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Clinical Science (1983) 64,247-252
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EDITORIAL REVIEW
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Biochemical mechanisms of hepatic encephalopathy
I. R. C R O S S L E Y , E. N. W A R D L E A N D R O G E R W I L L I A M S
Liver Unit, King’s College Hospital and Medical School, London
Although there are similarities between the
encephalopathy of acute hepatic failure and that
due to cirrhosis, it is clear that some of the
biochemical abnormalities arise in different ways
and the relative roles of the various factors
contributing to the production of encephalopathy
may differ. In addition, in fulminant hepatic
failure, changes in the permeability of the bloodbrain barrier may enhance the effects of biochemical abnormalities and this may also be
important in the genesis of cerebral oedema,
which commonly complicates this form of
encephalopathy. When considering encephalopathy complicating cirrhosis, it is important to
recognize that the latter can be precipitated by a
variety of insults each of which may lead to
encephalopathy. Most research has concentrated
on the accumulation in the blood of ‘toxic’
substances normally metabolized by the liver.
Although no single toxin has yet been identified
which alone can be responsible for hepatic
encephalopathy, excess ammonia, mercaptans,
fatty acids and an abnormal plasma amino acid
profile have been incriminated in its pathogenesis. Irrespective of the ‘toxin’, three main
pathogenetic mechanisms have been proposed to
account for its action: (a) disturbed brain energy
metabolism, (b) deranged neurotransmitter
balance, (c) direct effects on neuronal membranes. These mechanisms are not regarded as
mutually exclusive but have their final common
effect of interrupting normal neurotransmission.
Key words: Na+/K+-dependent-ATPase, ammonia,
false
neurotransmitters,
hepatic
encephalopathy, mercaptans, middle molecules,
phenols.
Correspondence: Dr Roger Williams, Liver Unit,
King’s College Hospital and Medical School, Denmark Hill, London S.E.5.
Hyperammonaemia
Reasons for considering ammonia as an important cerebral toxin in hepatic encephalopathy are
that blood and cerebrospinal fluid ammonia
concentrations are raised in hepatic coma and
glutamine and ketoglutamate, products of cerebral ammonia metabolism, are elevated in the
cerebrospinal fluid and correlate with coma grade
[ 1, 21. Ammonia loading in patients with chronic
liver disease or in high dosage in animals will
produce coma 131 and coma occurs in children
with hyperammonaemia due to congenital defects
of the urea cycle [41.
The gastrointestinal tract has long been
thought to be the major site of ammonia
production [51, as a result of bacterial degradation, especially in the colon, of nitrogenous
compounds, chiefly dietary protein or urea which
diffuses into the intestinal lumen. However,
clinical and experimental studies in germ-free
animals suggest that non-bacterial sources of
ammonia are also important [6, 71. In the
non-fasting state 40% of ammonia from the
gastrointestinal tract is produced by bacteria and
60% from small intestinal digestion of dietary
protein, and metabolism of circulating glutamine
[8, 91. Liver, muscle, brain, kidney and erythrocytes also possess mechanisms for ammonia
production via the purine nucleotide cycle [ 101.
Kidney and brain, however, appear to be
relatively minor sources. Ammonia production by
muscle increases arterial ammonia concentration
by 10% in patients with liver disease, whereas in
normal subjects increases in blood ammonia
occur only after heavy exertion [ 11,121.
Ammonia is detoxified to urea and glutamine.
The former process occurs principally in the liver,
and glutamine synthesis occurs in various organs,
including kidney and brain. Most urea is excreted
by the kidney but about 25% diffuses into the gut
and is subsequently hydrolysed to ammonia and
reabsorbed [ 131. Although the liver metabolizes
0143-5221/83/030247-06sZ.00 @ 1983 The Biochemical Society and the Medical Research Society
248
I. R . Crossley, E. N. Wardle and R . Williams
most of the ammonia in the portal blood, in the
presence of impaired liver function and/or portal
systemic shunting, muscle may become an important homoeostatic organ. One study (141 has
shown in normal subjects that 50% of arterial
ammonia is metabolized by muscle. However,
loss of muscle mass is common in chronic liver
disease and may contribute to hyperammonaemia [ 151. As a consequence of impaired hepatic
clearance, ammonia becomes available for cerebral metabolism. With a p K of 9.1, and being 5%
un-ionized at physiological pH, ammonia is free
to enter cells. Forty-seven per cent of ammonia in
arterial blood is extracted in one passage through
the brain [141. It enters the brain largely by
diffusion, and is probably metabolized in a small
pool of glutamate that is distinct from a larger
tissue glutamate pool located possibly in the
astrocytes [ 161.
