ENCHEPALOPATHY

Encephalopathy is a term that means brain disease, damage, or malfunction.

Encephalopathy can present a very broad spectrum of symptoms that range from
mild, such as some memory loss or subtle personality changes, to severe, such
as dementia, seizures,coma, or death. In general, encephalopathy is manifested
by an altered mental state that is sometimes accompanied by physical
manifestations (for example, poor coordination of limb movements).

The term encephalopathy is very broad and in most cases, is preceded by

various terms that describe the reason, cause, or special conditions of the patient
that leads to brain malfunction. For example, anoxic encephalopathy means
brain damage due to lack ofoxygen, and hepatic encephalopathymeans brain
malfunction due to liver disease. Additionally, some other terms either describe
body conditions or syndromes that lead to a specific set of brain malfunctions.
Examples of these are metabolic encephalopathy and Wernicke's
encephalopathy (Wernicke's syndrome). There are over 150 different terms that
modify or precede "encephalopathy" in the medical literature.

What causes encephalopathy?

The causes of encephalopathy are both numerous and varied.

Some examples of causes of encephalopathy include:

 infections (bacteria, viruses, parasites, or prions),

 anoxia (lack of oxygen to the brain),

 alcohol consumption,

 liver failure,

 kidney failure,
  metabolic diseases,

 brain tumors,

 many types of toxic chemicals,

 alterations in pressure in the brain, and

 poor nutrition.

These examples do not cover all of the potential causes of encephalopathy but
are listed to demonstrate the wide range of causes.

Although numerous causes of encephalopathy are known, the majority of cases

arise from several major categories:

1. infection,

2. liver damage,

3. anoxia, and

4. kidney failure.

What are the symptoms of encephalopathy?

Despite the numerous and varied causes of encephalopathy, at least one
symptom present in all cases is an altered mental state. The altered mental
state may be subtle and develop slowly over years (for example, in hepatitis the
decreased ability to draw simple designs, termed apraxia) or be profoundly
obvious and develop rapidly (for example, brain anoxia leading to coma or death
in a few minutes). Often, symptoms of altered mental status can present as
inattentiveness, poor judgment, or poor coordination of movements.
Other symptoms that may occur include:

 lethargy,
  dementia,

 seizures,

 tremors,

 muscle twitching, and

 coma.

Often the severity and type of symptoms are related to the severity and cause of
the brain disease or damage. For example, alcohol-induced liver damage
(alcoholic cirrhosis) can result in involuntary hand tremors (asterixis), while
severe anoxia (lack of oxygen) may result in coma with no movement.

How is encephalopathy diagnosed?

The diagnosis of encephalopathy is usually done by clinical tests done during the
physical examination (mental status tests, memory tests, coordination tests) that
document an altered mental state. With most cases, findings on clinical tests
either diagnose or presumptively diagnose encephalopathy. Usually, the
diagnosis occurs when the altered mental state accompanies another primary
diagnosis such as chronic liver disease, kidney failure, anoxia, or many other
diagnoses.

Consequently, physicians may utilize several different tests at the same time to
diagnose both the primary condition (the cause of encephalopathy) and the
encephalopathy itself. This approach to diagnosis is done by most physicians,
because many doctors view encephalopathy as a complication that occurs
because of a primary underlying health problem. The most frequently utilized
tests are listed below with some of the major primary causes the tests may help
diagnose:

 Complete blood count or CBC (infections, loss of blood)

  Blood pressure (high or low blood pressure)

 Metabolic tests (blood levels of electrolytes, glucose, lactate, ammonia,

oxygen, and liver enzyme levels)

 Drugs or toxin levels (alcohol, cocaine, amphetamines, and many others)

 Blood and body fluid cultures and analyses (infections of many types)

 Creatinine (kidney function)

 CT and MRI scans (brain swelling, anatomical abnormalities, infections)

 Doppler ultrasound (abnormal blood flow to tissues, abscesses)

 Encephalogram or EEG (brain damage, abnormal brain wave patterns)

 Auto-antibody analysis (dementia caused by antibodies that destroy

neurons)

This list is not exhaustive, and not all of the above tests need to be done to reach
a diagnosis; specific testing is usually ordered by the treating physician according
to the symptoms and history of the patient.

