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

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Chapter | 12 Diagnostic Enzymology of Domestic Animals
ALP
Ethanolamine
GPI-PLD + Bile acids
Plasma Membrane
Glycan
PO 4
Inositol
FIGURE 12-2 The glycosylphosphatidylinositol membrane anchor of
alkaline phosphatase and the site of release of ALP from the membrane
anchor by phosphatidyl inositol-specific phospholipase D, which is facilitated
by bile acids.
are increased in both blood and hepatic tissue and facilitate
the release of ALP from its membrane attachment, serum
and tissue bile acids are not increased in the prednisonetreated
model. However, within 2 to 4 h following cholecystokinin
(CCK) administration to initiate the enterohepatic
circulation and a flux of bile acids through the portal vein
and liver, there is a significant increase in the serum LALP
activity ( Solter et al. , 1997 ). This provides support for a bile
acid-facilitated release of ALP from hepatocyte sinusoidal
membranes, most likely by activation of PIPLD and cleavage
of the phosphatidylinositol anchor ( Fig. 12-2 ). Whether
the bile acids actually activate the PIPLD or simply allow
accessibility to the PI anchor of ALP is unclear.
The marked increase of serum CALP and presence of
CALP on the sinusoidal membrane of dogs with spontaneous
hyperadrenocorticism or chronically treated with
glucocorticoids and an absence of cholestasis provides
additional support to the conclusion that the mechanism of
serum ALP increase from liver does not require regurgitation.
Because CALP is attached to the membrane by the
same PI anchor as LALP, it is released by PIPLD during
flux of bile acids through the liver ( Solter and Hoffmann,
1995 ).
Although cholestasis is the most recognized cause of
increased LALP activity, increases in serum LALP activity
are also observed in steroid hepatopathy in dogs, especially
early in the condition ( Solter et al. , 1994, 1997 ; Syakalima
et al. , 1997 ). Mild to moderate increases in serum LALP
are also observed in dogs with other hepatic diseases and
secondary to primary conditions ranging from enteritis to
pancreatitis. In cats, increased serum LALP activity is most
commonly associated with cholestasis, cholangiohepatitis,
hepatic lipidosis, and hyperthyroidism. Increase in serum
LALP activity is the first observed laboratory abnormality
observed in cats with experimentally induced hepatic
lipidosis, occurring before the onset of hyperbilirubinemia
( Biourge et al. , 1994 ). Although the increased serum ALP
activity in hyperthyroid cats is attributed to both LALP
and BALP activity, LALP activity is the most consistently
increased isoenzyme and makes up the major portion of the
ALP activity ( Archer and Taylor, 1996 ; Foster and Thoday,
2000 ).
An increase in serum BALP activity is generally associated
with increased osteoblastic activity and has been
increasingly evaluated as a marker of bone formation in
several domestic species ( Allen et al. , 1998 ; DeLaurier
et al. , 2002 ; Price et al. , 2001 ). Increased serum BALP
activity is observed in all young animals and is up to
10-fold greater in puppies than adult dogs ( Allen et al. ,
2000 ; Sanecki et al. , 1993 ). In newborn foals, serum BALP
activity is nearly 100-fold greater than in adult serum, but
it drops precipitously during the first 3 weeks after birth
and then more gradually over the next 2 to 4 years ( Hank
et al. , 1993 ; Price et al. , 1995 ). Increased serum BALP
activity can be observed in dogs with hyperparathyroidism,
renal disease, and during fracture healing. Peak serum
total ALP activity (presumably BALP) is reported to occur
in dogs at approximately 10 days after surgical fixation of
long bone fractures and returns to normal within 2 months
with normal healing but can remain increased 3 to 5
months with delayed union ( Komneuou et al. , 2005 ). This
study reported no increase in serum ALP activity in dogs
that had nonunions and suggested that monitoring serum
ALP activity may be a useful tool for identifying dogs at
risk for progressing to nonunion. Familial hyperphosphatasemia
with increased BALP activity has been reported in a
family of Siberian huskies ( Lawler et al. , 1996 ).
By far the highest values of serum BALP have been
observed in selected cases of canine osteosarcoma, but this
is not consistently observed. Hence, serum BALP activity
has poor diagnostic sensitivity for osteosarcoma. However,
serum BALP is of prognostic value as increased preoperative
serum BALP activity is associated with shorter survival
time and disease-free (metastasis) intervals following
surgery and chemotherapy ( Ehrhart et al. , 1998 ; Garzotto
et al. , 2000 ; Kirpensteijn et al. , 2002 ). Furthermore, whereas
a drop in serum BALP activity is often noted following surgical
removal of the primary tumor, persistence of increased
serum BALP activity following surgery is associated with a
shorter survival time. Dogs with increased serum total ALP
activity did not benefit from additional chemotherapy; however,
dogs with serum ALP activity in the normal range did
benefit ( Kirpensteijn et al. , 2002 ). The absence of increased
serum BALP activity in a majority of dogs with osteosarcoma
presents an intriguing question. Cells obtained via fine
needle aspirates of all canine osteosarcomas stain positive
for ALP activity ( Barger et al. , 2005 ). The mechanism that
allows some of these patients to have increased serum BALP
activity but not others is unclear but does not appear to relate
to tumor mass ( Ehrhart et al. , 1998 ).