Management problems in liver disease

Hepatic encephalopathy

Whats new?

Norma C McAvoy

Ammonia and the glutamateglutamine cycle are

important in the pathogenesis of hepatic encephalopathy

Peter C Hayes

Minimal encephalopathy is easily overlooked but

important for the patient
Encephalopathy indicates liver failure, and should
prompt consideration of liver transplantation

Abstract
The presence of hepatic encephalopathy, whether it occurs in patients
with acute or chronic liver injury, indicates liver failure and is a serious
complication. The pathogenesis of hepatic encephalopathy remains elusive, but the importance of ammonia, the glutamineglutamate cycle,
the involvement of other putative humoral factors and receptors as well
as the importance of astrocytes are described. Patients with hepatic encephalopathy may present with a wide variety of clinical features ranging
from easily overlooked mild cognitive impairment to coma with cerebral
oedema. Although essentially a clinical diagnosis supportive data may be
obtained from a variety of diagnostic tools and these are described. In
the management of patients with hepatic encephalopathy the importance
of removal of precipitants such as infection, reduction in dietary nitrogen
load using agents such non-digestible disaccharides, is described, as is
the management of hepatic encephalopathy in patients with fulminant
hepatic failure. Finally, the importance of recognizing encephalopathy as
a sign of liver failure is discussed and its presence should trigger the
consideration of liver transplantation, where appropriate.

Pathogenesis
The precise pathogenesis of HE remains elusive but several
hypotheses have been proposed. It is, however, widely accepted
that this complex syndrome results from the failure of detoxification of a number of gut-derived toxins normally cleared by
the liver. This is caused by intra- and extra-hepatic shunting
that occurs with liver failure. It has also been suggested that an
abnormal bloodbrain barrier occurs in patients with HE which
further exacerbates the crossover of high levels of circulating systemic toxins into the CNS. Ammonia, which is derived from protein breakdown in the gut, has long been suspected to be the key
toxin. This is based on the observations that high concentrations
of ammonia occur both in the systemic and cerebrospinal fluid
of patients with HE and also that treatment aimed at reducing
circulating levels of ammonia results in clinical improvement. It
should be noted, however, that a poor correlation exists between
blood levels of ammonia and the severity of encephalopathy,
suggesting that it is not a direct effect.
Recent research has confirmed that ammonia affects a number of neurotransmitter systems and exerts its effect through its
products of metabolism (e.g. glutamate and glutamine). In the
brain, ammonia is normally detoxified within the astrocytes and
eliminated by the amidation of glutamate. Glutamate is an important excitatory neurotransmitter; after reacting with post-synaptic
receptors, it is converted within astrocytes to glutamine by glutamine synthetase. Although glutamine is generally regarded to
be neuronally inactive, variation in its concentration modifies
astrocyte signalling and also influences the action of glutamate.
In HE:
cerebral glutamine levels are increased
cerebral glutamate levels decreased
glutamate re-uptake mechanisms are abnormal
glutamate-binding sites on post-synaptic neurones are
down-regulated.
Increased glutamine in astrocytes causes osmotic stress, leading to cellular swelling and cellular change, termed Alzheimer
type 2 astrocytosis (Figure 1). In addition, GABA-ergic tone and
peripheral benzodiazepine receptor binding are increased in
HE with serotonin and dopamine neurotransmission also previously shown to be abnormal. It therefore appears that, although
ammonia probably has a central role in the pathogenesis of HE,
its effects are mediated through alteration of a number of neurotransmitter concentrations and cellular changes of the astrocytes, along with an alteration of the bloodbrain barrier. This

Keywords ammonia; glutamineglutamate cycle; hepatic encephalopathy;

liver failure

Hepatic encephalopathy (HE) is a reversible neuropsychiatric

syndrome that may complicate acute or chronic liver failure.
Encephalopathy is part of the definition of the former; HE or ascites is generally present in the latter. Diagnosis of HE is essentially
clinical. Two abnormalities (hepatocellular failure and portosystemic shunting) tend to be present in those in whom encephalopathy develops.

Norma C McAvoy MRCP is Lecturer in Gastroenterology and Hepatology,

Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK. She qualified
from Glasgow University. Her main research interests include
non-alcoholic fatty liver disease, insulin resistance and hepatitis C.
Competing interests: none declared.
Peter C Hayes PhD FRCP(Ed) is Professor of Hepatology at the University
of Edinburgh and the Scottish Liver Transplant Unit, Edinburgh, UK.
He qualified from Dundee University and trained in Dundee, Kings
College Hospital and Edinburgh. His research interests include portal
hypertension and liver transplantation. Competing interests:
none declared.