Treatment of encephalopathy varies with the primary cause of the symptoms;

consequently, not all cases of encephalopathy are treated the same. The best
treatments are designed by the treating physician once the patient's primary
diagnosis is made. Treatments are highly variable because the causes are so
different.

Examples can show how different "encephalopathy treatment" may change

according to the cause:

 Anoxia short-term (usually less than two minutes): oxygen therapy

 Anoxia long- term: rehabilitation
 Alcohol toxicity short- term: IV fluids or no therapy
  Alcohol abuse over the long-term (cirrhosis or chronic liver failure):oral
lactulose, low-protein diet, antibiotics
 Uremic encephalopathy (due to kidney failure): correct the
underlying physiologic cause, dialysis, kidney transplant
 Diabetic encephalopathy: glucose to treat hypoglycemia, removal of blood
glucose to treat hyperglycemia
 Hypo- or hypertensive encephalopathy: raise (for hypotensive) or reduce
(for hypertensive) blood pressure
The key to treatment of any encephalopathy is to understand the basic cause
and thus design a treatment scheme to reduce or eliminate the cause(s). There
is one type of encephalopathy that is difficult or impossible to treat; it is static
encephalopathy (an altered mental state or brain damage that is permanent).
The best that can be done with static encephalopathy is, if possible, to prevent
further damage and implement rehabilitation to allow the individual to perform at
their highest possible functional level.

What are the complications of encephalopathy?

Complications of encephalopathy vary from none to profound mental
impairments that lead to death. The complications can be similar in some cases.
Also, many investigators consider encephalopathy to be a complication that
arises from a primary health problem or primary diagnosis.

Complications depend on the primary cause of encephalopathy and can be

illustrated by citing a few examples from the wide variety of causes:

 Hepatic (liver) encephalopathy (brain swelling with herniation, coma, death)

 Metabolic encephalopathy (irritability, lethargy, depression, tremors;

occasionally coma or death )

 Anoxic encephalopathy (wide range of complications, from none in short-

term anoxia to personality changes, severe brain damage to death in long-
term anoxic events)
  Uremic encephalopathy (lethargy, hallucinations, stupor, muscle twitching,
seizures, death)

 Hashimoto's encephalopathy (confusion, heat intolerance, dementia)

 Wernicke's encephalopathy (mental confusion, memory loss, decreased

ability to move eyes)

 Bovine spongiform encephalopathy or "Mad Cow disease" (ataxia, dementia

and myoclonus or muscle twitching without any rhythm or pattern)

 Shigella encephalopathy (headache, stiff neck, delirium, seizures, coma)

 Infectious causes of pediatric encephalopathy (irritability, poor

feeding,hypotonia or floppy baby syndrome, seizures, death)

The best way to understand potential complications is to discuss these with the
diagnosing doctor who can discuss the possible problems associated with the
specific cause(s) of the type of encephalopathy.

What is the prognosis (outlook) for encephalopathy?

The prognosis for a patient with encephalopathy depends on the initial causes
and, in general, the length of time it takes to reverse, stop, or inhibit those
causes. Consequently, the prognosis varies from patient to patient and ranges
from complete recovery to a poor prognosis that often leads to permanent brain
damage or death. One good example of this highly variable prognosis are
patients that get encephalopathy from hypoglycemia. If patients with
hypoglycemia are given glucose at the first signs of encephalopathy (for
example, irritability, mild confusion), most patients recover completely. Delays in
correcting hypoglycemia (hours to days) may lead to seizures or coma which
may be halted by treatment with complete or partial recovery (minimal permanent
brain damage). A long delay or multiple delays in treatment can lead to a poor
prognosis with extensive brain damage, coma, or death.
Although the symptoms and time frame vary widely from patient to patient and
according to the initial causes of encephalopathy (see above sections for
examples of causes), the prognosis of each case usually follows the pattern
described in the hypoglycemic example above and depends upon the extent and
rapidity with which the underlying cause is treated. The doctor or team of doctors
treating the underlying cause of encephalopathy can offer the best information on
the individual's prognosis.

Can encephalopathy be prevented?

Many cases of encephalopathy can be prevented. The key to prevention is to
stop or limit the chance of developing any of the multitudes of causes of
encephalopathy. If encephalopathy develops, the quicker the underlying cause is
treated, the more likely that severe encephalopathy can be prevented.

