A syndrome of altered consciousness,
altered neuromuscular activity in a patient with hepatocellular failure
or portosystemic shunting.
The mechanism and cause of hepatic encephalopathy is not known.
However, several factors are believed to be important in the
pathogenesis of this disease. The most important two factors are
liver cell failure and
portal hypertension. This
results in intrahepatic and extrahepatic shunting of portal venous
blood into the systemic circulation so that the liver is largely
bypassed. As a result of these processes, various toxic substances
absorbed from the intestine are not detoxified by the liver and lead
to metabolic abnormalities in the central nervous system (CNS).
Blood levels of ammonia is commonly raised in many patients with
hepatic encephalopathy. Furthermore, ammonia levels decrease on
recovery from encephalopathy. Hence, ammonia has long been regarded as
the main contributing factor.
Other compounds and metabolites that may contribute to the
development of encephalopathy include mercaptans (derived from
intestinal metabolism of methionine), short-chain fatty acids, and
phenol. False neurochemical transmitters (e.g., octopamine), resulting
in part from alterations in plasma levels of aromatic and
branched-chain amino acids, may also play a role.
An increase in the permeability of the blood-brain barrier to some
of these substances may be an additional factor.
Several observations suggest that excessive concentrations of g-aminobutyric
acid (GABA), an inhibitory neurotransmitter, in the CNS are important
in the reduced levels of consciousness seen in hepatic encephalopathy.
Increased CNS GABA may reflect failure of the liver to extract
precursor amino acids efficiently or to remove GABA produced in the
intestine. In support of this, there is also evidence to suggest that
endogenous benzodiazepines, which act through the GABA receptor, may
contribute to the development of hepatic encephalopathy.
Manganese deposits in the basal ganglia
Finally, the observation of hyperintensity in the basal ganglia by
magnetic resonance imaging in cirrhotic patients suggests that
excessive manganese deposition may also contribute to the pathogenesis
of hepatic encephalopathy.
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Symptoms of encephalopathy
Encephalopathy may be acute and reversible or chronic and
progressive. In severe cases, irreversible coma and death may occur.
Acute episodes may recur with variable frequency.
The complex neuropsychiatric syndrome is characterized by
disturbances in consciousness and behavior, personality changes,
fluctuating neurologic signs, asterixis or "flapping tremor," and
distinctive electroencephalographic changes.
In the patient with otherwise stable cirrhosis, hepatic
encephalopathy often follows a clearly identifiable precipitating
bleeding: which leads to an increase in the production of
ammonia and other nitrogenous substances, which are then absorbed.
- increased dietary protein may precipitate encephalopathy as a
result of increased production of nitrogenous substances by colonic
- Electrolyte disturbances, particularly hypokalemic alkalosis
secondary to overzealous use of diuretics, vigorous paracentesis, or
vomiting, may precipitate hepatic encephalopathy. Systemic alkalosis
causes an increase in the amount of nonionic ammonia (NH3) relative
to ammonium ions NH4+). Only nonionic (uncharged) ammonia readily
crosses the blood-brain barrier and accumulates in the CNS.
Hypokalemia also directly stimulates renal ammonia production.
- Injudicious use of CNS-depressing drugs (e.g., barbiturates,
benzodiazepines) and acute infection may trigger or aggravate
hepatic encephalopathy, although the mechanisms involved are not
- Other potential precipitating factors include superimposed acute
viral hepatitis, alcoholic hepatitis, extrahepatic bile duct
obstruction, constipation, surgery, and other coincidental medical
The diagnosis of hepatic encephalopathy should be considered when
four major factors are present:
- Acute or chronic hepatocellular disease and/or extensive
portal-systemic collateral shunts
- Disturbances of awareness and mentation, which may progress from
forgetfulness and confusion to stupor and finally coma;
- Shifting combinations of neurologic signs, including asterixis
(flapping tremors), rigidity, hyperreflexia, extensor plantar signs,
and rarely, seizures. Fetor hepaticus, a unique musty odor of the
breath and urine believed to be due to mercaptans, may be noted in
patients with varying stages of hepatic encephalopathy.
- A characteristic (but nonspecific) symmetric, high-voltage,
triphasic slow-wave (2 to 5 per second) pattern on the
The diagnosis of hepatic encephalopathy is usually one of
Early recognition and prompt treatment of hepatic encephalopathy
are essential. Patients with acute, severe hepatic encephalopathy
(stage IV) require the usual supportive measures for the comatose
patient. Specific treatment of hepatic encephalopathy is aimed at (1)
elimination or treatment of precipitating factors and (2) lowering of
blood ammonia (and other toxin) levels by decreasing the absorption of
protein and nitrogenous products from the intestine.
In the setting of acute gastrointestinal bleeding, blood in the
bowel should be promptly evacuated with laxatives (and enemas if
necessary) in order to reduce the nitrogen load. Protein should be
excluded from the diet, and constipation should be avoided.
Intestinal ammonia production by bacteria can also be decreased by
oral administration of a "nonabsorbable" antibiotic such as neomycin.
Equal benefits may be achieved with broad-spectrum antibiotics such as
The use of agents such as levodopa, bromocriptine, keto analogues
of essential amino acids, and intravenous amino acid formulations rich
in branched-chain amino acids in the treatment of acute hepatic
encephalopathy remains of unproven benefit.
Flumazenil, a short-acting benzodiazepine antagonist, may have a
role in management of hepatic encephalopathy precipitated by use of
benzodiazepines, if there is a need for urgent therapy.
Hemoperfusion to remove toxic substances and therapy directed
primarily toward coincident cerebral edema in acute encephalopathy are
also of unproven value. The efficacy of extracorporeal liver assist
devices employing hepatocytes of porcine or human origin to bridge
patients to recovery or transplantation is as yet unproven but is
currently being studied.
Chronic encephalopathy may be effectively controlled by
administration of lactulose. Management of patients with chronic
encephalopathy should include dietary protein restriction (usually to
60 g/d) in combination with low doses of lactulose or neomycin.
Nephrotoxicity or ototoxicity may be limiting in prolonged usage of
neomycin. There are suggestions that vegetable protein may be
preferable to animal protein.