Disturbances of cerebral energy metabolism
Early studies in patients with hepatic
encephalopathy demonstrated a decrease in cerebral oxygen metabolism and ammonia was
thought to be responsible since it was thought to
be detoxified via the a-ketoglutarate-glutamateglutamine pathway. Depletion of a-ketoglutarate
in the tricarboxylic acid cycle due to its diversion
into the glutamine pathway would result in
decreased operation of the cycle, with a fall in
high energy phosphates and oxygen consumption [ 171. A decrease in cerebral a-ketoglutarate,
however, has not been confirmed [181 and recent
evidence also suggests that glutamine derives
from a pool of glutamate that is rapidly turning
over, rather than from eketoglutarate [161.
Subsequent studies in dogs in coma after hepatectomy did show a reduction in many of the
tricarboxylic acid cycle substrates, including
a-ketoglutarate, but this was no different from
that bbserved with simple sedation or anaesthesia
[ 191.
Direct measurement of high energy phosphates (adenosine triphosphate and phosphocreatine) in the central nervous system of animals
with ammonia-induced coma has yielded conflicting results 118-251. Such substances are
extremely labile and artifactual decreases due to
tissue hypoxia during freezing and subsequent
separation of the various parts of the brain for
analysis are difficult to avoid. More recent
experiments using improved fixation techniques in
rats with chronic hyperammonaemia after portocaval shunt operations, showed that after an
acute ammonia challenge which induced coma,
brain-stem concentrations of high energy phos-
phates decreased but only after 1 h of coma 1261.
Thus changes in cerebral energy metabolism
could be the result rather than a cause of coma.
Neurotransmitter inbalance
Inhibition of acetylcholine synthesis has been
suggested but never substantiated 127, 281.
Accumulation of y-aminobutyric acid (GABA),
an inhibitory neurotransmitter which is derived
from glutamate during cerebral ammonia detoxilication, has also been incriminated although
measurements of brain concentrations of GABA
in rats with ammonia toxicity or after liver
damage were normal [24,291. Hindfelt et al. [261
have demonstrated decreased cerebral concentrations of the excitatory neurotransmitters glutamate and aspartate, in addition to decreased
concentrations of some tricarboxylic acid cycle
substrates, in rats challenged with ammonia after
a portacaval shunt. Such changes occurred
during precoma and were followed by alterations
in the malate aspartate shuttle of reducing
equivalents from cytoplasm to mitochondria, with
subsequent alteration of the NAD/NADH ratio
within mitochondria. Such changes could ultimately inhibit oxidative energy coupling as a
secondary event. Although criticism has been
levelled at the calculation used to derive the
NAD/NADH ratio [301, this study would provide a link between the early depletion of
neurotransmitters which may be the key abnormality in hepatic coma and the late and possibly
secondary findings of decreased cerebral energy
metabolism.
Direct effects on neuronal membrane Na+,K+dependent A V a s e
High concentrations of the enzyme are found
in the brain, where it is responsible for the
maintenance of transmembrane ion gradients
which are necessary for normal neuronal activity
[311. Interference with this system may impair
membrane repolarization and cause coma, as well
as disturbing the functional integrity of the
blood-brain barrier. Ammonia has been shown to
inhibit neuronal Na+,K+-ATPase activity by
competing with K+ [21l. High concentrations of
ammonium ions may partly substitute for intracellular sodium and block the outwardly directed
chloride pump, which normally maintains a high
transmembrane chloride gradient necessary for
repolarizaton [321. Studies with brain slices in
vitro have also shown that ammonia alters its
permeability to ions with inhibition of the frequency of spike potentials 1331. Although often
Biochemical mechanisms of hepatic encephalopathy
only a poor correlation can be demonstrated
between blood ammonia concentration and degree of coma [341, in terms of toxicity the intracerebral ammonia concentration is likely to be the
more important factor. Intracellular levels of
ammonia can be 10-15 times the concentrations
in blood because migration of ammonia is
influenced by pH, lipophdicity and intracellular
metabolism. Furthermore, the synergism between
ammonia, fatty acids and mercaptans in the
experimental production of coma (see below)
could well blunt any relationship between the
blood concentrations and coma grade.
Amino acid imbalance in blood and brain
Hepatic failure is associated with a considerable
increase in plasma concentrations of aspartate,
glutamate, phenylalanine, tyrosine, methionine
and free tryptophan. Most attention has been
focused on phenylalanine and tyrosine because of
the precursor relationship to brain catecholamines, and on tryptophan which is converted
into the inhibitory neurotransmitter serotonin.
