HEPATIC ENCEPHALOPATHY: The Biochemical Basis

DR. PRABHASH BHAVSAR

Hippocrates described a patient with fulminant hepatitis- who ‘barked like a dog, could not be held and said things which could not be comprehended’.

What Is HE ?

• It’s a Neuropsychiatric disorder occurring due to liver

dysfunction. It is a reversible condition.

• Manifests by broad spectrum of neuropsychiatric disturbances-

• In the severe form it can lead to coma and death.

Cognitive Behavioral LocomotivePsychomotorEmotional

Etiology….• The root cause is – liver failure

• Liver failure alone to cause HE is rare. If occurs, it is mostly in acute liver failure.

• But in most of the chronic liver failure HE is caused by an variety of precipitating factors like-

Excessive nitrogen load- protein rich diet, GI bleeding, renal failure, constipation.

Electrolyte disturbances

Drugs- sedatives, alcohol,

Infection- UTI, bacterial peritonitis etc.

Pathogenesis…

- The pathogenesis of HE is complex.

- Basic cause is diminished detoxification of toxic compounds by liver.

- In both acute and chronic liver disease, the basic cause is same but mechanism is somewhat different.

•

Major toxins of HE

• Ammonia

• Mercaptans

• FFA

• Phenols

• Manganese

These all are believed to act in synergism.

Effect Of Ammonia On BBB

Ammonia disrupts the tight junctions of endothelium and causes malfunctioning BBB.

Increased permeability of various toxins into the brain.

Ammonia And Cerebral Edema

ASTROCYTES FORMS THE 1/3 OF TOTAL VOLUME OF BRAIN.

CEREBRAL EDEMA

INCREASED ICT

CEREBRAL HERNIATION

ACUTE COMA AND DEATH

* CELL TRIES TO COUNTERACT THIS OSMOTIC EFFECT BY RELEASING OSMOLYTES (MYOINOSITOL & TAURINE) FROM INSIDE THE CELL.

Ammonia And Neurosteroid

Ammonia And Excitatory NTransmission

• Exposure of astrocyte to high ammonia levels leads to release of glutamate.

• Glutamate contributes to increased neuronal activation, which may be the cause of agitation and seizure in HE.

Ammonia And Generation Of False NTs

• Failing liver cannot metabolize aromatic amino acids but

• Branched chain amino acids continue to metabolize normally in muscles.

• Causing increased AAA/BCAA ratio.

Increased influx of AAA in the astrocytes

generation of false neurotransmitters like phenylethanolamine and octapamine.

Impairment of GABAergic, Serotonergic and Glutamatergic NTransmission

Manifesting as altered sleep cycle, irritability and other cognitiveand psychomotor dysfunction

Ammonia And Brain Energy Metabolism• Brain comprises 2% of the body mass but utilizes 20% of

total energy.

• Ammonia imparts its toxic effect on brain by reducing its energy production causing lethargy, somnolence and confusion.

NH3 generates ROS and RNS in

mitochondrion

increased permeability of Mitochondrial

membrane

loss of ionic gradient

decreased ATP generation.

Effect Of Manganese

• Manganese which escape detoxification in hepatocytes accumulates in basal ganglia.

• Hyperintense signal on MRI of brain are believed to be due to manganese deposition.

• Disturbed basal ganglia functions leads to extrapyramidal symptoms like tremor, rigidity, and akinesia.

Effect Of Secondary Infections

• Secondary infections causes SIRS to set in.

• SIRS generates TNF.

• TNF stimulates astrocytes to secrete IL-1 & IL-6, which further increases BBB permeability.

Small Intestinal Bacterial Overgrowth

• It is associated with methionine degradation and formation of mercaptans.

• Excessive production of mercaptans and their absorption into blood also plays synergistic role in hepatic encephalopathy, although exact causes are not known.

• Mercaptans excretion into breath causes the foul smell, k/a foetor hepaticus.

Role Of Ammonia Measurement In Mx

• Serial monitoring of ammonia level is not advisable-

• Ammonia level do not correlate with severity of encephalopathy

• However normal level of ammonia can be used to rule out the diagnosis of hepatic encephalopathy.

• Clinical examination and psychometric analysis is preferred over ammonia estimation.

Clinical Features

• Symptoms can be graded according to west haven classification system:

Grade C/F

0 Minimal hepatic encephalopathy, lack of detectable change in memory, personality. Minimal change in cognitive and motor functions. Asterixis absent.

I Trivial lack of awareness, short attention span, altered sleep pattern, mild confusion

II Lethargy, inappropriate behavior, slurred speech, asterixis present. Disorientation wrt Time.

III Somnolent, can be aroused. Disoriented wrt to time and place. Marked confusion, amnesia , seizures and incomprehensible speech

IV Coma with or without response to painful stimuli

Management

treatment to decrease intestinal ammonia production:

• protein restricted diet-recommended or not recommended ??????

• cathartics:non absorbable disaccharides- lactulose and lactitol

• antibiotics:neomycin and rifaximine

Treatment to increase ammonia clearance:

• L-ornithine L-aspartate (LOLA)

• Zinc- increases activity of ornithine trancarbamoylase

• Sodium benzoate (glycine to hippurate), sodium phenylbutyrate (glutamine to phenylacetylglutamine)

• L- carnitine