Prepared by

HEPATIC ENCEPHALOPATHY Darien Liew Daojuin

8 May 2017
DEFINITION
Hepatic encephalopathy (porto-systemic encephalopathy) is a
spectrum of reversible neuropsychiatric abnormalities seen in patients
with cirrhosis after exclusion of neurologic and/or metabolic
abnormalities.
Some differentials to consider

Davidsons Principles and Practice of

Internal Medicine, pp. 941
CLASSIFICATION BASED ON DISEASE
STATE
Type A: Hepatic encephalopathy associated with acute liver failure
Type B: Hepatic encephalopathy associated with portal-systemic
bypass with no intrinsic hepatocellular disease
Type C: Hepatic encephalopathy associated with cirrhosis and portal
hypertension or portal-systemic shunts. In cases of chronic liver
disease, type C hepatic encephalopathy can be episodic or persistent.
PATHOPHYSIOLOGY
Hepatic encephalopathy is thought to be due to a disturbance of
brain function provoked by circulating neurotoxins that are normally
metabolised by the liver.
These neurotoxins are unknown, but are thought to be mainly
nitrogenous subtances produced in the gut, which is then metabolised
by the liver.
ASTROCYTE MORPHOLOGY AND
PHYSIOLOGY
Some investigators contend that hepatic encephalopathy is a disorder of
astrocyte function.
Astrocytes account for about one third of the cortical volume.
Function
1. regulation of the blood-brain barrier.
2. maintaining electrolyte homeostasis
3. providing nutrients and neurotransmitter precursors to neurons.
4. detoxification of a number of chemicals, including ammonia.
It is theorized that neurotoxic substances, including ammonia and
manganese, may gain entry into the brain in the setting of liver failure.
These neurotoxic substances may then contribute to morphologic changes in
astrocytes.
CHANGES IN ASTROCYTE MORPHOLOGY
AND PHYSIOLOGY
In necropsy studies, brains of cirrhotic patients exhibit Alzheimer type
II astrocytosis, characterized by swollen astrocytes with enlarged
nuclei and chromatin displaced to the perimeter of the cell.
Type II astrocytosis is hypothesized to be caused in part by the
detoxification of ammonia. Astrocytes, the only cells in the brain that
can metabolize ammonia, contain glutamine.
Ultimately, the development of advanced portosystemic
encephalopathy may be accompanied by cerebral edema, which may
contribute to neurological impairment. While cerebral edema has its
most obvious manifestations in the patient with
PATHOPHYSIOLOGY AMMONIA
HYPOTHESIS
Ammonia is produced in the gastrointestinal tract by bacterial
degradation of amines, amino acids, purines, and urea. Enterocytes
also convert glutamine to glutamate and ammonia by the activity of
glutaminase.

Hyperammonemia
1. Decrease in functioning hepatocytes, resulting in fewer
opportunities for ammonia to be detoxified.
2. Portosystemic shunting may divert ammonia-containing blood away
from the liver to the systemic circulation.
PATHOPHYSIOLOGY GABA HYPOTHESIS
GABA is a neuroinhibitory substance produced in the gastrointestinal
tract. It was believed that there were increased levels of GABA and
endogenous benzodiazepines in plasma.
These chemicals would then cross an extrapermeable blood-brain
barrier, binding to a supersensitive neuronal GABA receptor complex
permitted the influx of chloride ions into the postsynaptic neurons,
leading to the generation of an inhibitory postsynaptic potential.
However, experimental work has demonstrated that there is NO
CHANGE in brain GABA or benzodiazepine levels.
AMMONIA AND GABA
In experimental models, neurotoxins, like ammonia and manganese,
increase the production of the peripheral-type benzodiazepine
receptor (PTBR) in astrocytes.
PTBR, in turn, stimulates the conversion of cholesterol to pregnenolone
to neurosteroids.
Neurosteroids are then released from the astrocytes. They are
capable of binding to their receptor within the neuronal GABA
receptor complex and can increase inhibitory neurotransmission.
GRADING
The degree of encephalopathy can be graded from 1 to 4, depending
on the features and this is useful in assessing response to therapy.

Grading of the symptoms of hepatic encephalopathy is performed

according to the West Haven classification system.

Two broad categories of hepatic encephalopathy are covert (CHE) and

overt (OHE) hepatic encephalopathy.

