Transcript Hepatic encephalopathy (HE)

Hepatic Encephalopathy
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)
Subclinical or latent HE
diagnosed only by precise mental tests or EEG, no
obvious clinical and biochemical abnormalities
Incidence/prevalence

Universal feature of acute liver failure

50%~70% in chronic hepatic failure

Difficult to estimate
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 portalsystemic shunts, primary liver cancer
Due to one or more potentially reversible
precipitating factors
Common precipitating factor
Nitrogenous
Non-Nitrogenous
Encephalopathy
Encephalopathy
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
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)
Postulated factors/mechanisms:
 Ammonnia
neurotoxicity

Synergistic neurotoxins

Excitatory inhibitory neurotransmitters and
plasma amino acid imbalance hypothesis

γ-Aminobutyric acid（GABA）/BZ hypothesis
Ammonia 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 neurotoxicity

Elevation of ammonia:
 Absolute
detected in 60%~80%
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 neurotoxins
 Ammonia

Mercaptans (硫醇)

Short-chain fatty acids
Excitatory inhibitory neurotransmitter &
plasma amino acids imbalance
Neurotransmission:
 Mediated by both excitatory and inhibitory
neurotransmitters
 Their synthesis
controlled by brain
concentration of the precursor amino acids
Excitatory inhibitory neurotransmitter &
plasma amino acids imbalance

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 &
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)
γ- 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
Pathohistology

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 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 manifestation
Criteria for clinical stages

Personality and mental changes
 Asterixis
 Abnormal
EEG patterns
Clinical Grading of HE
Grade
Symptoms
Sign
EEG
Abnormalities
IProdrome
Altered sleep patterns
Fluctuating moodeuphoria,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
Abnormal
elicitated)
Slower rhythms
Ataxia（共济失调）
Fetor hepaticus肝臭
Clinical Grading of HE
Grade
Symptoms
Sign
EEG
Abnormalities
IIIModerate
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 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
Psychometric tests ----Number connection test
Reitan trail-making test
Psychometric tests ----Digit symbol test
Writing chart
Diagnosis and
differential diagnosis
Diagnosis

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
Diagnosis

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 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）
Treatment
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、Identification and treatment of
precipitating 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、Decreasing nitrogen load and ammonia
productions 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 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: 0.81.0g/kg.d
 Vegetable
and dairy sources are preferable to animal
protein
A positive
nitrogen balance positive efects
Bowel cleaning

Clysis

Laxative (e.g. magnesium citrate 硫酸镁)
Notes: all enemas must be neutral or acidic to reduce
ammonia absorption
Nonabsorbable 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
Antibiotics
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 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、Drugs that affect
neurotransmission
 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、GABA/BZ receptor
antagonists

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 evidencebased data
Liver transplantation
Ultimate answer to the problem of chronic HE
Summary
Key issues of the HE topic
Clinical
manifestations------ Clinical stages of HE

Diagnosis and differential diagnosis

Factors precipitating and/or aggravating HE