (usually
nitrogenous substances) most likely
originate in the intestine.
• 2. Because of portal-systemic shunts,
these toxic substances bypass the liver,
where they normally are metabolized.
• 3. After bypassing the liver, these toxic
substances cross the blood-brain barrier
and exert direct or indirect neurotoxic
effects on the central nervous system.
52
Pathogenesis of HE
Ammonia intoxication hypothesis
False neurotransmission hypothesis
imbalance of plasma amino acid
hypothesis
GABA hypothesis
53
Ammonia intoxication hypothesis
The first experiment implicating a nitrogenous substance as a
cause of hepatic encephalopathy was performed by Eck, a turnof-the-century Russian physiologist who created portal-systemic
shunts in healthy dogs and observed that these dogs promptly
became comatose after eating meat. This important observation
was ignored for more than 50 years until this condition was
"rediscovered," and ammonia intoxication became a leading
suspect.
54
• The role of ammonia has been
postulated on the basis of the following:
a reproducible increase in blood
ammonia levels of patients with
cirrhosis; the development of hepatic
coma in patients with advanced liver
disease and in experimental animals
after ingestion of ammonia;
55
source of ammonia
• 1.Forty percent of ammonia is generated in the
intestine from ingested nitrogenous substances that
are broken down by bacterial ureases and amino acid
oxidases.
• 2. The remaining 60% is derived from the metabolism
of glutamine and the deamination and transamination
of other amino acids.
glutaminase
• glutamine
ammonia+glutaminic acid
56
• 3. Additional sources of ammonia are skeletal
muscle and the kidneys. ammonium ion is
synthesized from glutamine, which is actively
transported into the epithelial cells of the
proxiamal tubules, thick ascending limb of the
loop of the proximal tubules. in the collecting
tubules, hydrogen ion is secreted by the
tubular membrane into the lumen, where it
combines with ammonia to form NH4+,which
is then excreted. Ammonia is adenylic acid’s
catabolism product. when the muscles shrink
aggravatelly, Adenylic acid’s catabolism
intensify.Thus, Ammonia increase.
57
• Ammonia liberated in the intestine normally
is metabolized in the liver through the cycle
of urea synthesis into urea, which is
excreted through the kidneys and into the
colon.
• Formation of glutamine from glutamate by
glutamine synthetase in the liver and brain
is another means of detoxifying ammonia.
• ammonia+glutaminic acid
glutamine
58
• The net reaction for one turn of the urea
cycle is
• CO2 + NH4+ + 3 ATP + Aspartate +
2H2O -> Urea + 2 ADP + 2 Pi +AMP +
PPi + Fumarate
• synthesis of urea is energetically
expensive.
59
Ammonia intoxication hypothesis
the patient with hepatic cirrhosis has
hyperammonemia and encephalopathy
occuring is due to entering of ammonia
into the brain. All of the
neuropsychiatric symptoms are due to
the poisonous action of ammonia to
central nervous system.
60
causes of hyperammonemia
• excess of the ammonia formation
• insufficiency of the ammonia elimination
61
excess of the ammonia formation
• 1)Varices can rupture, causing sudden GI
(gastrointestinal) hemorrhage. so
nitrogenous substances in the intestine
increase. And Forty percent of ammonia is
generated in the intestine from ingested
nitrogenous substances that are broken
down by bacterial ureases and amino acid
oxidases. So plasma ammonia increase.
62
• 2)portal hypertension→increased capillary
blood presure→congestion and edema of
gastrointestinal tract→disorders of the
function(motion, secretion, absorption,
degestion) →inadequate digestion of
protein and excess reproduction of intestinal
bacteria(remainder protein is decomposed
by bacteria enzyme) → increased plasma
ammonia
63
• 3) severe liver disease→renal
