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

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Chapter | 13 Hepatic Function
membrane by nonionic diffusion ( Castell and Moore,
1971 ; Stabenau et al., 1959 ; Warren and Nathan, 1958 ).
These principles are important in determining the amount
of ammonia absorbed from the gastrointestinal tract or the
amount that can pass from blood into the brain and to other
tissues ( Dimski, 1994 ).
Because of its influence on acid-base parameters,
potassium status may be an important determinant of NH 3
toxicity. Potassium deficiency ultimately favors the development
of metabolic alkalosis that, in turn, causes a shift
in the NH 3 /NH 4
equilibrium in the direction of the toxic
freebase.
Blood ammonia ultimately is derived from dietary nitrogen.
The gastrointestinal tract is the major source of blood
NH 3 , but other tissues also produce NH 3 (e.g., muscle and
kidney). Renal ammonia is produced from glutamine and to
a lesser extent from other amino acids. Synthesis of ammonium
ion by the kidney represents a normal physiological
mechanism for H excretion. The renal excretion of NH 4
is
related directly to the pH gradient between blood and urine,
and total urinary excretion of NH 4
is high in acid urine and
proportionately low in alkaline urine.
The gastrointestinal tract is the major source of blood
NH 3 based on the high concentration of NH 3 found in portal
blood compared to peripheral venous blood. Part of the
ammonia in the hepatic portal vein is derived from the action
of bacterial enzymes on dietary amino and amide nitrogen
and part is derived from urea, which is present in alimentary
tract secretions and is hydrolyzed by bacterial urease of
the gastrointestinal tract. The question of whether gastrointestinal
urease is produced in part by mammalian cells or is
entirely of bacterial origin was the subject of controversy for
many years. Using germ-free rats, it was demonstrated that
gastrointestinal urease was exclusively of bacteria in origin
( Levenson and Tennant, 1963 ), and this observation has
been confirmed in germ-free dogs ( Nance et al., 1974 ).
The relative importance of NH 3 produced by gastrointestinal
bacteria and that produced from nonbacterial
sources is still not fully known. Nance et al . (1971, 1974)
and Nance and Kline (1971) have demonstrated that germfree
dogs with Eck fistulae develop encephalopathy associated
with hyperammonemia. This suggests that at least
with vascular shunts, endogenous sources of NH 3 contribute
to encephalopathy. The intestine metabolizes significant
quantities of glutamine independent of intestinal
bacteria, and at least 30% of the glutamine nitrogen that
reaches the intestine appears in the portal blood as NH 3 /
NH 4
(Windmuller and Spaeth, 1974).
The liver plays a critical role in maintenance of the
blood glucose concentration, and marked hypoglycemia is
sometimes associated with liver failure. In fulminant hepatic
failure in the horse, the blood glucose has been reported
in some cases to be as low as 20mg/dl or less ( Hjerpe,
1964 ; Tennant et al., 1975 ). Hypoglycemia also has been
reported in dogs with hepatic insufficiency associated
with vascular shunts ( Cornelius et al., 1975b ; Ewing et al.,
1974 ).
Other neurotoxic substances may be involved in the
pathogenesis of hepatic encephalopathy, and the role of
these factors has been reviewed ( Center, 1996 ; Maddison,
1992 ). Indole and indolyl derivatives that are formed from
tryptophan by intestinal bacteria have been suggested as
encephalotoxic compounds capable of inducing coma
( Zieve et al., 1974 ). Other studies have incriminated short
chain fatty acids and, in experimental models of hepatic
failure, total volatile fatty acids (VFA) increase significantly
before death ( Zieve et al., 1968 ). Increased plasma
VFA concentrations also have been observed in spontaneous
hepatic encephalopathy and, when infused intravenously
into experimental animals, VFA produces cerebral
depression followed by coma.
The etiological role of ammonia in hepatic encephalopathy
is generally recognized, and there is convincing
evidence that cerebral edema is important in pathogenesis
( Ahboucha and Butterworth, 2007 ; Butterworth, 1994 ).
Astrocytes are recognized as a target of ammonia in the
CNS ( Albrecht and Norenberg, 2006 ), but how ammonia
brings about astrocyte swelling, brain edema, and cerebral
hypertension is not fully understood. It has been suggested
that as a result of ammonia detoxification, glutamine accumulates
in astrocytes and the resulting osmotic force of
glutamine leads to cell swelling. In experimentally induced
hepatic encephalopathy, accumulation of cerebral ammonia
was associated with increased cerebral glutamine,
with the development of Alzheimer type II astrocytes,
and with a significant increase in the level of water in the
brain ( Jover et al., 2006 ). Based on studies of cultured
astrocytes, Jayakuman et al. (2006) concluded, however,
that glutamine was not acting as an osmolyte but rather
that ammonia evoked oxidative stress or abnormalities of
mitochondrial function (mitochondrial permeability
transition) that caused injury and swelling of astrocytes
( Albrecht and Norenberg, 2006 ; Norenberg et al., 2005,
2007 ).
The management of hepatic encephalopathy involves
restriction of protein intake and provision of a readily
digestible dairy or vegetable protein source. Further
control is directed at the reduction of the production and
absorption of ammonia and other neurotoxic substances
from the intestine. One approach is the oral administration
of a nonabsorbable disaccharide such as lactulose, which
upon reaching the colon is fermented by resident bacteria
to produce short chain fatty acids and which has a cathartic
effect. By decreasing colonic pH, the equilibrium between
ammonium ion and the freebase is shifted to poorly
absorbed ammonium ion. An alternative approach is the
administration of a nonabsorbable, broad spectrum antibiotic.
The antibiotic inhibits production of ammonia and
other organic toxins produced by bacteria in the colon ( Festi
et al., 2006 ; Rothenber and Keeffe, 2005).