By

DR. EFFA MUJEEB KHAN House Officer Medical Unit 4 Civil Hospital Karachi

Hepatic encephalopathy (HE) is a complex metabolic mental state disorder with a spectrum of reversible neuropsychiatric abnormalities seen in patients with severe acute or chronic liver dysfunction after exclusion of other brain diseases

PREVALENCE
It can be found in up to 50 to 70% of cirrhotic patients.

The occurrence of hepatic encephalopathy is only possible under the following conditions:
1- Serious acute or chronic liver disease

in which the detoxification function is restricted

2- Functional or anatomic portosystemic collateral circulation must exist through which the nontoxified portal blood bypasses the liver, so that toxic substances reach the brain

The World Congress of Gastroenterology in 2002 classified hepatic encephalopathy: Type A: Associated with acute liver failure

Type B:
Type C:

Portal-systemic bypass without intrinsic hepato-cellular disease.

Cirrhosis and portal hypertension with portosystemic shunts.

Type C can be further divided into:

1-Episodic HE.

Precipitated

Spontaneous
Recurrent encephalopathy Mild Severe

2-Persistent HE.

Treatment-dependent persistent HE

3-Minimal HE.

CAUSES
Many causative factors have been implicated in the pathogenesis of HE, but it is the multiple-hit hypothesis that appears to be most important.

I) Neurotoxins
1-Ammonia 2) Other possible Toxins

II) Neurotransmitters
1-GABA (-Amino butyric Acid): 2-False Neurotransmitters

III) Alteration of Blood Brain Barrier (BBB) IV) Altered Brain Energy Metabolism V-Deficiency of Essential Substances VI) Decrease in Probiotics

I) Neurotoxins
1-Ammonia:
Production:

-Small intestine: catabolism of glutamine -Large intestine: microbial breakdown of protein, amino acids, urea -In peripheral tissues (esp. skeletal muscle) Detoxification: -Liver: synthesis of urea, glutamine -Skeletal muscle: by glutamine synthetase

How does ammonia affect the brain in HE?

1- Alters blood brain barrier 2- Brain ammonia is consumed in the conversion of glutamate to glutamine by glutamine synthetase in astrocytes. Glutamine is an osmolyte and increased Gln accumulation in these cells may contribute to cytotoxic brain edema (Alzheimer type 2 astrocytosis)

which often complicates FHF.

3- Alters brain energy metabolism 4- Exerts direct effects on neuronal membranes with

change in neurotransmitter receptors

(hypothesis of primary gliopathy)

4. Acute ammonia neurotoxicity, which may be a cause of seizures in FHF, is excitotoxic in nature, being associated with increased synaptic release of glutamate (Glu), the major excitatory neurotransmitter of the brain, and subsequent over-activation of the ionotropic Glu receptors, mainly the N-methyl-d-aspartate (NMDA) receptors.

5. Hepatic encephalopathy complicating chronic liver failure seems associated with a shift in the balance between inhibitory and excitatory neurotransmission towards a increase of inhibitory neurotransmission as a consequence of down-regulation of Glu receptors resulting in decreased glutamatergic tone. The downregulation follows excessive extrasynaptic accumulation of Glu resulting from its impaired reuptake into nerve endings and astrocytes. This is also induced by ammonia accumulation.

1-Nitrogenous intestinal content

2- Change in the intestinal flora 3- Degree of liver dysfunction

4- Extent of portocaval collaterals

5- Muscle wasting (muscles contain glutamine synthetase)

6- Enzyme defect in urea synthesis

2) Other possible Toxins:

(i) Mercaptans & methionine derivatives

(Synergism Hypothesis)
(ii) Phenolic Compounds

(iii) Short Chain Fatty Acids

- Inhibit various enzymes of urea cycle - Displace tryptophan from its binding to albumin tryptophan

II) Neurotransmitters
1-GABA (-Amino butyric Acid):
GABA is

the principal inhibitory neurotransmitter in

brain. Synthesis: a- In presynaptic neurons: from glutamic acid b- In intestine: by gut bacteria (enters portal vein and metabolized by liver) In liver failure or portosystemic shunting, GABA in the systemic circulation crosses BBB to interact with supersensitive postsynaptic GABA receptors.

 GABA binds

to specific GABA receptors in post-synaptic membrane. These receptors also bind benzodiazepines and barbiturates. binding of benzodiazepines to GABA receptors intensifies the effect of GABA.