CHE Grade 0 to Grade 1 (symptoms not obvious)

OHE Grade 2 to Grade 4 (symptoms obvious)
GRADE 0
Minimal hepatic encephalopathy (also known as Covert Hepatic
Encephalopathy) and previously known subclinical hepatic
encephalopathy);
Lack of detectable changes in personality or behavior;
Minimal changes in memory, concentration, intellectual function, and
coordination;
Asterixis is absent.
GRADE 1
Trivial lack of awareness;
shortened attention span;
impaired addition or subtraction;
hypersomnia, insomnia, or inversion of sleep pattern;
euphoria, depression, or irritability;
mild confusion;
slowing of ability to perform mental tasks
GRADE 2
Obvious asterixis
Disorientation
Lethargy or apathy;
Inappropriate behavior;
Slurred speech;
Drowsiness, lethargy,
Gross deficits in ability to perform mental tasks,
Obvious personality changes, inappropriate behavior, and
Intermittent disorientation, usually regarding time
GRADE 3
Somnolent but can be aroused;
Unable to perform mental tasks;
Disorientation about time and place;
Marked confusion;
Amnesia;
Occasional fits of rage;
Incomprehensible speech
GRADE 4
Coma with or without response to painful stimuli
CLINICAL PRESENTATION
Hepatic encephalopathy is characterized by
personality changes,
intellectual impairment, and
a depressed level of consciousness.
PHYSICAL EXAMINATION
Flapping tremor of the extremities is also observed in patients with
uremia, pulmonary insufficiency, and barbiturate toxicity.
Some patients with hepatic encephalopathy show evidence of fetor
hepaticus, a sweet musty aroma of the breath believed to be
secondary to the exhalation of mercaptans (thiols described as a
smell of natural gas).
Portosystemic Shunting
Extrapyramidal symtoms tremor, bradykinesia, cog-wheel rigidity, and shuffling
gait portosystemic shunting; may or may not be associated with hyperammonemia
Hepatic myelopathy lower extremity weakness, difficulty walking, spastic
paraparesis, and hyperreflexia.
INVESTIGATION
Blood ammonia level
EEG changes - associated with hepatic encephalopathy are high-
amplitude low-frequency waves and triphasic waves.
CT and MRI to rule of intracranial lesions
 PRECIPITATING FACTOR
Infection Infection may predispose to impaired renal function and to increased tissue
catabolism, both of which increase blood ammonia levels.
Renal Failure Decreased clearance of urea, ammonia, and other nitrogenous compounds.
GI Bleed The presence of blood in the upper gastrointestinal tract results in increased
ammonia and nitrogen absorption from the gut. Bleeding may predispose
to kidney hypoperfusion and impaired renal function. Blood transfusions
may result in mild hemolysis, with resulting elevated blood ammonia levels.
Constipation Constipation increases intestinal production and absorption of ammonia.
Drugs Drugs acting on CNS: opiates, benzodiazepines, antidepressants, and
antipsychotic agents

Diuretics: Decreased serum potassium levels and alkalosis may facilitate the
conversion of NH4+ to NH3.
Dietary Protein Infrequent cause of hepatic encephalopathy
Overload
TIPS Recent placement of a transjugular intra-hepaticportosystemic shunt (TIPS)
MANAGEMENT
Exclude and treat non-hepatic causes of altered mental function.
Main treatment is to decrease intestinal ammonia production
1. Diet
2. Cathartics Lactulose
Inhibit intestinal ammonia production
The conversion of lactulose to lactic acid and acetic acid results in acidification of
the gut lumen
Favors conversion of ammonia (NH3) to ammonium (NH4+)

3. Antibiotics - decrease the colonic concentration of ammoniagenic

bacteria Rifaximin
MANAGEMENT
Treatments to Increase Ammonia Clearance
1. L-ornithine L-aspartate (LOLA) results in loss of ammonia
2. Zinc Increase the urea metabolism
3. Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate,
glycerol phenylbutyrate
4. L-carnitine
REFERENCES
1. http://emedicine.medscape.com/article/182208-overview
2. http://emedicine.medscape.com/article/186101-overview#a2
3. Davidsons Principles and Practice of Medicine, 22nd Edition,
pp941-942