failure→azotemia(an abnormally high level
of nitrogen-type wastes in the
bloodstream.)→the urea in blood defuses
into intestine →it is decomposed(by urease
of bacteria) → increased ammonia
64
• 4) tic of the muscles(before HE, pateints
often are restlessness)→adenylic acid’s
catabolism intensify→ increased ammonia
65
• 5) increased pH of renal tubular
fluid→decreased ammonia secretion of
renal tubules→ increased ammonia
diffusion to blood
• increased pH of gastrointestinal
tract→decreased ammonia excretion of
gastrointestinal tract → increased ammonia
diffusion to blood
• NH3+H+→NH4 NH4 + OH-→ NH3 + H2O
66
insufficiency of the ammonia elimination
• dysfunction of the liver→decreased urea
syntheses due to lack of ATP, reaction
substrate and enzyme damage.
Disorder of detoxication
• ammonia in intestine
enter the
Portal-systmic shunts
blood
67
the mechanism of that ammonia
leads to encephalopothy
• (1)Ammonia leads to the disorder of energy
metabolism in the brain
• In normal conditions: Brain needs much of energy
steming from oxidation of glucose and glycogen
reserves are less in the brain. Excess ammonia
ultimately may cause cerebral energy failure due
to inhibition of key rate-limiting tricarboxylicacid-cycle enzymes.
68
69
• (2)The changes of the neurotransmitters in the
brain: decreased glutamic acid,
acetylcholine(excitatory transmitter), increased
GABA, glutamine(inhibitory transmitter). The
correct balance of neurotransmitters is critical to
the brain.so increased GABA, glutamine lead to
disorder of CNS.
ammonia+glutaminic acid→ glutamine→GABA；
so glutaminic acid↓ glutamine↑ GABA↑ ；
ammonia inhibite the activation of pyruvate
decarboxylase, so Acetyl-CoA↓; Acetyl-CoA+
bilineurine→ acetylcholine,SO acetylcholine ↓
70
(3) Ammonia disturbs the ions transfer of
the nervous cells membrane.
NH3
K+
Na+-K+-ATPase
Na+
71
• Na+-K+-ATPase which is located in the surface
membrane of cells is responsible for the active
transport of sodium and potassium ions between
extracellular fluid and cytoplasm. Ammonia may
contribute to changes in the activity of Na+-K+ATPase that are found in the brain in models of
HE.so the active transport of sodium and
potassium ions between extracellular fluid and
cytoplasm is damaged.thus Ammonia inhibits
excitatory postsynaptic potentials, thereby
depressing overall central nervous system function.
72
• However, not all data are consistent with the
ammonia toxicity theory. Poor correlation of
ammonia with hepatic encephalopathy, the
presence of this condition in the absence of
elevated ammonia levels, and the
neuroexcitatory effects of low ammonia
concentrations all cast doubt on the theory.
73
False neurotransmitter hepothesis
1、 Reticular activating system
 Reticular activating system is a structure in the brain
stem that is responsible for arousal and sleep. The
reticular activation system is responsible for getting you
up in the morning and putting you asleep at night .
 if the Reticular Activating System failed to activate the
cortex at all one would see a lack of consciousness or
even coma.
 Neurotransmitters (such as noradrenaline, dopamine) is
nessesary to fullfil the Reticular Activating System’s
function.
74
• In 1970, Parkes first reported bendopa treat HE
succesfully. Then Fischer et al proposed false
neurotransmitter hepothesis: In the pateint with
hepatic failure FNT(phenylethanolamine and
octopamine) is accumulated in the synapse of the
reticular structure(RS) in the brain stem. The FNT
can compete with true Neurotransmitter (TN,
noradrenaline(NE) and dopamine;DA) because
their chemical structure is similar to the TN. The
RS has a specific action to keep waking and
excitability of the pallium. When FNT replaces
TN in RS of brain stem, disorders of CNS occur.
75
76
77
Interstinal
Phenylala- bacteria