In chronic encephalopathy there is a two- to
four-fold rise in the plasma concentrations of the
aromatic amino acids, together with a decrease in
the plasma concentrations of the branched-chain
amino acids valine, leucine, and isoleucine [351. A
combination of catabolism and impaired hepatocellular function is probably responsible. Raised
plasma concentrations of glucagon stimulate
muscle catabolism with release of amino acids for
gluconeogenesis [361. However, when hepatic
function is poor the uptake and metabolism of
aromatic amino acids in the plasma are impaired.
In contrast, branched-chain amino acids are
preferentially metabolized in muscle and fat and
their low levels can be explained by their
enhanced uptake as a result of the hyperinsulinism [371. Levels of the aromatic amino
acids are considerably raised in fulminant hepatic
failure but concentrations of branched-chain
amino acids are normal 1381. This pattern is
thought to arise largely from massive necrosis of
liver cells with release of amino acids into the
circulation, and catabolism probably plays a less
important role.
Relation tofalse neurotransmitter hypothesis
Increased intracerebral concentrations of
phenylalanine and tyrosine may result in the
formation of ‘false neurotransmitter’ amines,
which are thought to displace true neurotransmitters from synaptosomes. Excess tyrosine is
decarboxylated to tyramine, which is then con-
249
verted by dopamine-Poxidase into octopamine,
and phenylalanine is converted into phenylethylamine and thence into phenylethanolamine.
Levels of octopamine and phenylethanolamine
were found to be raised in the brains of animals in
acute hepatic coma [391. In addition, phenylalanine competes with tyrosine for the enzyme
tyrosine hydroxylase, and tyramine competes
with dopamine for dopamine-8-oxidase,with the
result that intracerebral formation of the normal
stimulatory transmitters (dopamine and noradrenaline) may be reduced [401.
Concentrations of amino acids in the brain
depend on the integrity of the blood-brain barrier
and the activity of the carrier systems of amino
acids as well as on the plasma levels. The neutral
amino acids are transported across the bloodbrain barrier by a common carrier [41] and there
is usually competition between the aromatic and
branched-chain amino acids [421. Thus low
circulating levels of branched-chain amino acids,
together with their lower d n i t y constants for the
carrier, might be expected to favour transport into
the brain of the aromatic amino acids. Concentrations of branched-chain amino acids in the
cerebrospinal fluid have been observed to be
normal in animals during hepatic coma, despite
low plasma concentrations [431, possibly as a
result of increased activity of the carrier system
[441.
In acute liver failure, the blood-brain barrier is
commonly disrupted and may enhance the
cerebral effect of plasma amino acid imbalance.
Zaki et al. [451, by means of the Oldendorf
technique, have shown that the blood-brain
barrier is also disrupted in rats 6 weeks after a
portacaval anastomosis. Brain uptake of L-[l4C1glucose, D-[14Clsucrose,and [ 14Clinsulin, substances which do not normally cross the bloodbrain barrier, were all increased, in addition to a
selective increase in the uptake of neutral amino
acids.
The influx of neutral amino acids may be
geared to the slow sustained efAux of glutamine
[46], a product of ammonia metabolism, hence
providing a link between the ammonia toxicity
and the false neurotransmitter hypotheses.
Evidence against the false neurotransmitter
theory is that octopamine instilled into the
ventricles of rats produced a striking increase in
its concentration in the brain and a fall in whole
brain dopamine and noradrenaline to one-tenth of
normal values, without any disturbance in consciousness [471. Also, in a study in which brain
catecholamines were measured post mortem in
cirrhotic patients with encephalopathy, no reduction in dopamine or noradrenaline concentra-
250
I. R . Crossley,E. N. Wardle and R . Williams
tions was found and octopamine levels were
decreased compared with cirrhotic patients who
were not encephalopathic at the time of death
[481.
y-Aminobutyric acid
Neural inhibition in the mammalian brain is
principally mediated by the neurotransmitter
GABA. Instillation of less than 1 pmol of GABA
into the hippocampal region of the brain induces
a coma-like state with characteristic encephalographic features [491. A 12-fold increase in the
plasma concentration of GABA has been reported in animal models of fulminant hepatic failure
and this is thought to be due to impaired hepatic
metabolism of GABA synthesized by gut bacteria
[50, 511. Associated with the development of
encephalopathy was an enhanced permeability of
the blood-brain barrier and an increased number
of binding sites for GABA on postsynaptic
neurons within the brain [521. Thus gut-derived
GABA may contribute to the neural inhibition of
hepatic encephalopathy, and in liver failure an
increased number of binding sites may enhance
the cerebral sensitivity to drugs such as barbiturates and benzodiazepam, which share this
effector pathway.