Examples of prevention (and situations to avoid) are listed below:

 Diabetic encephalopathy: take daily glucose checks and always check

that insulin administration is the correct dosage.
 Hepatic encephalopathy: avoid alcohol intoxication, drug overdoses, and
IV injections of illegal drugs.
 Anoxic encephalopathy: prevent choking on food, avoid risky behavior
that could lead to head and neck trauma, avoid exposure to carbon
monoxide.
 Hypertensive encephalopathy: monitor blood pressure;
takeantihypertensive medication as directed and do not stop medications or
change medication without consulting your doctor.
 Infectious encephalopathy: avoid physical contact with individuals known
to be infected with organisms that may cause encephalopathy such as N.
meningitidis or Shigella.
 Uremic encephalopathy: do not skip or avoid scheduled dialysis, take all
medications as directed and have frequent assessments of mental status.
Methods for prevention of encephalopathy are about as numerous as the
underlying causes; however, some cases of encephalopathy may not be
preventable (for example, congenital and accidental traumatic encephalopathy).

Encephalopathy At A Glance

 Encephalopathy is a general term that means brain disease, damage, or

malfunction.

 The major symptom of encephalopathy is an altered mental state.

 The causes of encephalopathy are numerous and varied; they include

infections, anoxia, metabolic problems, toxins, drugs, physiologic changes,
trauma, and other causes.

 Encephalopathy is often considered a complication of a primary problem

such as alcoholic cirrhosis, kidney failure, or anoxia.

 Early treatment of many types of encephalopathy can eliminate, reduce, or

halt the symptoms of encephalopathy.

 Often, cases of encephalopathy can be prevented by avoiding the many

primary causes.

For more information on types of encephalopathy

 Wernicke Encephalopathy

 Hepatic Encephalopathy

 Hypertensive Encephalopathy

 Mad Cow Disease

 Kidney Failure

 Confusional States and Acute Memory Disorders

  EEG in Dementia and Encephalopathy

Treatment of Hepatic Encephalopathy

Stephen M. Riordan, M.D., and Roger Williams, M.D.

N Engl J Med 1997; 337:473-479August 14, 1997

Article

References

Citing Articles (121)

Letters

Hepatic encephalopathy is a complex neuropsychiatric syndrome that may occur in such

diverse clinical situations as inherited errors of the urea cycle, acute or chronic liver
disease, and spontaneous or iatrogenic portosystemic venous shunting, including that
following procedures to establish a transjugular intrahepatic portosystemic shunt. The
clinical manifestations of this syndrome range from subtle abnormalities detectable only
by psychometric testing to deep coma. Several grading systems have been proposed; one
based on clinical and electroencephalographic abnormalities is shown in Table 1Table 1

A Grading System for Hepatic Encephalopathy..1 Hepatic

encephalopathy may be present in 50 to 70 percent of all patients with cirrhosis,
including those with abnormalities demonstrable only by psychometric testing.2,3 Most
manifestations of hepatic encephalopathy are reversible with medical treatment. Some
patients with hepatic encephalopathy have progressive, debilitating syndromes, such as
dementia, spastic paraparesis, cerebellar degeneration, and extrapyramidal movement
disorders, associated with structural abnormalities of the central nervous system.1,4
These syndromes were formerly regarded as irreversible, but there may be gradual
improvement after successful orthotopic liver transplantation.5

The accumulation of unmetabolized ammonia, predominantly as a result of poor hepatic

function and portosystemic shunting, has traditionally been considered to have an
important role in the pathogenesis of hepatic encephalopathy. In addition, a number of
other possible mechanisms have recently been proposed, including production of false
neurotransmitters, activation of central γ-aminobutyric acid–benzodiazepine receptors by
ligands of endogenous origin, altered cerebral metabolism, and disturbed activity of
Na+/K+–ATPase. Decreased activity of urea-cycle enzymes due to zinc deficiency and
the deposition of manganese in the basal ganglia may also contribute to hepatic
encephalopathy.1,6-11 These pathogenetic mechanisms are not necessarily exclusive.
Most treatment measures of proved value are based on the ammonia hypothesis.

