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

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Chapter | 13 Hepatic Function
flow (cholestasis), or the induction of enzyme synthesis
( Center, 2007 ).
The serum enzymes used in the clinical assessment
of hepatobiliary disease have high activity in the liver. In
hepatocellular or cholestatic forms of liver injury, these
enzymes are released into the serum and the increased
activity is used diagnostically. The duration of elevation in
serum activity of the enzymes of hepatic origin depends on
a variety of factors including molecular size, intracellular
location, rate of plasma clearance, rate of enzyme inactivation,
and, in some cases (e.g., alkaline phosphatase [AP])
and glutamyltranspeptidase [GGT]), the rate of hepatic
synthesis.
The serum enzyme activities that increase when hepatic
necrosis is present are alanine aminotransferase (ALT),
aspartate aminotransferase (AST), ornithine carbamoyltransferase
(OCT), glutamic dehydrogenase (GD), sorbitol
dehydrogenase (SDH), and arginase. Elevated serum
activities of AP, GGT, and 5 nucleotidase (5 -ND) are
considered to indicate either intrahepatic or extrahepatic
cholestasis.
Because of its location between the splanchnic and systemic
circulation, the liver is exposed to a wide variety of
toxins, drugs and drug metabolites, bacterial toxins, and to
infectious agents that may influence the serum activity of
enzymes from the liver. The clinical assessment of aberrations
in liver enzymes should consider the type of enzyme
change (hepatocellular versus cholestatic), the degree of
increase in serum enzyme activity, the rate at which the
increase or decrease in serum activity occurs, and whether
fluctuations in enzyme activity occur over time or if there
is a unidirectional pattern of change in enzyme activity.
The reference range is characteristically established as
that within / 2 standard deviations of the mean value
observed in a “ normal ” animal population. By definition,
this means that up to 2.5% of individuals from a “ normal ”
population can be expected to have values above such a
reference range.
1 . Serum Alanine and Aspartate
Aminotransferases
The serum activity of the aminotransferases, AST and
ALT, are measured to detect hepatocellular injury. These
enzymes catalyze the transfer of the α -amino nitrogen
of aspartate or alanine to α -ketoglutaric acid resulting in
formation of glutamate. AST and ALT have key roles in
gluconeogenesis and in formation of urea. In the liver, ALT
catalyzes the transfer of the α -amino nitrogen of alanine to
α -ketoglutarate forming pyruvate, which can be utilized in
gluconeogenesis. In muscle, ALT transaminates pyruvate
to form alanine, which then transports non-ionized nitrogen
from muscle to the liver for processing (glucose-alanine
cycle).
The activity of ALT is higher in the liver than in other
tissues and in the dog, hepatic ALT is 10,000-fold higher
than in plasma. Hepatic ALT activity is also high in cats,
humans, and experimental rodent species in which measurement
of serum ALT is used routinely in the assessment
of hepatocellular injury. Hepatic ALT activity is lower
in horses, cattle, sheep, and swine, and in these species,
serum ALT is not measured routinely.
The activity of AST is high in the liver of all domestic
species and the serum activity is used routinely in all for
evaluation of liver cell injury. However, AST activity also
is high in the kidney, heart, and skeletal muscle, so elevations
in serum AST are considered less specific for liver
disease than elevations in serum ALT.
There are differences in the intracellular distribution
of ALT and AST within the hepatocyte. In the dog, most
hepatic ALT and AST activity resides within the cytosol.
An important fraction of AST (20%) and a lesser component
of ALT are present within mitochondria ( Keller,
1981 ). Distribution of the transaminases within the zones
of the acinus also differs. ALT has the highest activity in
Zone 1 hepatocytes, and AST has the highest activity in
Zone 3 hepatocytes and the relative activity of ALT or AST
in serum may reflect the acinar zone in which liver injury
occurs ( Rej, 1989 ).
The largest increases in serum ALT are observed with
hepatocellular inflammation and necrosis. In such conditions,
progressive decreases in ALT activity may be a sign
of recovery, and a 50% or greater reduction in serum ALT
activity over several days is considered a favorable prognostic
sign. Some animals with severe hepatic disease,
however, may have normal serum ALT activity, and declining
serum ALT activity may represent a significant reduction
in viable hepatocytes or reduction in transaminase
synthesis (e.g., microcystins, aflatoxin).
Following severe, acute hepatocellular necrosis, in the
dog serum ALT activity may increase by more than 100-
fold within 24 to 48 h, peaking during the first 5 postinjury
days. If the source of the injury is eliminated, ALT activity
will return more gradually to normal within 2 to 3 weeks.
Hepatotoxicity induced by acetaminophen is associated
with marked increases in serum ALT followed by a return
to near normal values within 72 h ( Hjelle and Grauer, 1986 ;
Ortega et al., 1985 ). Acute hepatocellular necrosis associated
with infectious canine hepatitis (adenovirus) results in
increased plasma ALT activity of 30-fold, peaking within 4
days ( Wigton et al., 1976 ). Thereafter, a sustained increase
in ALT activity may indicate development of chronic
hepatitis.
In all domestic species, the activity of AST is high in
the liver and serum activity characteristically is increased
in acute and chronic liver injury. Because AST activity also
is high in the muscle, kidney, pancreas, and erythrocytes,
when cells of these tissues are damaged, the AST activity
of serum also can be expected to be elevated. There is no