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

IV. Laboratory Assessment of Hepatic Function
393
TABLE 13-4 Total Serum Alkaline Phosphatase (AP)
Activity of Normal Adult Animals
Species U/liter Reference
Dog 39–222 Abdelkader and Hauge (1986)
30.6 9.9 Meyer and Noonan (1981)
10–82 Bunch et al . (1982)
Cat 8 0.7 Spano et al . (1983)
10–80 Peterson et al . (1983)
8.4 2.9 Meyer (1983)
1–39 Center et al . (1986)
Horse 184 57 Gossett and French (1984)
Cow 41 16 Rico et al . (1977b)
7–43 Putnam et al . (1986)
2–809 Allcroft and Folley (1941)
Sheep 91 41 Braun et al . (1978b)
63 28 Alemu et al . (1977)
21–1178 Allcroft and Folley (1941)
35–234 Leaver (1968)
Pig 100 35 Rico et al . (1977c)
27 Van Leenhoff et al . (1974)
Minipig 49 11 Kroker and Romer (1984)
osteoblasts may be involved in bone calcification. Activity
against both natural and synthetic nucleotides suggests a
role in nucleic acid metabolism.
In normal animals, the AP of serum ( Table 13-4 ) originates
primarily from liver and bone (Hoffman and Dorner,
1975; Rogers, 1976 ). Elevations of serum AP are observed
in normal growing animals or in adult animals with
increased osteoblastic activity. Serum AP activity may be
elevated in acute and chronic liver diseases. More marked
elevations indicate cholestasis, with the highest serum AP
activities observed in animals with cholangitis, biliary cirrhosis,
or extrahepatic bile duct obstruction.
The isozymes of alkaline phosphatase from various tissues
may be differentiated on the basis of differences in heat
stability, urea denaturation, inhibition by L-phenylalanine,
or by electrophoretic mobility ( Nagode et al., 1969a, 1969b ;
Ruegnitz and Schwartz, 1971 ). Alternatively, the origin
and significance of elevated serum AP may be determined
by measuring other related serum enzymes that are specific
for biliary tract disease. These include leucine aminopeptidase
( Everett et al., 1977 ), 5 NT ( Righetti and Kaplan,
1972 ), and GGT. When serum AP is significantly elevated,
overt clinical signs may allow separation of diseases
of the liver from those of tissues such as bone.
Unlike serum AST and ALT, elevations in AP are not
due simply to leakage of enzyme from damaged cells. It
was once believed that the high AP level of serum observed
in cholestatic liver disease was the result of decreased biliary
excretion of the enzyme because bile contains a great
deal of AP activity. It now is known that experimental
obstruction of bile flow stimulates de novo synthesis of
hepatic AP ( Kaplan and Righetti, 1969, 1970 ), and the
newly synthesized enzyme is refluxed into the circulation.
Partial hepatectomy also stimulates increased synthesis
of AP in the regenerating liver ( Pekarthy et al., 1972 ). It
seems likely that increased synthesis of AP is involved in
clinical extrahepatic bile duct obstruction, in intrahepatic
cholestasis, in infiltrative diseases of the liver (e.g., lymphoma,
hepatic metastases) in which terminal branches of
the biliary tree may be obstructed, and in the regenerative
processes that occur following liver injury.
There are significant species differences in the magnitude
of elevation of serum AP activity in bile duct obstruction
( Fig. 13-2 ). It has been recognized that cats differed
from dogs because in cases of extrahepatic bile duct
obstruction in cats there was inconsistent or negligible elevation
of AP. This was thought to be due to urinary excretion
of AP. Other studies have established that cholestatic
liver disease in cats can be expected to cause modest but
significant elevations in AP ( Everett et al., 1977 ), and
induction of alkaline phosphatase synthesis following bile
duct obstruction occurs in cats as it does in other species
( Sebesta et al., 1964 ).
In dogs, three AP isoenzymes (intestinal, steroid
induced, and hepatic) have been identified ( Wellman et al.,
1982b ). Two genes appear to be responsible for AP production
in dogs (Hoffmann and Dorner, 1977; Solter and
Hoffmann, 1995, 1999 ). The first is the AP gene responsible
for the AP isoforms of the liver, bone, and kidney
in which differences in posttranslational processing are
responsible for differences in glycosylation patterns ( Solter
and Hoffmann, 1995 ). The second gene codes for intestinal
AP and is specific for the AP isoenzyme of the intestinal
mucosa ( Solter and Hoffmann, 1995 ). AP can be induced
in dogs, but not in cats, by endogenous or exogenous steroidogenic
hormones and the steroid-induced isoenzyme is
of hepatic origin ( Wellman et al., 1982a ). Increased serum
activity of the hepatic AP isoenzyme in cholestasis is due
to enhanced translation and not to increased gene expression
( Seetharam et al., 1986 ). Hepatic AP enters the serum
either from the biliary canaliculus via the paracellular
shunt pathway or is derived directly from plasma membranes.
Increased bile acid concentrations associated with
cholestasis are believed to contribute to the release and
transport of solubilized hepatic AP to the serum ( Everett
et al., 1977 ; Sanecki et al., 1987, 1990; Schlaeger et al.,
1982 ) .
Although measurement of serum GGT activity has the
advantage of specificity, total serum AP activity remains
the test most often performed in the assessment of cholestasis
in horses, dogs, and cats. Serum AP is less valuable
in the evaluation of cholestatic syndromes of cattle and
sheep because of wide fluctuations in normal AP activity
( Ford, 1958 ; Harvey and Hoe, 1971 ).