Approach to Management

None of the manifestations of hepatic encephalopathy are specific to this disorder, and it

is essential to exclude alternative diagnoses (Table 2Table 2 Differential Diagnosis

of Hepatic Encephalopathy.).12 Although the level of ammonia in the arterial blood tends
to be elevated in patients with more advanced hepatocellular dysfunction, especially
when substantial portosystemic shunting is present, it is only poorly correlated with the
grade of hepatic encephalopathy.13 Consequently, this measurement is of little clinical
value in establishing the diagnosis or following the progress of patients with hepatic
encephalopathy. Conversely, practical bedside tests, such as the number-connection and
other trail-making tests,14,15 are easily administered and, in this era of cost-effective
medicine, provide useful information, especially in patients with subclinical hepatic
encephalopathy that would otherwise be overlooked.

The treatment of hepatic encephalopathy in patients with the rare condition of acute liver
failure and in those with the much more common chronic liver disease should be
considered separately. Hepatic encephalopathy in patients with acute liver failure is rapid
in onset and progression and is almost always complicated by cerebral edema in the later
stages. It is of paramount importance to consider orthotopic liver transplantation for such
patients on the basis of the prognosis.16,17 Patients with acute liver failure and grade 3
or 4 hepatic encephalopathy should undergo elective ventilation, sedation with fentanyl,
and paralysis with atracurium both to protect the airway and to facilitate the management
of cerebral edema by preventing surges in intracranial pressure related to psychomotor
agitation. Monitoring of extradural pressure is of value in these patients but carries some
risk.18 Mannitol given by repeated bolus injections (0.5 g per kilogram of body weight
over a period of 10 minutes) remains the main pharmacologic treatment of cerebral
edema in this setting. Acetylcysteine given by continuous infusion to patients with grade
4 hepatic encephalopathy has been reported to improve the cerebral blood flow and the
cerebral metabolic rate for oxygen. Epoprostenol (prostaglandin I2) also improves the
cerebral metabolic rate for oxygen.19 Hypoglycemia can be a lethal complication of
acute liver failure, and monitoring of blood glucose at least every four hours is
mandatory.

The further treatment of patients with acute liver failure is beyond the scope of this
review, which focuses on the treatment options for patients with hepatic encephalopathy
as a complication of chronic liver disease, in whom cerebral edema is much less frequent.
Most episodes of hepatic encephalopathy in patients with chronic liver disease are due to
a clinically apparent precipitating event or to the spontaneous development of
portosystemic shunting (Table 3Table 3 Factors Precipitating Hepatic
Encephalopathy in Patients with Chronic Liver Disease.). Several factors may be
operative in a given patient at the same time. For example, septicemia or bacterial
peritonitis, typically with gram-negative, colonic-type flora, develops within 48 hours in
about half of patients with Child–Pugh class C cirrhosis who have an acute
gastrointestinal hemorrhage.20 Hypokalemia and systemic alkalosis, complicating the use
of diuretic agents to treat the ascites, in turn lead to increased renal production of
ammonia and increased diffusion of ammonia across the blood–brain barrier,
respectively.21 Older age is generally considered to be an important influence on the
prevalence and severity of hepatic encephalopathy complicating surgical creation of a
portosystemic shunt.22 The number of patients referred for surgical creation of a shunt
has fallen with the advent of the transjugular intrahepatic portosystemic shunt, the
establishment of which has become a standard procedure in the treatment of recurrent
variceal hemorrhage in many centers. This procedure is associated with a 25 percent
overall incidence of chronic hepatic encephalopathy,23 which is more likely to occur in
women, patients over the age of 60 years, and patients with marked
hypoalbuminemia.23,24 Every effort should be made to identify the precipitating factor
and, if possible, correct it.

Other therapeutic measures are described below according to the various hypotheses
relating to the pathogenesis of hepatic encephalopathy. The use of these measures is not
in every case currently supported by the results of controlled clinical trials (Table 4Table

4 Results of Controlled Trials of Treatments for Hepatic Encephalopathy as a

Complication of Chronic Liver Disease.). Hepatic encephalopathy as a complication of
spontaneous or surgically created portosystemic anastomoses or transjugular intrahepatic
portosystemic shunts is usually successfully managed along conventional lines.
Transhepatic embolization or surgical ligation of portosystemic shunts is occasionally of
benefit when hepatic encephalopathy is refractory to other treatments.25,26 Refractory
hepatic encephalopathy as a complication of transjugular intrahepatic portosystemic
shunts can be successfully managed by implanting a reducing stent.27

Reduction of Production and Absorption of Ammonia

The intestinal production of ammonia can be reduced by restricting the intake of dietary
protein and inhibiting urease-producing colonic bacteria. Although the restriction of
dietary protein has long been recognized as an effective treatment,12,28 patients with
cirrhosis often require minimal daily protein intakes of 0.8 to 1.0 g per kilogram to
maintain nitrogen balance.29 Long-term restriction to values below this range should be
avoided if possible. After dietary protein has been initially limited to 20 g a day, the
intake should be increased by 10 g every three to five days until the patient's protein
tolerance has been established.

