Hepatic%20insufficiency

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Hepatic insufficiency

• Wang Jing-jing
• Department of Pathophysiology
• Shandong University

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• Introduction
• Concept
• Etiology and classification
• The functional and metabolic changes
• Hepatic encephalopathy

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• Introduction
• 1. Blood Supply
• Portal vein 3/4 of the
• blood flow (which drains
• the stomach, intestine,
• spleen, and pancreas)
• Hepatic artery 1/4 of
• the blood flow

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• 2. Internal Structure Liver lobule
• A central vein (coalesce into
• hepatic veins, which empty
• into the vena cava)
• 4-6 portal triad (branches of
• hepatic artery, hepatic portal
• vein and bile duct)

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Rows of liver cells (Hepatocytes, hepatic
stellate cells, sinusoidal endothelial cells,
Kupffer cells and liver-associated lymphocytes
which are in close contact with blood-filled
sinusoids
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Hepatic cirrhosis pseudolobule
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3. Functions

• Excretion bile (help the absorption of vitamin
  K)
• Clearing the blood of particles and infections
  including bacteria 
• Synthesis albumin, lipoproteins, coagulation
  factors, as well as protein C, S and
  antithrombin.
• Metabolism protein, lipid, carbohydrate
• Neutralizing and destroying drugs and toxins 
• Manufacturing, breaking down and regulating
  numerous hormones including sex hormones 

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• Concept of Hepatic insufficiency
• Severe damage in liver cells result in
  degeneration, necrosis, fibrosis and cirrhosis,
  manifesting as jaundice, bleeding, infection,
  renal dysfunction or encephalopathy, termed all
  together the syndrome of Hepatic insufficiency

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• Etiology

1. Infections hepatitis virus (HBV), bacteria,
parasites
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HBV ????????????? HbsAg ? HbeAg ? HBcAg ? T
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Cirrhosis
HBV multiplies, spreads and eventually leads to
scarring, liver damage, cirrhosis and cancer.
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Some bacteria, such as Escherichia coli ( E. coli
) or staphylococcus (staph), tubercle bacillusor
amoeba caused Liver abscesses
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• 2. Medicines Industrial toxins, drugs are
  modified or degraded in the liver
• Hepatic cytotoxicity Degeneration and necrosis
  of hepatic cells or synthesis of some proteins.
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• Cholestasis inhibit Na-K ATP, fluidity of
  cell membrane ????

.
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3. Alcohol
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Alcoholic Fatty Liver
Normal liver
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• 4. Nutritional causes
• everything we eat must be refined and detoxified
  by the liver
• liver disease are always found among starving
• populations.
• good nutrition - a balanced diet can actually
  help the damaged liver to regenerate new liver
  cells.
• .

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5. Inherited conditions Wilson's disease a
rare inherited condition. inability to excrete
copper into bile. resulting in the toxic
accumulation of copper in the liver and nervous
system.
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6. Immunosuppression SLE, rheumatoid arthritis,
Crohn's disease, Systemic infections, such as
tuberculosis, may spread to the liver.
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• Classification of hepatic insufficiency

Acute short course of onset? acute extensive
necrosis chronic long course ? late-staged
chronic liver disease
Hepatic encephalopathy Hepatorenal syndrome
Hepatic failure
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• The functional and metabolic changes

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• 1. Substance metabolism
• (1) Carbohydrate Metabolism
• Glycogenolysis, Glycogenesis, Gluconeogenesis
• Hypoglycemia, abnormal glucose tolerance
• (2) Fat metabolism synthesises lipoproteins,
• cholesterol, phospholipids, lipogenesis and
  lipolysis
• ???,???,???,??????

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• (3) Protein metabolism CRP, urea ,albumin ?
• ??,????,??????
• (4) Vitamine metabolism
• Absorption of liposoluble vitamine ?
• Storage of Vit A, Vit D, Vit E, Vit K ?
• Synthesis of vitamine ?
• ??,????,????
• (5) Energy metabolismATP ?