Role of mercaptans, fatty acids and bile acids
Bacterial metabolism of methionine in the gut
produces methanethiol (methyl mercaptan),
which has long been recognized as a cerebral
toxin. Blood methanethiol concentration in
cirrhotic patients with encephalopathy was fourtd
to be significantly higher (975 rf: 64 pmol/l) than
in non-encephalopathic patients with cirrhosis
(636 i-29 pmol/ml). Furthermore, blood levels
correlated with the degree of encephalopathy
[531. Experimental studies in animals have shown
than mercaptans induce reversible coma, albeit at
higher concentrations (SO00 pmol/ml) 1541.
Studies using low concentrations of methanethiol
(0.03 pmolll) in vitro have demonstrated
inhibition of microsomal Na+,K+-ATPase activity. Serum concentrations of short-chain fatty
acids are raised four-to-five-fold in hepatic coma
1551 and have been shown to cause coma in
animals [561. Studies in vitro have demonstrated
that low concentrations inhibit Na+,K+-ATPase
in brain homogenates and microsomes 157-591,
probably by competitive inhibition of K+, unlike
mercaptans which are thought to inhibit the
Na+-dependent portion of the reaction 1601. No
correlation has been found between the serum
concentrations of short-chain fatty acids and the
clinical course of patients with fulminant hepatic
failure [6 11. However, at pathological concentrations both mercaptans and free fatty acids
interfere with ammonia detoxification in the urea
cycle, and in addition act synergistically with
ammonia to produce coma at blood concentrations lower than those required for each substance individually b41. Free fatty acids also
displace tryptophan from its binding sites on
albumin, thus raising the availability of free
tryptophan to the brain, which may enhance
cerebral serotonin formation 1621. Methionine
may also be metabolized to taurine, which may
cause cerebral dysfunction [631.
Free phenol concentrations are increased in the
plasma in hepatic encephalopathy complicating
fulminant hepatic failure [641; they are lipophilic
compounds derived from phenylalanine and
tyrosine. They, too,. have been shown to be
inhibitors of Na+,K+-ATPase as well as many
other membrane-bound enzymes [651 and on a
molar basis are more toxic than ammonia or free
fatty acids [661.
Raised concentrations of bile salts have been
found in the serum, cerebrospinal fluid and brain
of patients in fulminant hepatic failure [671. Bile
acids are toxic in many biochemical systems and
in vitro cause uncoupling of oxidative phosphorylation [68, 691. However, the concentrations of serum bile acids found in fulminant
hepatic failure were similar to those found in
chronic liver disease without encephalopathy, and
indeed lower than concentrations found to inhibit
brain respiration in vitro. Protein 'binding in vivo
will reduce toxic effects; in fact, patients with
cholestasis seem to suffer only from intractable
itching.
Middle molecules
Improvement of encephalopathy in patients with
fulminant hepatic failure after haemodialysis with
polyacrylonitrile membrane as opposed to the
cuprophane membrane suggested that substances in the middle molecular weight range
(500-5000)may be involved in the pathogenesis
of hepatic encephalopathy, since the polyacrylonitrile membrane was more permeable to larger
solutes. With Sephadex G15 gel filtration, substances as yet uncharacterized, with molecular
weights within this range, have been identified in
the sera of patients with fulminant hepatic failure
and chronic encephalopathy 1701 and also in the
plasma and brain of animals with acute hepatic
failure [71]. Further studies have shown that the
serum of patients with fulminant hepatic failure
inhibits leucocyte plasma membrane Na+,K+-
Biochemical mechanisms of hepatic encephalopathy
ATPase and that the main inhibitory components appeared in peaks 3, 4 and 5 (the middle
molecular weight range) of the ultrafiltrate [721.
Haemodialysis with the polyacrylonitrile membrane removed the middle molecular weight peaks
[721. A similar inhibitory mechanism in the brain
might explain a defect in neurotransmission as
well as the development of cerebral oedema.
Conclusions
Current evidence would seem to favour neurotransmitter imbalance or direct effects on
neuronal membrane function as the main mechanism of hepatic encephalopathy. Further work
in the field of toxic 'middle molecular weight'
fractions is indicated. Almost certainly the aetiology is multifactorial, as shown by the demonstrated synergistic toxic effects of ammonia, fatty
acids, mercaptans and phenols. Furthermore, the
effect(s) of the toxic factor(s) are likely to be
moderated by endogenous metabolic abnormalities such as hypoxia, hypoglycaemia and
acid-base and electrolyte abnormalities.
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