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1 "With ordinary talent and extraordinary perseverance, all things are attainable." - Thomas E. Buxton "Achievement is connected with action…..!” - Conrad
1 "With ordinary talent and extraordinary perseverance, all
things are attainable." - Thomas E. Buxton "Achievement is
connected with action..! - Conrad Hilton
Slide 2
2 Pathophysiology of Liver Guo xiaosun Shandong University
Slide 3
3 Liver anatomy: Four Lobes
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4 Anatomy Lungs Heart Liver Omentum Diaphragm Gall bladder
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5 Structure of Liver Lobule
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6
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Normal Liver Histology
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8 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.
Slide 9
9 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)
Slide 10
10 Alcoholic Fatty Liver
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11 Jaundice A yellowing of the skin, sclerae, and other tissues
caused by excess circulating bilirubin.
16 CHOLESTASIS A clinical and biochemical syndrome that results
when bile flow is impaired.
Slide 17
17 Etiology intrahepatic causes hepatitis, drug toxicity, and
alcoholic liver disease. intrahepatic and extrahepatic causes duct
stone and pancreatic cancer
Slide 18
18 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
Slide 19
19 The pathophysiologic effects mixed hyperbilirubinemia
pruritus steatorrhea and hypoprothrombinemia osteoporosis or
osteomalacia hyperlipidemia
Slide 20
20 Portal Hypertension Increased pressure in the portal venous
system.
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21
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22
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23 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.
27 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.
Slide 28
28 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 by- passing the liver (shunting). As a result,toxins are more
concentrated in the blood and are more likely to produce damaging
effects.
Slide 29
29 Massive ascites in an elderly woman.
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30
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31
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32
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33 Ascites Free fluid in the peritoneal cavity
Slide 34
34 Etiology cirrhosis chronic hepatitis, severe alcoholic
hepatitis without cirrhosis, and hepatic vein obstruction
Slide 35
35 review:Pathogenesis of edema 1. imbalance of exchange
between intra- and extra-vascular fluid increased capillary blood
presure decreased plasma colloid osmotic presure increased
capillary permeability obstruction of lymphatic flow; 2. imbalance
of exchange between intra- and extra- body fluid: decreased
filtration rate of glomeruli increased water and sodium
reabsorption in renal.
Slide 36
36 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
Slide 37
37 (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.
Slide 38
38 (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 renin-
angiotensin-aldosterone systems, promoting renal sodium and water
retention in an attempt to restore the effective arterial blood
volume and maintain blood pressure.
Slide 39
39 patient with alcoholic cirrhosis and portal hypertension.
Note the parotid hypertrophy, distended abdomen from ascites, and
scrotal and pedal edema.
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40
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41
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42 SYSTEMIC ABNORMALITIES Depression of the livers chemical and
drug detoxification function Skin and endocrine changes Spider
nevi, palmar erythema Complex derangements in the metabolism of sex
hormones Other endocrine derangements
44 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.
Slide 45
45 Liver palms: thenar and hypothenar erythema in a patient
with chronic liver disease.
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46
Slide 47
47 Hepatic Encephalopathy A neuropsychiatric syndrome caused by
liver disease and usually associated with portal-systemic shunting
of venous blood.
Slide 48
48 Etiology fulminant hepatitis ( viruses, drugs, or toxins)
cirrhosis or other chronic disorders
Slide 49
49 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
Slide 50
50 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
Slide 51
51
Slide 52
52 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.
Slide 53
53 Ammonia intoxication hypothesis False neurotransmission
hypothesis imbalance of plasma amino acid hypothesis GABA
hypothesis Pathogenesis of HE
Slide 54
54 Ammonia intoxication hypothesis The first experiment
implicating a nitrogenous substance as a cause of hepatic
encephalopathy was performed by Eck, a turn- of-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.
Slide 55
55 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;
Slide 56
56 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. glutamine
ammonia+glutaminic acid glutaminase
Slide 57
57 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 acids catabolism
product. when the muscles shrink aggravatelly, Adenylic acids
catabolism intensify.Thus, Ammonia increase.