The

2-False Neurotransmitters:

The liver plays an essential part in metabolism of amino acids. In chronic liver disease: 1- Aromatic amino acids (AAA) like

tyrosine, phenylalanine and tryptophan

(Due to the failure of hepatic deamination)

2- Branched-chain amino acids (BCAA) like valine and leucine

(Due to increased metabolism by skeletal muscle and kidneys)

cerebral tryptophan increases synthesis of serotonin (depressant of consciousness)

Phenylalanine in brain inhibits tyrosine 3hydroxylase ( key enzyme for synthesis of catecholaminergic neurotransmitter)

Tyrosine increases synthesis of tyramine, octapamine which competes with catecholamine neurotransmitters for the same receptor site Brain dopamine due to displacement of dopamine by false neurotransmitter impairment of dopaminergic neurotransmission

III) Alteration of Blood Brain Barrier (BBB)

BBB

is a complex physiologic barrier by which the brain is protected from metabolic changes in the body. BBB is located at endothelial cells of cerebral capillaries. Transport depends on: 1- Lipid solubility 2- Mediation by specific carriers

In hepatic encephalopathy, there is:

1) Increase in the permeability causing:

a- Brain edema
b- Exposure of brain to circulating neurotoxins

c- Loss of neurotransmitter
2) Alterations of specific carrier systems causing:

a- Increased transport of neutral amino acids

b- Decreased transport of glucose and basic amino acids

IV) Altered Brain Energy Metabolism:

Glucose In

is the most important cerebral energy fuel.

cases of cirrhosis with HE, the glucose metabolism is disturbed. in terminal stages of liver failure may be a consequence of impaired hepatic gluconeogenesis.

Hypoglycemia

V-Deficiency of essential substances

Cirrhosis leads to deficiency of certain vitamins, minerals and micronutrients

Zinc:
Zinc

is a cofactor in urea cycle

Found

in vesicles of glutaminergic presynaptic terminals affecting neurotransmission

Replacement

should be considered if the patient is deficient

VI) Decrease in Probiotics

Probiotics

are live micro-organisms beneficial to the host organism. In a malnourished patient like one who has a cirrhotic liver, the levels of these defensive bacteria strains (Bifidobacterium and Lactobacillus) decline. decline results deprives the patient of their several benefits (discussed later).

Their

1- Increased protein load -Upper GI hemorrhage -Ingestion of large protein meal 2- Decreased excretion of ammonia -Renal failure -Constipation 3- Electrolyte disturbance (e.g. hypokalaemia) 4- Dehydration 5- Paracentesis 6- Creation of portacaval shunts 7- Infection (SBP) 8- Drugs (e.g. sedatives) 9- Superimposed acute liver injury

CLINICAL MANIFESTATIONS
CLINICAL GRADE Grade 1 CLINICAL SIGNS Poor concentration, slurred speech, disordered sleep rhythm (day night reversal)

Grade 2

Drowsy but easily rousable, occasional aggressive behaviour, lethargic (flapping tremors on examination)
Marked confusion, sleepy but responds to pain and voice, gross disorientation ( Increased tone on examination) Unresponsive to voice, may or may not respond to painful stimuli, unconscious

Grade 3

Grade 4

1) Asterixes: -Characteristic but not pathgnomonic -Usually bilateral, but not synchronous -Unilateral asterixis - rare (with focal lesions of the thalamus and parietal cortex). 2) Hyperreflexia 3) Extensor plantar reflexes

FINDINGS ON EXAMINATION

4) Neck stiffness rare

5) Fetor hepaticus: Sweet musty odor in the breath usually present in hepatic encephalopathy. It does not correlate with the degree or duration of HE and is attributed to mercaptans which are formed in the intestine by action of bacteria and are normally degraded by the liver

FOUR CLINICAL VARIANTS 1-Sub-clinical H. Encephalopathy

It can be defined as a state of chronic liver disease with no clinical symptoms of brain dysfunction, but unsatisfactory performance on pyschometric tests. It has high prevalence (30 - 70%). Psychometric testing show that such patients perform well in tests of intellect, language, memory but poor in tests requiring visual, motor and constructional skills. These tests include Number Connection Test, Trail Test and Block Design Test.

2-Acute episodic (recurrent) form

It is an acute confusional syndrome with impaired mental state, neuromuscular abnormalities, fetor hepaticus, hyperventilation.
The

symptoms appear abruptly and develop over a period of hours to days, with oscillation of severity over time. is very characteristic

Asterixis

Relapses

are common.
well to treatment.

Responds

3-Fulminant liver failure:

The clinical features are essentially the same as those seen in patients with cirrhosis but
The

onset is generally abrupt. hepatic fetor is present at an early stage.

Marked

Neuropsychatric
Signs

picture is more aggressive.

of increased intracranial pressure (bradycardia, hypertension, dilated pupils, decerebrate posturing) may also be seen.

4-Chronic persistent encephalopathy:

A rare, irreversible encephalopathic syndrome Found in patients with extended collateral circulatory pathways Neuropsychiatric disorder dominates the picture Picture of liver disease may be equivocal The most frequent features are:

1- Progressive paraplegia 2- Damage to basal ganglia & cerebellar system. 3- Focal cerebral symptoms (Epilepsy, Dementia)

INVESTIGATIONS Preliminary:
Liver

MANAGEMENT

function tests Bl. Glucose Serum electrolyte Blood Urea nitrogen Serum Creatinine Arterial blood gases Cultures: Blood, urine, sputum Blood ethanol level Serum and urine drug screen

Suggestive of PSE:
Clinical Tests (Psychometric tests) CSF exam: Raised glutamine Arterial Ammonia:

-Raised but does not correlate with degree of encephalopathy Electroencephalography (EEG): -Slowing of the normal alpha waves with eventual development of delta waves -Sensitive means of detecting hepatic encephalopathy but not specific for hepatic encephalopathy. Evoked Potentials Other Monitoring:
C.T. Brain I C P Monitoring

Our treatment objectives should be

1. 2. 3.