Supplementation with vegetable, rather than animal, protein may be advantageous in

patients whose total daily dietary protein tolerance is less than 1 g per kilogram, since
controlled studies have suggested that supplementation with vegetable protein may result
in a substantial improvement in nitrogen balance without precipitating or worsening
hepatic encephalopathy.30 This beneficial effect may be due to the higher content of fiber
in a vegetable diet than in an animal diet with an equal amount of nitrogen. The fiber
increases the rate of transit of food through the intestine and lowers the pH of the colonic
lumen as a result of its fermentation by colonic bacteria.29 Most patients will accept a
diet containing 30 to 40 g of vegetable protein, although restriction of sodium will render
such a diet unpalatable.

The physiologic shedding of gut epithelial cells provides additional luminal protein to be
metabolized to ammonia by bacteria. Both dietary and endogenous ammoniagenic
substrates are removed from the intestinal lumen by the osmotic cathartic action of
nonabsorbable disaccharides such as lactulose (β-galactosidofructose) and lactitol (β-
galactosidosorbitol). These compounds are currently the main therapeutic agents for
chronic hepatic encephalopathy. The efficacy of oral lactulose for the treatment of
hepatic encephalopathy has been established in controlled trials.31 The daily dose of
lactulose should be titrated to result in two to four soft, acidic (pH less than 6) stools
daily. For most patients the daily dose is between 30 and 60 g.

As well as having a cathartic effect, lactulose lowers the colonic pH as a result of the
production of organic acids by bacterial fermentation. The decrease in pH creates an
environment that is hostile to the survival of urease-producing intestinal bacteria and may
promote the growth of non–urease-producing lactobacilli, resulting in reduced production
of ammonia in the colonic lumen. In addition, acidification of the colonic secretions not
only reduces the absorption of ammonia by nonionic diffusion, but also results in the net
movement of ammonia from the blood into the bowel lumen.21 Enemas containing
lactulose or other carbohydrates may be used if oral or nasogastric administration of the
carbohydrate is impossible. Conversely, water enemas are ineffective, suggesting that
acidification of the colonic lumen, rather than bowel cleansing alone, is responsible for
the therapeutic effect.32

Although it is not licensed for use in the United States at present, oral lactitol at a dose of
30 to 45 g daily is as effective as lactulose for treating hepatic encephalopathy and has
the advantage of being more palatable and associated with a lower incidence of side
effects, such as flatulence.33,34 Oral lactose at a dose of 100 g daily is another proved
alternative in lactase-deficient patients.35

Antibiotics with activity against urease-producing bacteria, such as neomycin or

metronidazole, also reduce the production of intestinal ammonia and have proved
value.31,36,37 The efficacy of neomycin (6 g daily) is similar to that of lactulose.37 A
small percentage of this drug is absorbed from the gastrointestinal tract and may cause
ototoxic and nephrotoxic effects, especially with continuous use over several months.38
This drug should be used with particular caution by patients with renal insufficiency. The
efficacy of metronidazole (800 mg daily) for one week is similar to that of neomycin,36
although the possibility of gastrointestinal disturbance and other systemic side effects
limits the use of this agent for longer periods. Rifaximin, a nonabsorbed derivative of
rifamycin, is a proved alternative at a dose of 1200 mg daily.39

Since the therapeutic effects of nonabsorbable disaccharides depend on their metabolism

by colonic flora, a question of considerable clinical relevance is whether combined
treatment with lactulose and antibiotics is effective in patients with hepatic
encephalopathy refractory to either agent alone. The effectiveness of combined therapy
depends on whether the lactulose can be metabolized by a population of intestinal
bacteria resistant to the antibiotic. The limited data available suggest that lactulose and
neomycin may have an additive effect in reducing the intestinal production of ammonia,
accompanied by an enhanced clinical response, in the majority of patients who have an
inadequate response to lactulose alone.40,41 However, an increase in stool pH after the
addition of an antibiotic suggests that disaccharide-metabolizing intestinal bacteria have
been eradicated; combination therapy should then be discontinued.41