Slide 58
58 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
Slide 59
59 The net reaction for one turn of the urea cycle is CO2 +
NH4+ + 3 ATP + Aspartate + 2H2O -> Urea + 2 ADP + 2 Pi +AMP +
PPi + FumarateATPAspartateUreaADPAMPFumarate synthesis of urea is
energetically expensive.
Slide 60
60 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.
Slide 61
61 causes of hyperammonemia excess of the ammonia formation
insufficiency of the ammonia elimination
Slide 62
62 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.
Slide 63
63 2)portal hypertensionincreased capillary blood
presurecongestion and edema of gastrointestinal tractdisorders 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
Slide 64
64 3) severe liver diseaserenal failureazotemia(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
Slide 65
65 4) tic of the muscles(before HE, pateints often are
restlessness)adenylic acids catabolism intensify increased
ammonia
Slide 66
66 5) increased pH of renal tubular fluiddecreased ammonia
secretion of renal tubules increased ammonia diffusion to blood
increased pH of gastrointestinal tractdecreased ammonia excretion
of gastrointestinal tract increased ammonia diffusion to blood NH 3
+H + NH 4 NH 4 + OH - NH 3 + H 2 O
Slide 67
67 insufficiency of the ammonia elimination dysfunction of the
liverdecreased urea syntheses due to lack of ATP, reaction
substrate and enzyme damage. ammonia in intestine enter the blood
Portal-systmic shunts Disorder of detoxication
Slide 68
68 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 tricarboxylic- acid-cycle
enzymes.
Slide 69
69
Slide 70
70 (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
glutamineGABA so glutaminic acid glutamine GABA ammonia inhibite
the activation of pyruvate decarboxylase, so Acetyl-CoA;
Acetyl-CoA+ bilineurine acetylcholine,SO acetylcholine
Slide 71
71 (3) Ammonia disturbs the ions transfer of the nervous cells
membrane. Na + -K + -ATPase Na + K+K+ NH 3
Slide 72
72 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.
Slide 73
73 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.
Slide 74
74 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 Systems function. False
neurotransmitter hepothesis
Slide 75
75 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.
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76
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78 Interstinal bacteria decarboxylase Tyromine phenylethylamine
their concentration in blood phenylethanolamine octopamine Into the
brain hydroxylase produce liver metabolism Potal-systemic shunt
Phenylala- nine tyrosine (food)
Slide 79
79 Note (1)congestion and edema of gastrointestinal
tractdisorders of the function(motion, secretion, absorption,
degestion) inadequate digestion of proteinproduce Tyromine
phenylethylamine (2) Tyromine and phenylethylamine can be cleared
from the blood by the process of enzymatic degradation in
liver.
Slide 80
80 FNT competes with TN but their physiological effects are
very weak. Dysfunction of RSlethargy, coma
Slide 81
81 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.
Slide 82
82 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 )
Slide 83
83
Slide 84
84 Causes(BCAA): undernutrition, starvationdecomposition of
BCAA(for energy supply); stressglucocorticosteroiddecomp -osition
of intra-musculi BCAA; hyperinsulinemiauptake and utilization of
BCAA in muscular and fatty tissue Causes(AAA): insufficiency of
elimination of AAA in the liver.
Slide 85
85 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.
Slide 86
86 (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 decarboxylase Tyromine phenylethylamine hydroxylase
phenylethanolamine octopamine Phenylala- nine tyrosine (food)
Slide 87
87 AAA/BCAA AAA enter into brain : true neurotran- smitters
false neurotran- smitters inhibitory neuro- transmitters
Slide 88
88 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.
Slide 89
89 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 GABA.
Slide 90
90 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.
92 When GABA crosses the extrapermeable blood- brain 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.
94 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
theres 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.
Slide 95
95 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.
Slide 96
96 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.
Slide 97
97 6.Diuretic therapy: Decreased serum potassium levels and
alkalosis may facilitate the conversion of NH 4 + to NH 3.
7.Dietary protein overload: This is an infrequent cause of hepatic
encephalopathy.
Slide 98
98 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
Slide 99
99 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 NH 4 + to NH 3 and the passage
of NH 3 from tissues into the lumen.
Slide 100
100 (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.
Slide 101
101 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
Slide 102
102 Learn from the mistakes of others. You can't live long
enough to make them all yourself!