Tyromine
nine
decarboxylase phenylethylamine
tyrosine
(food)
↑produce
↓liver metabolism
Potal-systemic
shunt
Into the brain
↑their
concentration
in blood
↑phenylethanolamine
hydroxylase
octopamine
78
• Note：(1)congestion and edema of
gastrointestinal tract→disorders of the
function(motion, secretion, absorption,
degestion) →inadequate digestion of
protein→↑produce（Tyromine
phenylethylamine）
• (2) Tyromine and phenylethylamine can be
cleared from the blood by the process of
enzymatic degradation in liver.
79
• FNT competes with TN but their
physiological effects are very weak.
• Dysfunction of RS→lethargy, coma
80
Plasma amino acid imbalance hypothesis
Patients with cirrhosis have a decreased
ratio of branched-chain amino acids
(BCAA) to aromatic amino acids (AAA),
from 3.5:1 to 1:1. BCAA include valine,
leucine, and isoleucine. AAA include
phenylalanine, tyrosine, and tryptophan.
81
• The decrease in BCAA is caused
predominantly by their excessive use by
skeletal muscle. The increase in AAA is
caused predominantly by failure of hepatic
deamination. It has been postulated that the
increase in AAA in the central nervous system
may interfere with physiologic
neurotransmission by competitively inhibiting
"normal" neurotransmitters (ie, dopamine,
norepinephrine) and favoring formation of
weak, false neurotransmitters (ie, octopamine,
phenylethanolamine)
82
83
• Causes(↓BCAA): undernutrition,
starvation→↑decomposition of
BCAA(for energy supply);
stress→↑glucocorticosteroid→↑decomp
-osition of intra-musculi BCAA;
hyperinsulinemia→↑uptake and
utilization of BCAA in muscular and fatty
tissue
• Causes(↑AAA): insufficiency of
elimination of AAA in the liver.
84
• Both BCAA and AAA are neutral amino
acid. They are through blood-brain
barrier by the aid of the same carrier. So,
there is competition between AAA and
BCAA, finally, AAA enters in to the brain
more and formation of FNT is more too.
Thus, decreased ratio of BCAA/AAA
relates to encephalopathy due to FNT
formation in CNS. So, this hypothesis is
an extension of FNH.
85
• (1)As increased phenylalanine enter
into the brain and phenylalanine can
inhibite the activation of tyroxine
hydroxylase, physiologic
neurotransmission decrease.
• (2)in the brain,increased FNT
Phenylalanine
tyrosine
decarboxylase
(food)
hydroxylase
Tyromine
↑phenylethanolamine
phenylethylamine octopamine
86
AAA/BCAA ↑→
AAA enter into
brain ↑:
true neurotransmitters ↓①
false neurotransmitters ↑ ②③④
inhibitory neuro②
①
③
transmitters ↑④
④
87
This attractive hypothesis raises the possibility
that correction of the AAA:BCAA ratio may lead
to amelioration of hepatic encephalopathy.
However, a multitude of clinical trials have
failed to prove that changes in the ratio through
intravenous or oral administration of BCAA
result in significant improvement of clinical
signs or symptoms of this condition.
88
GABA hypothesis
• In the 1980s, Basile and Jones at the
National Institutes of Health promoted
gamma-aminobutyric acid (GABA), the major
inhibitory neurotransmitter in the central
nervous system, as a cause of hepatic
encephalopathy. GABA is a neuroinhibitory
substance produced in the gastrointestinal
tract. Of all brain nerve endings, 24-45% may
be GABAergic. Increased GABAergic tone is
observed in patients with cirrhosis, perhaps
because of decreased hepatic metabolism of
89
GABA.
• A major sources of the increased plasma
GABA levels observed in liver failure is
considered to be the gut (that is,intestinal
bacteria and the interstinal wall ).If the
permeablity of the blood-brain barrier to
plasma GABA is increased in liver failure, and
if some of this GABA is not catabolized or
taken up by neurons, it may reach GABA
receptors , augment GABA-ergic
neurotransmission and lead to disorder of
CNS.
90
Post-synapse inhibition