The idea of populating the colonic lumen with non–urease-producing bacteria as a

treatment for hepatic encephalopathy was first raised more than 30 years ago, when an
uncontrolled study suggested that high oral doses of Lactobacillus acidophilus might
have a beneficial effect in patients with cirrhosis and hepatic encephalopathy.42 Few
controlled data are available, although one small study showed that the addition of L.
acidophilus supplements for one to four weeks produced clinical improvement in 71
percent of patients with hepatic encephalopathy refractory to neomycin alone. The results
of a crossover study in three patients suggested that treatment with L. acidophilus alone
was ineffective.43 Conversely, oral administration of Enterococcus faecium for three
periods of four weeks, separated by two-week drug-free intervals, reduced systemic
ammonia levels and was at least as effective as lactulose in patients already on a
restricted diet of 1 g of protein per kilogram. In contrast to the effect of lactulose, the
therapeutic effect of E. faecium was sustained during treatment-free intervals. No adverse
effects have been reported.44

Surgical approaches to reducing the intestinal production of ammonia, such as colectomy

or colonic-exclusion procedures, were used in the past for patients with hepatic
encephalopathy refractory to other measures.25 The operative morbidity and mortality
were high, and today such patients should be considered for orthotopic liver
transplantation.

In addition to ammonia produced in the intestinal lumen, ammonia generated in the

stomach by urease-producing Helicobacter pylori has recently been suggested to
contribute substantially to blood ammonia levels, especially in the presence of gastric
hypochlorhydria, and to precipitate or exacerbate hepatic encephalopathy in patients with
cirrhosis.45,46 Although the importance of H. pylori as a risk factor for hepatic
encephalopathy remains unclear and the efficacy of eradication therapy has not been
proved in controlled trials, our current practice is to eradicate this organism in patients
with cirrhosis and a history of hepatic encephalopathy.

Increased Metabolism of Ammonia in the Tissues

Ornithine and aspartate are important substrates in the metabolic conversion of ammonia
to urea and glutamine, respectively. Ornithine aspartate thus provides substrates for both
of these ammonia-detoxification pathways. Controlled trials suggest that both enteral and
parenteral formulations of ornithine aspartate, but not ornithine α-ketoglutarate,
significantly reduce ammonia levels and have useful therapeutic effects in patients with
cirrhosis and mild hepatic encephalopathy.47-50 In one study, an oral dose of 9 g three
times daily had an efficacy similar to that of lactulose.48 Treatment with benzoate or
phenylacetate, which react with glycine to form hippurate and with glutamine to form
phenacetylglutamine, respectively, is also of proved value51,52; there is evidence that
sodium benzoate at a dose of 10 g daily may be as effective as lactulose.52

Two of the five enzymes responsible for the metabolism of ammonia to urea in the urea
cycle are zinc-dependent. Zinc deficiency is common in patients with cirrhosis and is
caused predominantly by increased loss of zinc in the urine.53 There are reports of overt
hepatic encephalopathy precipitated by zinc deficiency and reversed by supplementation
with oral zinc.54 In a recent controlled trial, the rate of formation of urea from amino
acids and ammonia was increased in eight patients with cirrhosis, zinc deficiency, and
mild hepatic encephalopathy who were given 600 mg of oral zinc sulfate per day for
three months. A significant improvement in psychometric test scores accompanied the
resultant restoration of plasma zinc levels and reduction in systemic ammonia levels.10
Similar beneficial effects of zinc supplementation for periods ranging from seven days to
three months have also been reported in other controlled studies,55,56 as well as some
negative results.57,58 Although further studies are required, zinc-deficient patients with
cirrhosis should receive supplementation in view of the widespread importance of this
trace element for the synthesis of DNA and protein and the function of metalloenzymes.

