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

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Chapter | 27 Clinical Biochemistry in Toxicology
blood flow delivers the bile acids to the liver where, in
healthy animals, they are efficiently cleared by the hepatocytes.
Increased serum bile acids in fasting animals are
a result of decreased biliary excretion or decreased clearance
by hepatocytes. Increased serum bile acids are highly
sensitive for hepatobiliary dysfunction; however, there are
many diseases that may cause hepatobiliary dysfunction
( Stockham and Scott, 2002 ). Bile acids may be useful for
detecting hepatic dysfunction in instances where enzyme
levels or clinical signs are equivocal ( Lassen, 2004 ). Acute
toxic hepatic necrosis increases serum bile acids (cholic
and chenodeoxycholic) in the dog, horse, sheep, and cow
( Bain, 2003 ). Some studies have recommended tests for
urine bile acids as a possible alternative to serum bile acids
to detect hepatic dysfunction in the dog and cat ( Balkman
et al. , 2003 ; Trainor et al. , 2003 ).
Ammonia is generated by microbial activity and digestion
of protein within the intestinal tract. It is absorbed
from the intestine and transported to the liver by the portal
venous system where it is converted to urea by the healthy
liver. Elevations of plasma ammonia during fasting or following
ammonia challenge suggest reduction in clearance
from the blood, frequently resulting from a decrease in
functional hepatic mass. Urea toxicosis in cattle and consumption
of ammoniated forages by cattle can result in
high plasma ammonia levels because of increased production
and consumption of ammonia, respectively ( Stockham
and Scott, 2002 ).
Severe hepatic insufficiency may result in hypoproteinemia
(Kaneko, 1997a) with reduction of plasma oncotic
pressure that promotes tissue edema and effusions that
mimic the effects of cardiotoxins ( Table 27-3 ) .
The clinical signs of acute submassive or massive
hepatic necrosis may include anorexia, vomiting, icterus,
hepatic encephalopathy, disseminated intravascular coagulopathy,
edema, and effusions. Surprisingly, there may be
few or no clinical signs in some cases. The activity of ALT
and SDH with short half-lives may be elevated but often
fall rapidly. Inducible enzymes such as ALP and GGT may
increase gradually. All enzymes may return to normal in the
presence of chronic severe liver disease. Hyperbilirubinemia
may follow if lesions progress to chronicity and fibrosis.
Chronic hepatotoxicity has sequelae for most organ systems,
but especially the nervous (hepatic encephalopathy),
integumentary (secondary photosensitization in herbivores),
and cardiovascular systems. Cardiotoxins and pneumotoxins
may produce enzyme elevations suggestive of hepatic
or renal disease as a result of ischemia/hypoxia.
Ingestion of toxic plants ( Table 27-1 ) tends to be more
common in herbivores than carnivores; however, nonherbivorous
species are often susceptible if they are willing
to ingest them. In addition to hepatotoxins, the blue-green
algae (actually classified as cyanobacteria), which contaminate
water (Carmichael, 1994), possess neurotoxins that
may induce sudden death that precedes alterations of clinical
biochemistry and morphological changes. However, one
report documents marked elevations of ALT and AST in
a dog 12 h post ingestion of a blue-green algae ( DeVries
et al. , 1993 ).
Therapeutic drugs can also occasionally have hepatotoxic
effects in animals. Nonsteroidal anti-inflammatory
drugs, barbiturates, antineoplastic agents, and antiparasitic
compounds have all been found to have hepatotoxic effects
( Kristal et al. , 2004 ; Macphail et al. , 1998 ; Roder, 2003 ).
Carprofen, a nonsteroidal anti-inflammatory drug, has been
reported to cause acute hepatocellular necrosis and cholestasis
in some dogs. This adverse reaction is associated
with marked increases in serum ALT, AST, ALP, and total
bilirubin ( Macphail et al. , 1998 ). The antineoplastic drug
1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) is
reported to occasionally cause hepatotoxicity in dogs with
increases in ALT, AST, ALP, GGT, and bilirubin noted in
the affected dogs ( Kristal et al. , 2004 ).
Hepatotoxic plants of the order Compositae include
Asaemia axillaris, Athanasia trifurcata, Helichrysum
blandowskianum, Lasiospermum bipinatum, and Xanthium
spp. The toxin in these plants has been identified as carboxyatractyloside.
Profound hypoglycemia is reported as a
finding in carboxyatractyloside poisoned animals ( Barr and
Reagor, 2001 ).
Cycadales contain methylazoxymethanol, which is converted
by hepatic microsomal activity to potent alkylating
agents. A report of dogs ingesting cycads indicates bilirubin,
ALT, and ALP are most commonly elevated values on
the chemistry panel ( Albretsen et al. , 1998 ).
Hepatotoxic plants of the order Myoporaceae include
Myosporum deserti, M. acuminatum, M. insulare,
M. tetramdum, and M. laetum . These plants contain furanosesquiterpenoid
oils, the best characterized of which is
ngaione.
Chronic intoxication of swine with fumonisins, mycotoxins
produced by Fusarium moniliforme , is associated
with elevations of serum total bilirubin, ALP, AST, GGT,
and cholesterol ( Casteel et al. , 1994 ). In addition, fumonisins
inhibit N-acetyl transferase resulting in loss of complex
sphingolipids and accumulation of sphinganine and sphingosine
in tissues and serum ( Riley et al. , 1993 ).
Iron toxicity from nutritional supplements may produce
hepatic necrosis in foals ( Acland et al. , 1984 ) and pigs
( Kelly, 1993 ). Excessive dietary copper may be associated
with elevation of GGT in goats (Solaimen et al. , 2001) and
llamas ( Weaver et al. , 1999 ).
Hepatotoxic pyrrolizidine alkaloids are found in the
plant species Amsinckia intermedia, Crotolaria spp.,
Cynoglossum officinale, Echium plantagineum, Heliotropium
europeaum, Senecio jacobea, S. vulgaris, and
S. longilobus. Acute intoxications with these plants result in
large increases in AST, ALP, GGT, and SDH ( Stegelmeier,
2003 ). Chronic exposure to small amounts of the plant is
more difficult to detect, though serum GGT levels have been