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Management problems in liver disease

Differential diagnosis of hepatic encephalopathy

The action of glutamate in the brain

Pre-synaptic neuron

Glutamine
Glutamate

Glutamine

Astrocyte

Differential Diagnosis

Examples

Metabolic
encephalopathies

Hypoglycaemia
Hypoxia or hypercapnia
Hyponatraemia or hypernatraemia

Drugs/toxins

Alcohol (intoxication and withdrawal)

Sedatives e.g. benzodiazepines

Intracranial structural
disorders

Subdural haematoma
Subarachnoid haemorrhage
Stroke
Space occupying lesion, including
cerebral abcess

Infection

Meningitis
Encephalitis

Miscellaneous

Seizures
Wernickes encephalopathy
Head injury

Glutamate

Post-synaptic neuron

Blood brain barrier

NH3 increased

Blood brain barrier is more permeable to NH3 (ammonia)

down regulation of glutamate receptors and uptake.
Net result:
increased extracellular glutamate
decrease in total brain glutamate
increase in astrocyte glutamine

Table 1

Chronic persistent encephalopathy is used to describe patients

with chronic liver disease that previously have had recurrent episodes of acute encephalopathy who then develop persistent neurological manifestations which may range from dysarthria and
ataxia to dementia, parkinsonism and myelopathy.
Subclinical encephalopathy is the term used to describe the
mild brain dysfunction that is commonly overlooked during cursory clinical examination, but may affect visuospatial and psychomotor abilities and interfere with quality of life (e.g. driving
may be impaired). HE should therefore be actively evaluated in
all patients with suspected liver disease and staged according
to the West Haven criteria (Table 3). Simple psychometric tests

Figure 1

explanation for the pathogenesis of HE may explain why many

treatments targeted at specific pathways (e.g. benzodiazepine
antagonists) have shown limited clinical efficacy.
Other toxins implicated in the pathogenesis of HE include
manganese, mercaptans, aromatic amino acids and short-chain
fatty acids.

Clinical features and investigations

Patients with HE can present with a variety of clinical features
ranging from life-threatening coma with cerebral oedema (most
often in fulminant hepatic failure) to subclinical, occult or minimal confusion/disorientation. Differential diagnoses are listed in
Table 1.
An episode of acute encephalopathy in pre-existing liver disease is characterized by the abrupt onset of a confusional state,
neuromuscular abnormalities and fetor hepaticus (a sweet,
musty smell on the breath from exhalation of unmetabolized
mercaptans), and may progress within a matter of hours from a
mild confusional state to deep coma. Its progress generally mirrors liver function or removal of precipitating factors (Table 2).
Asterixis (liver flap) should be sought and tendon reflexes tested;
the latter are often increased, unlike in many patients who are
drowsy.
The clinical features of encephalopathy in fulminant liver failure are essentially the same as those seen in patients with cirrhosis but as cerebral oedema is more common in these patients,
signs of raised intracranial pressure (bradycardia, hypertension,
dilated pupils, decerebrate posturing) may also be seen.

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Factors which precipitate hepatic encephalopathy

Aetiology

Precipitating factor

Increased protein
load

Upper GI haemorrhage
Ingestion of large protein meal

Decreased excretion
of ammonia

Renal failure
Constipation

Other

Electrolyte disturbance (e.g. hypokalaemia)

Dehydration
Paracentesis
Creation of portacaval shunts
Infection
Drugs (e.g. sedatives)
Superimposed acute liver injury

Table 2

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Management problems in liver disease

performed on all patients, including an ascitic tap in patients

with ascites.

West Haven criteria for grading mental state in

hepatic encephalopathy
Grade

Clinical findings

Grade 0
Grade 1

No abnormality detected
Trivial lack of awareness, euphoria, anxiety
Reduced attention span
Impaired performance in addition or substraction
Lethargy, apathy, disorientation for time and place
Obvious personality change
Inappropriate behaviour
Somnolence to semi-stupor, but responsive to stimuli
Confusion
Gross disorientation
Coma
Mental state not testable