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Ecchymosis of skin
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• 2. Disorders of bile and hormone
• Hyperbilirubinemia
• Elimination of bilirubin ? ?serum bilirubin? ??
• (2) Intrahepatic cholestasis
• Production of bile salts ?
• ?fat and fat soluble vitamins ?
• ? Endotoxemia
• (3) Elimination of hormone ? ? estrogen ?
  aldosterone ?, ADH ?

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Jaundice yellow discoloration of the skin and
whites of the eyes
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the liver plays important roles in hormonal
modification and inactivation. Estrogen?? body
feminization
Spider angioma
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• 5. Disorders of blood coagulation
• Production of Blood coagulation factors ?
• Anticoagulin?
• (3) Fibrinolytic system ?
• (4) Plt ?
• 6. Function of detoxication ?
• 7. Immunological function ?

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• 8.metabolic disorders of water and electrolytes
• (1)Hepatic ascites accumulation of fluid that
  fills and distends the abdomen.

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• Cirrhosis, scar tissue, thrombosis in the portal
  vein ?Obstruction blocks the flow of blood
  through the liver?Portal hypertension ?
  ?capillary pressure?
• Obstruction of lymph ?capillary pressure?
• Liver insufficient ?synthesis of albumin??
  osmotic pressure?
• Hepatic failure ?aldosterone ?ADH ?
• Renal failure ? Water and salt rentention

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(2) Hyponatremia Intake? Lose ? ADH, Diuresis,
ascites (3) Hypokalemia Intake? Lose ?
aldosterone (4) Alkalosis PaO2 ? anemia,
Hyperammonemia 9. Disorders of organs HE,
hepatorenal syndrome
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Hepatic encephalopathy

• General Concept
• Classification
• Clinical Features
• Pathogenesis
• Precipitating Factors
• Principles of Treatment

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?. General Concept, Classification Clinical
Features

• A complex disturbance in central nervous system
  that occurs as a consequence of severe liver
  diseases.
• hepatic coma portal systemic encephalopathy
  (PSE) HE
• Hepatic coma refers only to a terminal stage of HE

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Endogenous HE spontaneous No apparent
pricipitating factor, the final consequence of
extensive liver cell destruction. Exogenous HE
Have apparent pricipitating factor, (the
development of portal-systemic shunts,
electrolyte ,acid-base imbalances, bleeding
,ingestion of large amounts of dietary protein,
etc)
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Portal-systemic shunts
1. Portal hypertension ?collateral circulation
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1. At the lower end of the esophagus

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• 2. At rectal venous plexus
• 3. At periumbilical venous rete
• 4. Portal-retroperitoneal anastomosis

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2. Transjugular Intrahepatic Portosystemic Shunt
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???????????(TIPS)
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Clinical features of HE generally divided into 4
stages
slight altered mood or behavior including
reversed sleep pattern
Coma, no response to painful stimuli
Coma but arousable slurred speech
Drowsiness, personality changes intermittent
flapping tremor
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Flapping tremor
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Precipitating factors in HE

• 1.Nitrogenous overload a frequent cause of HE.
• 2. GI 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.

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• 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. Renal failure Renal failure leads to
  decreased clearance of urea, ammonia, and other
  nitrogenous compounds

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• 6. Medications Drugs that act upon the central
  nervous system, such as opiates, benzodiazepines,
  antidepressants, and antipsychotic agents, may
  worsen HE.
• 7.Diuretic therapy Decreased serum potassium
  levels and alkalosis may facilitate the
  conversion of NH4 to NH3.

