Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

III. Clinical Manifestations of Hepatic Insufficiency
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In fulminant cases, horses may become delirious with the
head pressed forcibly against a wall for long periods of
time, or they may assume a variety of other unusual positions
or fall suddenly to the ground. Numerous unproductive
attempts to rise can be followed by violent thrashing.
When successful in rising, horses with hepatic encephalopathy
may be completely uncontrollable, lunging forward
violently and becoming a menace to attending personnel
and equipment.
The syndrome of hepatic encephalopathy in cattle may
have an abrupt onset and characteristically represents a
terminal manifestation of chronic liver disease ( Fowler,
1968 ; Pearson, 1977 ). Affected calves initially may be
dull, anorectic, and stand apart from other calves in a herd.
Behavioral abnormalities may include unprovoked, violent
charging or unusual and unrestrained bawling. Progressive
dysmetria and ataxia are followed by recumbency and
affected cattle may be unable to rise or even to assume a
sternal position. Tenesmus has been reported to be a conspicuous
clinical feature associated with prolapse of the
rectal mucosa and dribbling of urine. Characteristically,
death occurs within 2 days after onset of CNS signs ( Finn
and Tennant, 1974 ).
Hepatic encephalopathy is observed frequently in
dogs with congenital or acquired portosystemic vascular
shunts and may be one of the most prominent presenting
clinical features of this form of liver disease ( Audell et al.,
1974 ; Barrett et al., 1976 ; Cornelius et al., 1975a, 1975b ;
Ewing et al., 1974 ; Maddison, 1992 ; Schermerhorn et al.,
1996 ). Neurological signs associated with portosystemic
shunts often are episodic and may be present for some
months before recognition of the underlying hepatic disturbance.
Depression and stupor with amaurotic blindness
are observed in approximately half the cases of congenital
portacaval shunts in dogs, with circling, head pressing,
and intermittent seizures observed less frequently. Hepatic
encephalopathy also has been associated with other primary
diseases of the canine liver ( Center, 1996 ; Oliver, 1965 ;
Strombeck et al., 1975b ).
Inherited diseases involving the urea cycle are recognized
in domestic animals in which failure of urea synthesis
results in significant elevations in blood ammonia and
in signs of encephalopathy. Two cases of encephalopathy
in dogs have been reported that were linked to a deficiency
of argininosuccinate synthetase ( Strombeck et al., 1975a ).
Inherited argininosuccinate synthetase deficiency has been
described in neonatal cattle in which rapidly progressive
and fatal encephalopathy was associated with hyperammonemia
and citrullinemia ( Harper et al., 1986, 1988, 1989 ).
The argininosuccinate synthetase gene of cattle has been
cloned, sequenced, and the mutation of affected Holstein
calves described ( Dennis et al., 1989 ). Suspected ornithine
transcarbamylase deficiency has been described in a cat
( Washizu et al., 2004 ), and encephalopathy in two Morgan
foals associated with elevated blood ammonia has been
recognized and described as being similar to the human
syndrome of hyperornithinemia, hyperammonemia, and
homocitrullinuria ( McCornico et al., 1997 ). A syndrome
of hyperammonemia and encephalopathy associated with
acute gastrointestinal disease has been described in adult
horses ( Gilliam et al., 2007 ; Hasel et al., 1999 ; Peek et al.,
1997 ; Stickle et al., 2006 ). The pathogenesis of this syndrome
has not been fully explained, but the evidence suggests
that increased production and absorption of ammonia
from the colon are sufficient to exceed the detoxifying
capacity of the liver ( Stickle et al., 2006 ).
Hepatic encephalopathy must be differentiated clinically
from primary inflammatory, degenerative, or neoplastic
diseases of the brain, and this can be accomplished by
demonstrating the existence of underlying severe hepatic
disease. In the horse with acute hepatitis, clinical icterus
almost always is present at the time neurological signs are
observed. In the dog and in cattle, frank clinical icterus is
observed variably in animals with hepatic encephalopathy
so that other tests of hepatic function or liver biopsy are
required. In cases of primary hyperammonemia resulting
from deficiency of urea cycle enzymes, conventional
hepatic function tests are not expected to be abnormal
( Strombeck et al., 1975a ).
Factors responsible for encephalopathy associated with
hepatic failure are not completely understood. Ammonia is
present in normal peripheral blood at a concentration of 2 to
5 mM/l. In portal venous blood, the concentration may be
five times higher. Normally, most of the ammonia in the
hepatic portal vein is removed by the normal liver to form
urea, with only a small fraction passing into the systemic
circulation. In hepatic failure, synthesis of urea is reduced,
and in the horse ( Cornelius et al., 1965a, 1965b ; Tennant
et al., 1975 ) and dog ( Barrett et al., 1976 ; Strombeck,
1975b), significant elevations of blood ammonia have been
demonstrated. Ammonia has potent neurotoxic effects, and
many of the neurological signs of hepatic encephalopathy
can be produced when toxic doses of ammonium salts are
administered intravenously ( Hooper, 1972 ).
The reactions of blood ammonia are determined by
the physicochemical principles that apply to gases in solution
and to the dissociation of weak bases. The ammonia:
ammonium ion buffer system of blood can be described by
the Henderson-Hasselbalch equation:
NH
pH pKa
log
NH
The pKa for this system in the dog is approximately 9.1
( Bromberg et al., 1960 ), meaning that at physiological
pH (7.4), almost all of the ammonia of blood is ionized to
form (NH 4
). As blood pH increases, the relative amount
of free ammonia (NH 3 ) increases, and as pH decreases,
NH 3 decreases. Cells are almost impermeable to NH 4
but
are readily permeable to NH 3 , passing through the plasma
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