hepatic encephalopathy. definition (1) hepatic encephalopathy (he) it represents a reversible...

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