Grade 2

Grade 3

Grade 4

Reduction of nitrogen load dietary and drug measures

In addition to targeting precipitants, other regimens primarily
aim to reduce gut (particularly colon) protein load. The traditional dietary measures aim to reduce protein intake from the
normal 80 g/day to about 4060 g/day or, in severe cases, 20
g/day. However, this unbalanced diet is undesirable in the long
term and is likely to lead to malnutrition in patients who may be
already hyper-catabolic with wasting and reduced body mass.
During short-term protein restriction, an adequate calorie intake
of 2000 kcal/day should be maintained. There is evidence that
vegetable protein is less ammoniagenic and may allow a larger
protein intake; it is also associated with greater fibre content,
promoting regular bowel movement and elimination of nitrogenous wastes.
Drug measures generally revolve around non-digestible disaccharides, such as lactulose, which are used to lower colonic pH,
discouraging replication of ammonia-producing bacteria and
reducing ammonia absorption, and produce hyperosmolar diarrhoea, increasing faecal nitrogen elimination. Treatment should
be titrated to achieve one or two soft stools per day, avoiding diarrhoea. Lactitol is an alternative that acts in a similar manner and
is probably better tolerated, but it is less readily available. Sodium
benzoate increases ammonia removal. In most cases, enemas
(usually phosphate or magnesium sulphate) are often used early
in constipation before lactulose takes effect, to increase excretion
of nitrogenous waste products. Poorly absorbed antibiotics, such
as neomycin, have also been used to reduce gut bacterial flora
that produces ammonia. However, long-term use has been associated with ototoxicity and nephrotoxicity and therefore this agent
is now less commonly used. Other antibiotics (e.g. vancomycin,
metronidazole) may be effective. In patients with liver disease,
prophylactic use of, for example, norfloxacin to prevent complications such as spontaneous bacterial peritonitis can reduce episodes of encephalopathy by reducing the occurrence of sepsis.
Other drugs that have been used with variable effect in the
treatment of HE include the benzodiazepine antagonist flumazenil, L-dopa, bromocriptine and zinc. However, these are rarely
used in routine clinical practice.

Table 3

such as number connection and digit symbol substitution should

also be used. Asking the patient to copy a five-pointed star or
clock face is also very useful to identify abnormalities in visuospatial awareness.
Other techniques are used in clinical practice in an attempt
to confirm HE in difficult cases. Electroencephalography (EEG)
classically shows bilateral, synchronous slowing of frequency
from alpha to theta (47 Hz) or even to the delta range (<4 Hz),
but these abnormalities are not specific for HE. Other investigational options may include electrophysiological tests (e.g. visual
evoked potentials, brain stem auditory evoked potentials, somatosensory evoked potentials, P300 event-related potentials) and PET
scanning, but these are largely research tools.

Management
General supportive measures
Like any other patient with altered consciousness, adequate
hydration is important and this remains the case even in
patients with ascites. Diuretic therapy is generally discontinued until the patient recovers and then reintroduced cautiously.
Peripheral venous access is sufficient in most cases, but central
venous access is necessary in patients in whom it is difficult to
accurately assess fluid balance. Care should be taken to avoid
line sepsis.

Treatment of encephalopathy in patients with

portosystemic shunt
Increased shunting of blood past the liver with a surgical portosystemic shunt or a transjugular intrahepatic portosystemic stent
shunt may cause hepatic encephalopathy. This may be temporary but, if recurrent, may require reduction of the shunts diameter or even its closure. Before closure, eradication of varices by
endoscopic methods is advocated.

Removal of precipitants
In many patients, encephalopathy follows a discrete precipitant
(most importantly infection and upper gastrointestinal bleeding); reversal or removal of this leads to clear clinical improvement within 1224 hours. In some cases, encephalopathy is
precipitated or worsened by factors for which reversal is less
rapid (e.g. sedative drugs that require hepatic metabolism), and
in these patients recovery may take considerably longer. Several precipitating factors may be present and thus management
generally involves treatment of a number of precipitants until
further lab tests are available. A full septic screen should be

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Treatment of encephalopathy associated with fulminant

hepatic failure
Management of patients with fulminant hepatic failure (FHF)
requires intensive care support, and such patients commonly
require ventilation to protect their airway when they develop
grade III encephalopathy. They are much more at risk of
developing raised intracranial pressure (ICP) compared with
patients with cirrhosis and many centres will use intracranial
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Management problems in liver disease

e xtradural pressure monitoring to detect raised ICP. A pressure of

>20 mmHg for 10 minutes is an indication for treatment. It also
allows measurement of the cerebral perfusion pressure (CPP)
(mean arterial pressure minus ICP) with the goal of maintaining
the CPP >60 mmHg. Mannitol is the first-line treatment and may
need to be repeated. Repeated infusions may lead to hyperosmolality, and therefore plasma osmolality should be monitored. Second-line therapies include thiopentone and induction of moderate
hypothermia.

transplantation. All patients with encephalopathy should therefore be considered for orthotopic liver transplantation.

Further Reading
Blei A T, Butterworth R F et al. Hepatic encephalopathy. Semin Liver Dis
1996; 16: 2338.
Blei A T, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol 2001;
96: 196876.
Davies M G, Rowan M J, Feely J. Psychometrics in assessing hepatic
encephalopathy a brief review. Ir J Psychol Med 1991; 8: 1446.
Mas A. Hepatic encephalopathy: from pathophysiology to treatment.
Digestion 2006; 73(Suppl 1): 8693.
Vaquero J, Butterworth R F. The brain glutamate system in liver failure.
J Neurochemistry 2006; 93: 6619.

Liver transplantation
It should be remembered that HE is a clinical sign of liver failure. In many cases, liver transplantation is the only satisfactory
long-term treatment and this is true for both patients with FHF
and patients with chronic liver disease and chronic encephalopathy. Some reversibility of cognitive function occurs with

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