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?. Pathogenesis of HE

• Ammonia intoxication hypothesis
• False neurotransmission hypothesis
• Amino acid imbalance hypothesis
• GABA hypothesis

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1. Ammonia intoxication hypothesis

• (1) History
• 1877 Eck, Russian physiologist who created
  portal-systemic shunts in healthy dogs
• The beginning of the surgical treatment of portal
  hypertension
• the first vascular anastomosis

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• Ivan Pavlov Eck-Pavlov fistula
• In 1893 Observed that these dogs promptly became
  comatose after eating meat.
• meat intoxication
• in 1904 received Nobel Prize

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(3)Supporting evidence

• 6080 of HE show increased plasma ammonia level
• Patients with hepatocirrhosis have elevated
  level of ammonia
• Symptom of HE and alteration in
  electroencephalogram (EEG) after high protein
  diet

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(4) Contents
NH3 clearance ( urea cycle )
NH3 production
NH3 production
Under normal condition, the production and the
clearance of NH3 is in balance
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Severe hepatic dysfunction
Hyperammonemia
HE
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1) NH3 production

• AA deaminization amine oxidase
• Intestine unabsorbed aa or diffused urea that
  are broken down by bacterial amino acid oxidases
  or ureases. pH? NH3 absorbed?
• Renal tubular epithelial cells Hydrolysis of
  glutamine
• Skeletal muscles Deamination of other amino
  acids

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2) NH3 clearance

• Liver Urea cycle
• CO2 2HN3 3ATP 3H2O H2N-CO-NH2 2ADP
  4Pi AMP
• Brain and muscle Formation of glutamine by
  glutamine synthetase
• ammoniaglutaminic acid glutamine

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3) Why does the NH3 increase in HE?

• ? NH3 production ?
• Portal hypertension Capillary blood presure ? ?
• Congestion and edema of gastrointestinal tract ?
• AA digested and absorbed ?
• Bile ? Intestinal bacteria ? ? ureases ? ? NH3?
• Foods full of high protein or hemorrhage

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• Severe liver disease?renal failure?the urea in
  blood defuses into intestine ? NH3?
• Tic of the muscles? NH3?
• ? NH3 clearance?
• Liver Urea cycle ? ? NH3 clearance?
• ATP ? Function of enzyme ? Substrates ? and shunt

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Normal metabolism
NH3
urea
protein
NH3
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Brain NH3?
Liver failure
Shunting Circulation
Blood NH3?
?

NH3
urea
protein
NH3
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The reasons of NH3?
Production?
clearance ?

GI tract
urea syntheses
liver
renal
NH3
Portal-systmic shunts
muscles
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4)How does the NH3 lead to HE?

• 1.Decreasing energy production
• In normal conditions Because glycogen reserves
  are less in the brain, brain needs much of energy
  from oxidation of glucose.
• Excess ammonia ultimately may cause cerebral
  energy failure due to inhibition the energy
  production.

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Pyruvate decarboxylase
Krebs cycle
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• 2. Changing neurotransmitters
• increasing glutamine and GABA
• decreasing glutamic acid and
  acetylcholine
• The neurotransmitters include excitatory
  transmitters (acetylcholine, glutamic acid, etc )
  and inhibitory transmitters (GABA, glutamine,
  etc) .
• The correct balance of neurotransmitters is
  critical to the brain.
• HE?NH3??GABA, glutamine?, glutamic acid and
  acetylcholine ?? disorder of CNS.

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Krebs cycle
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The reasons of NH3?
Production?
clearance ?

GI tract
urea syntheses
liver
renal
NH3
Portal-systmic shunts
muscles
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Decreasing energy production
Krebs cycle
Changing neurotransmitters
Disturbing the ions transfer of the nervous cells
membrane.
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3. Ammonia disturbs the ions transfer of the
nervous cells membrane.

• Na-K-ATPase which is located in the surface
  membrane of cells is responsible for the active
  transport of Na and K between extracellular
  fluid and cytoplasm.
• NH3 ?ATP?? Na-K-ATPase ?? inhibits excitatory
  postsynaptic potentials?depressing CNS function.

NH3
K
Na-K-ATPase
Na
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• However, not all data are consistent with the
  ammonia toxicity theory.
• Plasma levels of NH3 correlate poorly with HE
• Acute NH3 intoxication may be characterized by
  seizures which are unusual in either acute or
  chronic HE.
• NH3 does not induce the EEG changes of HE.

