Hepatic EncephalopathyHepatic Encephalopathy
Definition (1)Definition (1)
Hepatic encephalopathy (HE)
It represents a reversible decrease in neurological
function, based upon the disorder of metabolism
which is caused by severe decompensated liver disease
.
严重肝病引起的以代谢紊乱为基础的神经、精神综合征。主要临床表现为意识障碍、
行为失常和昏迷
Definition (2)Definition (2)
Subclinical or latent HE
diagnosed only by precise mental tests or EEG, no
obvious clinical and biochemical abnormalities
Incidence/prevalenceIncidence/prevalence
Universal feature of acute liver failure
50%~70% in chronic hepatic failure
Difficult to estimate
Etiology Etiology
Fulminant hepatic failure
acute severe viral hepatitis, drug/toxin,
acute fatty liver of pregnancy
Due to acute hepatocellular necrosis Chronic liver disease
cirrhosis of all types , surgically induced portal-systemic shunts, primary liver cancer
Due to one or more potentially reversible precipitating factors
Common precipitating factorCommon precipitating factor
Deterioration in hepatic function
Drugs
Sedatives
potentially hepatotoxic
agents
Gastrointestinal bleeding
Excessive dietary protein
Uremia/azotemia
Infection
Constipation
Anesthesia and surgery
Hypoxia
Diuretics
hypokalemia,
Alkalosis
hypovolemia
Nitrogenous
Encephalopathy
Nitrogenous
Encephalopathy
Non-Nitrogenous
Encephalopathy
Non-Nitrogenous
Encephalopathy
Pathogenesis (1)Pathogenesis (1)
Toxic materials derived from nitrogeneous substrate
in the gut and bypass the liver
HE is caused by several factors act synergistically
Several putative gut-derived toxins identified
Pathogenesis (2)Pathogenesis (2)
Postulated factors/mechanisms:
Ammonnia neurotoxicity
Synergistic neurotoxins
Excitatory inhibitory neurotransmitters and
plasma amino acid imbalance hypothesis
γ-Aminobutyric acid ( GABA ) /BZ hypothesis
Ammonia neurotoxicityAmmonia neurotoxicity
Over production and/or hypoeccrisis
Poor hepato-cellular function:incomplete metabolism
Portal-systemic encephalopathy: bypass
Ammonia intoxication
Interfere with cerebral metabolism:
Depletion of glutamic acid, aspartic acid and ATP
Depression cerebral blood flow and oxygen
consumption
Ammonia neurotoxicityAmmonia neurotoxicity
Elevation of ammonia: detected in 60%~80%
Absolute concentration of ammonia, ammonia
metabolites in blood or cerebrospinal fluids,
correlates only roughly with the presence or severity
of HE
Few cases: within normal range
Synergistic neurotoxinsSynergistic neurotoxins
Ammonia
Mercaptans ( 硫醇 )
Short-chain fatty acids
Excitatory inhibitory neurotransmitter & Excitatory inhibitory neurotransmitter & plasma amino acids imbalance plasma amino acids imbalance
Neurotransmission: Mediated by both excitatory and inhibitory neurotransmitters
Their synthesis controlled by brain concentration of the precursor amino acids
Increased aromatic amino acids (AAAs)
Tyrosine (酪氨酸) Phenylalanine (苯丙氨酸) Tryptophan (色氨酸〕 Due to the failure of hepatic deamination
Decreased branched-chain amino acids (BCAAs)
Valine (缬氨酸) Leucine (亮氨酸) Isoleucine (异亮氨酸) Due to increased metabolism by skeletal muscle and kidneys
or increased insulin
Excitatory inhibitory neurotransmitter & Excitatory inhibitory neurotransmitter & plasma amino acids imbalance plasma amino acids imbalance
Imbalance of plasma amino acid:
More AAAs enter into blood-brain barrier and CNS
Decreased synthesis of normal neurotransmitters
Enhanced synthesis of false neurotransmitters
Octopamine( 苯乙醇胺 ) Tryptophan (- 羟酪胺 )
Excitatory inhibitory neurotransmitter & Excitatory inhibitory neurotransmitter & plasma amino acids imbalance plasma amino acids imbalance
γ- Aminobutyric acid hypothesisγ- Aminobutyric acid hypothesis
γ- Aminobutyric acid (GABA):
Principal inhibitory neurotransmitters
Generated in the gut by bacteria
Bypasses the diseased or shunted liver
Increased blood-brain barrier permeability
PathohistologyPathohistology
Brain may be normal or cerebral edema
Particularly in fulminant heptic failure
Cerebral edema is likely the secondly changes In patients with chronic liver disease
Astrocytes: increase in number and enlargement In a very long-standing case
Thin cortex, loss of neurons fibers, laminar
necrosis , pyramidal tracts demyelination
Clinical manifestationClinical manifestation Clinically, HE manifests diverse signs and symptoms.
Early forms, quite subtle changes in personality or
level of performance.
As HE advances, a disturbance of consciousness,
impaired intellectual function, neuromuscular
abnormalities, mood changes, inversion of the sleep
cycle, and slowed reaction time.
Day-night reversal is often an early manifestation.
