Hepatic Encephalopathy

Prof. Huiling Yang Dept. Pathophysiology

 Definition Etiology & Classification

Pathogenesis
Precipitating Factors Principles of Treatment

Definition
A complex, potentially reversible disturbance in central nervous system that occurs as a consequence of severe liver diseases.

 Definition Etiology & Classification

Pathogenesis
Principles of Treatment Precipitating Factors

Etiology
Advanced liver diseases
Acute or Chronic hepatic failure Viral infection or Toxins Congenital or Acquired Primary or Secondary

Classification
Etiology
Endogenesis

Exogenesis

Endogenous HE V.S.exogenousHE
Endogenous Etiology Preci Factor Acute HF none Exogenous Chronic HF some

NH3 Lab detection Hepatic function

Clinical feature
Reation to reduction of ammonia

Severe & acute

chronic +

Classification
Couse of Disease
Acute Chronic

Etiology
Endogenesis

Blood Ammonia
Non-nitric

Exogenesis

Nitric

Classification
Acute or subacute encephalopathy (EP)
Acute or subacute recurrent EP Chronic recurrent EP

Chronic permanent EP

 Definition Etiology & Classification

Pathogenesis
Principles of Treatment Precipitating Factors

Pathogenesis
Intoxication
Ammonia Others toxins

False neurotransmitters & amino acid imbalance

GABA hypothesis

Ammonia intoxication
Causes of Ammonia Elevation
Ammonia & HE

Causes of Ammonia Elevation

Ammonia detoxification
Urea cycle dysfunction: ATP, ENZYMES Portosystemic shunting

Ammonia production
Gastrointestinal tract -- BLEEDING
Kidney -- ACID-BASE IMBALANCE

Gastrointestinal Tract Origen

Protein

AA oxidase Urease

Enteric NH3
Porto-systemic shunting

Urea Hepatic function

NH3 in Blood

Causes of Ammonia Elevation

Ammonia detoxification
Urea cycle dysfunction: ATP, ENZYMES Portosystemic shunting

Ammonia production
Gastrointestinal tract -- BLEEDING Kidney -- ACID-BASE IMBALANCE

Renal Origen

Gln

Glu

+ NH3

Uric pH
H+

ammonium

H+

Effusing to blood

Causes of Ammonia Elevation

Ammonia detoxification
Urea cycle dysfunction: ATP, ENZYMES Portosystemic shunting

Ammonia production
Gastrointestinal tract -- BLEEDING Kidney -- ACID-BASE IMBALANCE Muscle wasting (consumptive catabolism)

Ammonia intoxication
Causes of Ammonia Elevation
Ammonia & HE

Ammonia & HE
Brain energy metabolism

Glucose
NADH NAD+

choline

Lactic acid

Pyruvate

AcetylCoA

acetylcholine

Oxaloacetat CoA
NADH NAD+

Succinate -ketoglutatrate
NADH

Citrate

GABA

NAD+

NH3
ATP ADP

Energy metabolism neurotransmitter

Glutamate
NH3

Glutamine

Ammonia & HE
Brain energy metabolism
Hypoglycemia
Hepatic gluconeogenesis Glucose ingestion

Substrates of Krebs cycle -ketoglutarate acid & Glu consumption

Alteration of neurotransmitters

Alteration of neurotransmitters
Activating
Glu Acetylcholine

Inhibiting
Gln GABA (early , later )

Glucose
NADH NAD+

choline

Lactic acid

Pyruvate

AcetylCoA

acetylcholine

Oxaloacetat CoA
NADH NAD+

Succinate

Citrate

GABA

-ketoglutatrate
NADH NAD+

NH3
ATP ADP

Early Later

Glutamate
NH3

Glutamine

Pathogenesis
Intoxication
Ammonia Others toxins

False neurotransmitters & amino acid imbalance

GABA hypothesis

Other Toxins
Mercaptans
Short chain fatty acids Phenols

Pathogenesis
Intoxication
Ammonia Others toxins

False neurotransmitters & amino acid imbalance GABA hypothesis

False Neurotransmitters & Amino Acid Imbalance

Amino Acid Imbalance
BCAA/AAA

Neurotransmitters imbalance
False Neurotransmitters Normal Neurotransmitters Inhibiting Neurotransmitters

Amino Acid Imbalance

BCAA / AAA normal3 ~ 3.5 hepatic coma: 0.6 ~ 1.2

Causes

Causes
BCAA
Insulin Muscle ingestion & catabolism Lipocyte of BCAA

AAA

Catabolism of Insulin/Glucagon Liver protein & muscle AAA

hepatic deamination gluconeogenesis in liver

False Neurotransmitters & Amino Acid Imbalance

Amino Acid Imbalance
BCAA/AAA

AAA Neurotransmitters imbalance

False Neurotransmitters Normal Neurotransmitters Inhibiting Neurotransmitters

False Neurotransmitters (FNTs)

---AAA is the precursors of FNTs
Synthesis of FNTs FNTs

FNTs & HE

Synthesis of FNTs
Phe Tyr Blood Blood-brain barrier Brain Phe Tyr Trp

Trp

Phenylethylamine

Dopa

tyramine

5-hydroxytryptophan

Phenylethanolamine

dopamine

octopamin

Seronine

False Neurotransmitters (FNTs)

---AAA is the precursors of FNTs
Synthesis of FNTs FNTs

FNTs & HE

FNTs

Noradrenalin

Phenylethanolamine

Dopamine

octopamin

Normal & False NTs

FNTs & HE
phenylethanolamine octopamin

competitive

Reticular formation:

maintain excitation of
cerebral cortex

NA Dopamine

Nerve pulse transfer

coma

Pathogenesis
Intoxication
Ammonia Others toxins

False neurotransmitters & amino acid imbalance GABA hypothesis

GABA hypothesis
--major inhibitory neurotransmitter Evidence
Patients: GABA-ergic tone Flumazenil related research

Causes
Decreased hepatic metabolism of GABA Gut wall permeability Advanced HE

GABA & HE

Glucose
NADH NAD+

choline

Lactic acid

Pyruvate

AcetylCoA

acetylcholine

Oxaloacetat CoA
NADH NAD+

Succinate

Citrate

GABA

-ketoglutatrate
NADH NAD+

NH3
ATP ADP

Early Later

Glutamate
NH3

Glutamine

GABA & HE
GABA in CNS GABA/ BZ receptor/Chloride Ionophore Complex Cl increase in neuron membrane hyperpolarization

Inhibitory postsynaptic potential

Coma

 Definition Etiology & Classification

Pathogenesis
Principles of Treatment Precipitating Factors

Principles of Treatment
Eliminating or correcting precipitating factors Reducing plasma ammonia and other toxins Correcting plasma amino acid imbalance and supplying normal neurotrasmitters Improving hepatocyte functions Liver transplantation

 Definition Etiology & Classification

Pathogenesis
Principles of Treatment Precipitating Factors

Precipitating Factors of HE
Gastrointestinal bleeding
ammonia and mercaptan hypovolemia, shock, and hypoxia

Sedatives and narcotic

Additive depressant effect

Precipitating Factors of HE (cont.)

Massive paracentesis and excessive diuresis Hypovolemia & K+ deficiency
prerenal azotemia gut & kidney generate ammonia

Precipitating Factors of HE (cont.)

Infections
hypoxiafever catabolism NH3 Sensitivity to NH3 Hypovolemia & renal dysfunction

Endotoxin & exotoxin of microbes precipitates liver lesion

Thanks