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4. Astrocytic swelling (1) Glutamin (2)
Oxidative Stress (3) Permeability of
mitochondrion (4) AQP4?
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?.False neurotransmission hypothesis
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False neurotransmission(FN) hypothesis

• What is FN? And what is true neurotransmission(TN)
  ?
• History of FN hypothesis?
• Why FN is increased in hepatic insufficient
  patients?
• What is the mechanisms of FN in hepatic
  insufficient patients?

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• 1. What is FN? And what is TN ?

What is neurotransmitters? Information is moved
around the brain, from nerve cell to nerve cell,
by means of chemical substances, called
neurotransmitters
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1.A message travels along the nerve and when it
approaches the nerve ending a neurotransmitter is
released. 2.The neurotransmitter is received by
the next neuron 3. some of the neurotransmitter
gets reabsorbed 4.When enough neurotransmitter
is received by the next nerve cell the message
moves forward.
The roles of NT
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• 1. What is FN? And what is TN ?

Excitatory neurotransmitter Ach, Aspartic
acid Inhibitory neurotransmitter GABA,
Glutamine
Neuro- transmitters
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The structure of FN and TN
TN
FNT
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Excitation of secondary neuron
Excitation of secondary neuron
?
synapse
FNT compete receptor
True NT
Normal
Hepatic failure
Mode shown replacement of TN to FN in HE
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Supporting evidence
2. False neurotransmitter (FN) hypothesis

• FN accumulates in liver failure.
• In the corpus striatum of rats with
  encephalopathy, concentrations of
  noradrenaline(NA) and dopamine(DA) decreased,
  octopamine increased.

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• In 1970, Parkes first reported bendopa treat HE
  succesfully.
• Fischer et al proposed FN hepothesis
• In the pateint with hepatic failure, FN
  (phenylethanolamine and octopamine) is
  accumulated in the synapse of the ascending
  reticular activating structure (ARAS) in the
  brain stem.
• The FN can compete with true Neurotransmitter
  (TN) noradrenaline (NE) and dopamine (DA)
  because their chemical structure is similar to
  the TN.
• When FN replaces TN in RAS of brain stem,
  disorders of CNS occur.

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• 3. Why FN is increased in HE patients?
• Congestion and edema of gastrointestinal
  tract?disorders of the function (motion,
  secretion, absorption, digestion) ? inadequate
  digestion of protein?Phe (phenylethylamine) and
  Tyr (tyramine) ?
• Tyr and phe cant be cleared by the process of
  enzymatic degradation in liver.
• Potal-systemic shunt make Tyr and phe flow in
  blood directly.

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Brain Tyr and phe ?
Liver failure
Shunting Circulation
?
Blood Tyr and phe ?
Tyr and phe

protein
Tyr and phe
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4. How does the FN compete with TN?
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?. Plasma amino acid imbalance hypothesis

• 1.What is branched chain amino acids (BCAA) and
  aromatic amino acids (AAA)?
• 2.What is the contents of Plasma amino acid
  imbalance hypothesis?
• 3.Why plasma amino acids are imbalance in HE
  patients?
• 4. What is the mechanisms?

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1.What is BCAA and AAA?
BCAA
AAA
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Phe
Try
Tyr
Plasma
BBB
Brain
decarboxylase
Phe
Tyr
Try
hydroxylase
decarboxylase
hydroxylase
tyramine
PEA
Hydroxylase
5-HTA
HPEA
5-HT
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• 2.What is the contents of Plasma amino acid
  imbalance hypothesis?
• In HE patients, blood BCAA is decreased, AAA is
  increased, so, AAA enters in to the brain more
  and form FN.
• Decreased ratio of BCAA/AAA relates to HE due to
  FN formation in CNS.
• So, this hypothesis is an extension of False
  Neurotransmitter Hypothesis.