Reduction of False Neurotransmitters

Treatment with formulas rich in branched-chain amino acids but low in aromatic amino
acids is based on the hypothesis that reduced concentrations of branched-chain amino
acids (leucine, isoleucine, and valine) and increased concentrations of aromatic amino
acids (phenylalanine, tyrosine, and tryptophan) may promote hepatic encephalopathy by
causing the production of false neurotransmitters.1,8,12 Randomized, controlled trials
involving the parenteral administration of formulas enriched with branched-chain amino
acids demonstrated no benefit, improvement in hepatic encephalopathy but not in
mortality rates, or improvement in both.59 Differences in the control treatments, duration
of therapy, selection of patients, precipitating events, and exclusion criteria make the
interpretation of these conflicting results difficult. Similar problems confound the
interpretation of the efficacy of enteral supplementation with formulas enriched with
branched-chain amino acids.60 Ornithine salts of branched-chain keto acids may be more
effective than branched-chain amino acids themselves.30 Although current results do not
support the general use of branched-chain amino acids as a treatment for hepatic
encephalopathy, they have a specific role in improving nitrogen balance without
precipitating hepatic encephalopathy in malnourished patients with cirrhosis who are
intolerant of protein supplementation.61 However, most patients with cirrhosis who
require parenteral feeding tolerate standard synthetic amino acid preparations.62

Decreased activity of dopaminergic neurotransmission has also been suggested to have a

role in the pathogenesis of hepatic encephalopathy.1,8,12 However, controlled trials in
patients with cirrhosis and hepatic encephalopathy failed to demonstrate any beneficial
effect of treatment with levodopa or bromocriptine.63,64

Inhibition of γ-Aminobutyric Acid–Benzodiazepine Receptors

Benzodiazepines exert their depressant effects on the central nervous system by

interacting with high-affinity binding sites on the γ-aminobutyric acid–benzodiazepine
receptor complex. Binding to this receptor by a benzodiazepine-like ligand not present in
the normal brain has been proposed as an important factor in the pathogenesis of hepatic
encephalopathy.1,7,12 However, controlled trials of the efficacy of treatment with the
benzodiazepine-receptor antagonist flumazenil in small numbers of patients demonstrated
typically incomplete improvement in the clinical grade of hepatic encephalopathy in 18 to
78 percent, which included only 50 percent of the patients who had recently received
benzodiazepines.65-67

Correction of Manganese Deposition in the Basal Ganglia

Clinical observations suggest that manganese may accumulate in the basal ganglia of
patients with cirrhosis, as shown by hyperintensity of the globus pallidus on T1-weighted
magnetic resonance images.11 It has been suggested that the deposition of manganese in
the basal ganglia may contribute to the pathogenesis of hepatic encephalopathy.11 This
suggestion is based on similarities between aspects of chronic hepatic encephalopathy
and manganese intoxication68 and reports of the reversibility of hepatic encephalopathy
and this magnetic resonance imaging abnormality after liver transplantation.69 However,
reports conflict as to whether the intensity of the T1-weighted signal in the globus
pallidus correlates with either neuropsychiatric test scores or the clinical grade of hepatic
encephalopathy.70,71 Longitudinal studies are needed to investigate the possible
therapeutic effects of chelation of manganese with edetate calcium disodium or treatment
with sodium para-aminosalicylic acid, which has been reported to be of value in chronic
manganese poisoning from occupational exposure.72

Orthotopic Liver Transplantation

Orthotopic liver transplantation is increasingly being used in the treatment of patients

with end-stage cirrhosis, even older patients, many of whom have hepatic encephalopathy
along with other manifestations of severe hepatic decompensation. Liver transplantation
is also indicated in the small group of patients with severe, refractory hepatic
encephalopathy, including such syndromes as dementia, spastic paraparesis, cerebellar
degeneration, and extrapyramidal disorders, even when hepatic encephalopathy is the
sole manifestation of hepatic decompensation. In practice, therefore, medical
management of hepatic encephalopathy is mainly used for patients who do not yet meet
the criteria for liver transplantation and in whom hepatic encephalopathy is likely to be
mild, and for those in whom transplantation is contraindicated because of other medical
or social problems. The latter group represents a substantial number of patients, because
of the increasing life expectancy of patients with cirrhosis and the comorbidity associated
with advancing age.

There is some divergence of opinion as to whether treatment is warranted for patients

with subclinical hepatic encephalopathy. We do not treat truly asymptomatic patients
who have isolated abnormalities on psychometric analysis. However, patients identified
in this way should be thoroughly assessed for functional impairment, since intervention
may enhance the capacity to perform practical tasks such as driving an automobile.73

Source Information

From the Institute of Hepatology, University College London Medical School, 69–75
Chenies Mews, London WC1E 6HX, United Kingdom, where reprint requests should be
addressed to Dr. Williams.