Clinical manifestationClinical manifestation
Criteria for clinical stages
Personality and mental changes
Asterixis
Abnormal EEG patterns
Clinical Grading of HE
Grade Symptoms Sign EEG Abnormalities
I-Prodrome
Altered sleep patterns
Fluctuating mood-
euphoria,depression
Inappropriate behavior
Apathy
Loss of affect
Writing difficult
Constructional
apraxia
Asterixis may be
present
May be present
II-Mild HE Mild confusion
Disorientation
Drowsiness (嗜睡)
Asterixis(easily elicitated)
Ataxia (共济失调)Fetor hepaticus 肝臭
Abnormal
Slower rhythms
Clinical Grading of HE
Grade Symptoms Sign EEG Abnormalities
III-Moderate HE
Marked confusion
Arousable from sleep
Responsive
Asterixis
Rigidity of limbs
Hyperflexia
Clonus
Grasping and sucking reflexes
Babinski
Moderate
IV-Coma Unconsciousness
Unresponsive to
stimuli
Flaccid limbs
Diminished
reflexes
No muscle tone
significant
Laboratory and other testsLaboratory and other tests
Serum ammonia Elevation of serum ammonia: 60%~80%
particularly in chronic HE
(with portosystemic shunting) Electroencephalogram (EEG)
Severe slowing with frequencies in the theta
and delta Evoked potentials
Variation, lack of specificity and sensitivity
Reitan trail-making test Reitan trail-making test
Psychometric tests ----Number connection test
Writing chartWriting chartPsychometric tests ----Digit symbol test
Diagnosis and Diagnosis and
differential diagnosisdifferential diagnosis
DiagnosisDiagnosis
Patients with severe liver disease and/or
portal hypertension, portosystemic shunting
Mental changes: confusion, somnolence, coma
Factors precipitating or aggravating HE exist
Severely impaired liver function and/or
hyperammonemia
Flapping tremor and typical EEG changes
DiagnosisDiagnosis
Recognition of the latent and/or subclinical HE
Important for view of the prevalence of cirrhosis In the absence of characteristic features
Abnormal neuropsychiatric function:
Number connection test
Digit symbol tests
Block design
Visual reaction times
Differential diagnosisDifferential diagnosis
Hypoglycemia (低血糖) Uremia
Diabetic ketoacidosis (糖尿病酮症酸中毒) Nonketotic hyperosmolar syndrome (非酮症高渗综合症) Subdural hematoma (硬膜下血肿) Cerebrospinal infection (脑脊髓感染)
TreatmentTreatment
The goals of therapy The goals of therapy
To treat the underlying liver disease and improve
mental.
The most important initial aspects of care are to
diagnose the condition properly, exclude other causes
of encephalopathy, and search for precipitating factors
一、一、 Identification and treatment of Identification and treatment of precipitating factorsprecipitating factors
These precipitating events may be readily apparent or
subtle. Therefore, detailed discussions and a careful
assessment of changes in laboratory values are necessary.
Supportive care
Correction of fluid, electrolyte, glucose, acid-alkaline
abnormalities
Management of cerebral edema, bacteremia
二、二、 Decreasing nitrogen load and ammonia Decreasing nitrogen load and ammonia productions and absorption of enteric toxinsproductions and absorption of enteric toxins
Decreasing ammonia productions
Dietary protein restriction
Bowel cleaning(clysis 灌肠 , catharsis 导泻 )
Nonabsorbable disaccharides
Antibiotics
eradication of Hp
Increasing ammonia metabolisms
Dietary protein restrictionDietary protein restriction
Restriction of dietary protein at the time of acute HE
with subsequent increments to assess clinical tolerance
is a classic cornerstone of therapy
Protein restriction: 0.81.0g/kg.d
Vegetable and dairy sources are preferable to animal
protein
A positive nitrogen balance positive efects
Bowel cleaningBowel cleaning
Clysis
Laxative (e.g. magnesium citrate 硫酸镁 )
Notes: all enemas must be neutral or acidic to reduce
ammonia absorption
Nonabsorbable disaccharidesNonabsorbable disaccharides
Lactulose (乳果糖) Synthetic disaccharide First-line pharmacological treatment Release lactic and acetic acids by colonic bacteria Decreasing stool pH to about 5.5 Reduce portion of ammonia and its absorption Effective in 80% of patients Cause 2~3 soft stool/d
AntibioticsAntibiotics
Neomycin (新霉素) : 2~4g/D
Litter is absorbed
Impaired hearing or deafness ( long term use)
Long term use (>1 month) is not advisable Metronidozol (甲硝唑) : 0.2g qid
as effective as neomycin Rifaximin (利福昔明)
Increasing ammonia metabolismsIncreasing ammonia metabolisms
L-Ornithine-L-asparagic acid ( L- 鸟氨酸 -L- 天冬氨酸)
Benzoate (苯甲酸盐), Phenylacetic acid (苯乙酸)
Zinc ( 锌 )
Potassium glutamate( 谷氨酸钾 ) , sodium glutamate ( 谷
氨酸钠 )
Arginine( 精氨酸 )
三、三、 Drugs that affect Drugs that affect neurotransmissionneurotransmission
Administration of BCAAs
Oral or parenteral administration
L-dopa (左旋多巴)Precursor of the neurotransmitter
norepinephrine dopamine
penetrate blood-brain barrier
Increase the normal neurotransmitter
四、四、 GABA/BZ receptor GABA/BZ receptor antagonistsantagonists
Flumazenil (氟马西尼) and others: may have
a therapwutic role in selected patients
A formal recommendation on the use of these
drugs cannot be made on the basis of evidence-
based data
Liver transplantationLiver transplantation
Ultimate answer to the problem of chronic HE
Summary Summary Key issues of the HE topicKey issues of the HE topic
Clinical manifestations------ Clinical stages of HE
Diagnosis and differential diagnosis
Factors precipitating and/or aggravating HE
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