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• 3.Why plasma amino acids are imbalance in HE
  patients?
• BCAA?
• Hepatic dysfunction?degradation of glucagon?
• Portal systemic shunts? glucagon enter into blood
  directly
• ? glucagon ?? BCAA is excessive used by skeletal
  muscle

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AAA?
Brain Tyr and phe ?
Liver failure
Shunting Circulation
?
Blood Tyr and phe ?
Tyr and phe

protein
Tyr and phe
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Phe
Tyr
Try
Plasma
BBB
Brain
NAA
decarboxylase
Phe
Tyr
Try
hydroxylase
decarboxylase
FNT, Phe, Try
hydroxylase
Dopa
FNT, NAA,5-HT
tyramine
PEA
Hydroxylase
Dopamine
5-HTA
FNT
NA
HPEA
5-HT
AAA/BCAA??AAA enter into brain??TN??FNT?
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• 4. The mechanisms of Plasma amino acid imbalance
• 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 failure or shunt.
• BCAA/AAA?in CNS may interfere with normal
  neurotransmission by competitively inhibiting TN
  (DA, NA) and favoring formation of FN
  (octopamine, phenylethanolamine)

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? GABA hypothesis

• In the 1980s, Basile and Jones promoted
• gamma-aminobutyric acid (GABA), the major
  inhibitory neurotransmitter in the CNS, as a
  cause of HE.
• Of all brain nerve endings, 24-45 may be GABA
  ergic.
• Increased GABA ergic tone is observed in patients
  with HE

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Brain GABA?
BBB?
?
Blood GABA ?
Shunting Circulation

clear
GABA
Liver failure
bacteria in intestine ?
Foods full of glumatic acid
GABA
Edema, congestion ? digestion?,absorb?
Liver failure
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• GABA crosses the blood-brain barrier?released by
  Vesicle of excited presynaptic neuron cell ? GABA
  receptors( in conjunction with receptors for
  benzodiazepines and barbiturates) ? Cl- channel
  opens ? Cl- influxs into the postsynaptic neuron
  ? membrane hyperpolarization ? inhibitory
  postsynaptic potential.

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GABA
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Cl-
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BZ
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BR
GABAR? ?
cell
Cl-
Liver failure
Post-synapse inhibition
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Treatment

• 1. Identification and Removal of Precipitating
  Factors
• (1)Dietary protein should be eliminated
• (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.

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• (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.

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• 2. reducing plasma ammonia and other toxins
• levodopa, a precursor of normal neurotransmitters
• bromocriptine, a dopamine agonist
• infusions of branched chain amino acids
• flumazenil, a benzodiazepine antagonist
• 3. Liver transplantation

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Risk Factors

• 1. Risk Factos in People with Alcoholism
• Only 10 of heavy drinkers develop advanced liver
  disease. Not eating when drinking and consuming a
  variety of alcoholic beverages are factors that
  increase the risk for liver damage.
• Obesity is a major factor for all stages of liver
  disease.
• Women develop liver disease at lower quantities
  of alcohol intake than men. The reason for this
  may be due to women's inability to metabolize
  alcohol as quickly as men, so it stays in the
  bloodstream longer.
• Genetic factors that regulate the immune
  responses in the intestine also play role in
  increasing the risk for liver injury from
  alcoholism.

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• 2. Risk Factors in People with Chronic Hepatitis
• Hepatitis C at higher risk for liver damage,
  especially Co-infection with hepatitis B or HIV.
• Being diabetic and overweight, particularly if
  fat is distributed in the abdomen (an
  apple-shape). This condition poses a higher risk
  for nonalcoholic fatty liver disease (NASH),
  which in turn is apt to become scarred and
  cirrhotic.
• High exposure to toxic chemicals or
  environmental contaminants.

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Weight gain in the area of and above the waist
(apple type) is more dangerous than weight gained
around the hips and flank area (pear type). Fat
cells in the upper body have different qualities
than those found in hips and thighs.
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3. Risk Factors for Cirrhosis in Autoimmune Liver
Diseases 4. Obesity and Other Risk Factors for
Cirrhosis obesity increased the risk of death
from cirrhosis in those who drank little or no
alcohol, but not in alcoholics. Men are at higher
risk than women and African Americans have a
higher risk than Caucasians.
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