4.

Normalization of neurological functions Elimination of precipitating factors Suppressing production of neurotoxins by bacteria in the bowel Monitoring and stabilization of cardiovascular, respiratory and metabolic parameters

I- Treatment based on ammonia hypothesis

II- Treatment based on false neurotransmitter

hypothesis
III- Treatment based on GABA hypothesis

IV- Adjuvant therapy

V- Probiotics

Ammoniogenic substrate

Intestinal ammonia production

Metabolic ammonia fixation

1-

Dietary protein 2- Enema

1- Antibiotics 2- Lactulose

1-Ornithine aspart 2-Benzoate & Phenylacetate

(i) Decrease Ammoniogenic Substrates

a) Reduce dietary protein :

Subclinical HE
Grade 1 or 2

40 gm/day
30 gm/day

Acute and severe attack (Grade 3 or 4)

-Withdraw all dietary protein

- Calories intake is maintained at 2000 cal /day or above either oral or IV

During Recovery:
Protein

intake is increased by 10 gm/day every 3rd day until normal intake (60-80 gm/d) protein restriction to 40-60 gm/day

In Chronic Cases:
Permanent

Vegetable Protein:
Tolerated Less

better than animal protein

ammoniogenic

More

laxative due to its high fiber content

b) Enema
In

acute and severe coma especially in highly constipated patients or in cases of massive GIT bleeding
volume used should be at least 1000 ml ml Lactulose with 700 ml water are efficacious

The 300

(ii) Inhibition of Intestinal Ammonia Production

a) Antibiotics:

Neomycin
Alters

gut flora (Decreases E-coli , a urease producing organism)

absorption of ammonia

Impairs

Inhibits uptake of glutamic acid by mucosal cells

1-2 gm/6h orally or rectally used for short-term therapy (oto- and nephrotoxicity)

Dose: Only

Metronidazole
Active

against bacteroides and other anerobes As effective as neomycin Dose: 200 mg/6hrs daily orally Should not be used long-term (CNS toxicity)

Vancomycin
Reduces

bacteroides Successfully used in patients with lactulose therapy failure Dose: 0.5 gm/6hrs daily orally

b) Lactulose -Non absorbable, synthetic disaccharide. Mode of action: 1-Exerts osmotic laxative effect 2-Promotes lactobacilli growth increased lactic, acetic, and formic acids decreased colonic pH inhibits growth of urease-producing bacteria especially E-coli 3-Traps luminal ammonia and its absorption. 4-Increases diffusion of ammonia from the mucosal blood into the gut -Dose: 30-50ml/8hrs orally

(iii) Stimulation of Metabolic Ammonia Fixation

a) Ornithine -keto glutarate or ornithine aspartate

-Ornithine is a substrate of urea synthesis

-Ornithine aspartate reinforces glutamine synthesis which serves to detoxify ammonia -They improves HE in cirrhotic patients b) Benzoate and Phenylacetate:

-Successfully used in treatment of congenital enzymatic defect of urea synthesis

II-Treatment based on the False Neurotransmitter Hypothesis

(i) Branched-Chain Amino Acids:
May

be of value for long term treatment of HE

Provide

safe and well-tolerated source of nutrition in patients with cirrhosis treatment leads to:

BCAAs

1- Improvement in nitrogen balance

2- Less protein catabolism 3- Enhanced protein synthesis

(ii) L-Dopa and Bromocriptine:

Decreased dopaminergic neurotransmission is a component of false neurotransmitter theory. a) Levo-dopa: A precursor of the neurotransmitters norepinephrine and dopamine b) Bromocriptine : -Specific dopamine receptor agonist

-Provides improvement in chronic portosystemic encephalopathy

III- Treatment Based on the GABA Hypothesis: Flumazenil

Benzodiazepine-receptor Induces

antagonist

transient improvement in 70% of patients with HE 0.2- 0.3 mg IV bolus, followed by 5mg/h as IV infusion

Dose:

IV-Adjuvant therapy
(i) Piracetam
Nootropic Improves

substance

typical electrical brain activities

(ii) L-Carnitine
Markedly

reduces hyperammonaemia

Improve

the clinical symptoms of HE in cirrhotic

patients

(iii) Zinc

V-Probiotics
They have multiple beneficial effects in treatment of minimal HE by: 1- Decreasing total ammonia in portal blood by: a) bacterial urease activity b) ammonia absorption by decreasing pH c) intestinal permeability d) improving nutritional status of gut epithelium 2- Decreasing inflammation and oxidative stress in hepatocyte hepatic clearance of ammonia 3- Decreasing uptake of other toxins

PROGNOSIS
The

presence of HE is a serious prognostic development in liver diseases. ALF, it defines the disease and the prognosis is generally very bad. cirrhosis, the 1 year survival rate after any episode of encephalopathy is only 40%.

In

In

Chronic or refractory hepatic encephalopathy is one of the main indications for liver transplantation.