 
 
 








Cl
Cl
BZ




GABA


Cl
BR
GABAR
Cl
cell
91
• When GABA crosses the extrapermeable bloodbrain barrier of patients with cirrhosis and is
released by Vesicle of excited presynaptic neuron
cell, it interacts with supersensitive postsynaptic
GABA receptors. The GABA receptor, in
conjunction with receptors for benzodiazepines
and barbiturates, results in the opening of a Cl- ion
channel. As [Cl-]out is more than [Cl-]in, binding
of GABA to its receptor permits an influx of
chloride ions into the postsynaptic neuron causing
membrane hyperpolarization and leading to the
generation of an inhibitory postsynaptic potential.
92
Pre-synapse inhibition

 
 
 








Cl
BZ




GABA


BR
Cl
GABAR
Cl
Cl
cell
93
• GABA also causes an inhibitory presynaptic
potential. The same point is Binding of GABA to
GABA receptors results in the opening of a Cl- ion
channel located in neurite membrane. But there’s
different between postsynaptic and presynapse. As
[Cl-]in is more than [Cl-]out, binding of GABA to
its receptor permits an outflux of chloride ions out
of the presynaptic neuron causing membrane
depolarization.so it results in releasing less
neurotransmitters when pulses come and also
causes an inhibitory presynaptic potential.
94
Precipitating factors in hepatic
encephalopathy
• 1.Renal failure: Renal failure leads to
decreased clearance of urea, ammonia, and
other nitrogenous compounds
• 2. Gastrointestinal bleeding: The presence of
blood in the upper gastrointestinal tract
results in increased ammonia and nitrogen
absorption from the gut. Bleeding may
predispose to kidney hypoperfusion and
impaired renal function.
95
• 3. Infection: Infection may predispose to
impaired renal function and to increased
tissue catabolism, both of which increase
blood ammonia levels.
• 4. Constipation: Constipation increases
intestinal production and absorption of
ammonia.
• 5.Medications: Drugs that act upon the
central nervous system, such as opiates,
benzodiazepines, antidepressants, and
antipsychotic agents, may worsen hepatic
encephalopathy.
96
• 6.Diuretic therapy: Decreased serum
potassium levels and alkalosis may
facilitate the conversion of NH4+ to NH3.
• 7.Dietary protein overload: This is an
infrequent cause of hepatic
encephalopathy.
97
Treatment
• 1. Provision of Supportive Care
– Prevention of falls in disoriented patients at
earlier stages of HE may require special
measures. In deeper stages of HE, the
need for prophylactic tracheal intubations
needs to be considered. Adequate nutrition
should be provided during the period of
altered mental state
98
• 2. Identification and Removal of
Precipitating Factors
– (1)Dietary protein should be eliminated and
oral or IV carbohydrate should be given to
supply lost calories.
– (2)Oral lactulose should be given
• Lactulose is degraded by colonic bacteria and
converted to lactic acid and other acids, with
resulting acidification of the gut lumen. This
favors conversion of NH4+ to NH3 and the
passage of NH3 from tissues into the lumen.
99
– (3) Gastrointestinal bleeding must be
stopped. The intestines must be emptied of
blood. Blood breaks down into protein
components that are converted to
ammonia.
– (4)Treatment of infections, renal failure,
and electrolyte abnormalities (especially
potassium) is important.
• 3. Sedation deepens encephalopathy
and should be avoided, even if the
patient is agitated.
100
• 4. Other potential therapies
– include levodopa, a precursor of normal
neurotransmitters; bromocriptine, a
dopamine agonist; infusions of branched
chain amino acids or of keto-analogs of
essential amino acids; flumazenil, a
benzodiazepine antagonist; and sodium
benzoate, for enhanced urinary nitrogen
excretion. However, none of these
therapies has proved effective.
• 5. Liver transplantation
101
Learn from the mistakes of others. You can't
live long enough to make them all yourself…!
102