Diagnostic approach in dogs with increased ALP activity (Proceedings)
An increase in serum alkaline phosphatase (ALP) activity is a common laboratory finding in dogs. It is typically used as a diagnostic marker for cholestatic liver disease. However, increased ALP activity has a high sensitivity (86%) but poor specificity (49%) for canine liver disease. This is due to the large number of non-hepatic diseases and drugs that may induce production of this enzyme. Alkaline phosphatases comprise a heterogeneous group of enzymes, widely distributed in mammalian cells, for which the exact physiologic function is unknown. ALP has been isolated from the kidney, liver, bone, placenta, and intestine of dogs. Dogs also produce a unique isoform, in response to increased endogenous or exogenous corticosteroids. Although numerous isoforms have been identified, only three have long enough half-lives (approximately 70 hours) to be detected in canine serum. These include the liver isoform (L-ALP), bone isoform (B-ALP), and corticosteroid isoform (C-ALP). Isoforms from the intestine, kidney, and placenta are not detected in the serum because of the short half-life (minutes). The total ALP is routinely measured. The C-ALP isoform, but not the L-ALP or B-ALP isoform can be specifically measured in some diagnostic laboratories.
The proportion of isoforms in the serum of normal dogs varies with age. In dogs less than one year of age, the B-ALP predominates, because of increased osteoblastic activity that occurs with bone growth. In dogs older than one year, L-ALP predominates. C-ALP comprises 10-30% of total ALP in normal dogs. As dogs age, the proportion of B-ALP progressively decreases to approximately 25%, and the proportion of C-ALP increases to about 30%. The liver isoform is associated with bile canaliculi and sinusoidal membranes. Increased L-ALP occurs with hepatobiliary disease, both from increased production of the enzyme and elution from hepatocyte and biliary epithelial membranes. The largest increases occur with cholestasis. Phenobarbital is the best characterized example of drug-induction of L-ALP. Glucocorticoids also induce L-ALP as well as C-ALP (discussed below).
C-ALP is synthesized de novo by the liver in dogs after exposure to endogenous or exogenous glucocorticoids. C-ALP cannot be used as a diagnostic test for hyperadrenocorticism (or recent glucocorticoid administration), because it is increased in many other situations beyond excess glucocorticoids. Most dogs with hyperadrenocorticism have increased C-ALP, which accounts for 70-100% of the total ALP; however, specificity for hyperadrenocorticism is low (18%). Consequently, the clinical usefulness of C-ALP in the evaluation of dogs suspected to have hyperadrenocorticism, is that the absence of C-ALP makes hyperadrenocorticism unlikely. Other causes of increased C-ALP include phenobarbital therapy, diabetes mellitus, primary liver diseases, and acute or chronic stress or illness that is associated with increases in endogenous glucocorticoids. Progesterones are also thought to induce C-ALP production in dogs.The effects of corticosteroid administration on serum ALP have been studied. Increased ALP is due to enzyme induction, and does not reflect hepatic dysfunction. Dogs treated experimentally with immunosuppressive doses of prednisone (4.4 mg/kg/day IM) for 10 days had an increased total ALP by 3 days with progressive increases over the 10-day period. Initially, the isoform was primarily L-ALP. C-ALP was first detected at 7 days, but by day 10 was still only 6% of the total ALP. This probably reflects delayed expression of the steroid ALP gene expression in liver tissues. With exogenous corticosteroid administration, the percentage of C-ALP increases over time. In the clinical setting, dogs treated with corticosteroids (dose and duration not defined) had 60-100% of the total ALP attributed to C-ALP. There appears to be substantial individual variation. Topical ophthalmic and otic preparations that contain glucocorticoids can also have significant systemic absorption, induce ALP activity, and cause clinical features of hypercortisolemia. When corticosteroids are discontinued, increases in ALP activity will persist for variable periods of time, depending on the dose, duration, and type of corticosteroid. Three weeks duration is suggested for short-acting glucocorticoids (prednisolone) and 5 weeks for longer-acting corticosteroids. Higher (immunosuppressive doses) will also prolong the duration. Most dogs with iatrogenic hyperadrenocorticism (caused by a variety of preparations and dosages), had a return of ALP to baseline by 6 weeks. However, dogs receiving prednisone at 4.4 mg/kg/day IM for 14 days, ALP remained increased at 8 times baseline at 6 weeks after stopping therapy.
B-ALP is attached to the cellular membrane of osteoblasts. Increased serum levels are seen with bone growth in young animals, osteosarcoma, fracture healing, and nutritional bone disease. Increases in B-ALP in dogs with osteosarcoma are usually mild (less than 4x the upper limit of normal) and are associated with a poor prognosis. Increases are found in tumors with increased osteoblastic activity (osteoblastic osteosarcoma). Benign familial hyperphosphatasemia, a rare condition described in Siberian Huskies, is associated with increased B-ALP.