Hypoadrenocorticism (Addison disease) is an uncommon disease in dogs and has been referred to as the great pretender because its clinical manifestation often mimics that of other common diseases.1 Most dogs are affected by primary hypoadrenocorticism caused by immune-mediated destruction of all layers of the adrenal cortex, which results in deficiencies of glucocorticoid (cortisol) and mineralocorticoid (aldosterone).2 Typically, dogs with hypoadrenocorticism have hyponatremia and hyperkalemia (MGDH). However, dogs with hypoadrenocorticism sometimes have no alterations in Na and K concentrations (GDH). Dogs with GDH represent a minority (4% to 24%) of the cases, but identifying GDH is a major diagnostic challenge.3–5
The criterion-referenced standard for the diagnosis of hypoadrenocorticism is the ACTH stimulation test.6,7 Measurement of the basal cortisol concentration was established as an effective screening test to rule out hypoadrenocorticism in dogs.6,7 A basal cortisol concentration of < 2 μg/dL has a high sensitivity (100%) and also a high negative-predictive value for ruling out hypoadrenocorticism in dogs that are not receiving corticosteroids, mitotane, or ketoconazole.6,7 However, measurement of cortisol concentrations is not typically conducted unless hypoadrenocorticism is already suspected, which makes it less useful as an initial screening test.
Various routine hematologic and biochemical variables have been evaluated in an attempt to improve the screening process and optimize decision making regarding cortisol measurements. A Na-to-K ratio of < 27 is useful as a screening value for MGDH but not for GDH.8 Hypocholesterolemia, hypoalbuminemia, and lack of a stress leukogram were suggested as markers for GDH, but their use as screening variables were not assessed.4 In 1 study,8 the total lymphocyte count combined with the Na-to-K ratio provided more accurate screening for hypoadrenocorticism, compared with screening by use of the Na-to-K ratio alone or the lymphocyte count alone.
Corticosteroid-induced ALP is one of several isoenzymes of ALP.9–12 Typically, CiALP is detected in canine serum after dogs have had prolonged exposure to endogenous or exogenous glucocorticoids.9 Elevations in CiALP activity have been reported for dogs with hyperadrenocortisolism, diabetes mellitus, hypothyroidism, and other chronic diseases that affect the hypothalamic-pituitary-adrenal axis.10,13–15 Thus, high CiALP activity is a sensitive but not specific test for hyperadrenocortisolism, which restricts its use to that of a screening variable.10,13,16
The objective of the study reported here was to assess the diagnostic value of CiALP activity and other variables that are routinely measured on a CBC and biochemical analysis of dogs suspected of having hypoadrenocorticism. Because of the effect of stress during chronic disease on CiALP activity and the fact that dogs affected by hypoadrenocorticism are cortisol deficient, we hypothesized that CiALP activity would be within the reference interval in dogs with hypoadrenocorticism and therefore would be a good means to discriminate between hypoadrenocorticism and the diseases it mimics. The CiALP activity can be measured by automated biochemical analyzers as a part of routine biochemical analysis, which makes it a good candidate to use to screen for hypoadrenocorticism (particularly GDH). We further hypothesized that the combination of CiALP activity with results of other routine hematologic tests (eg, lymphocyte count) would yield an improved discriminatory test for hypoadrenocorticism in dogs.
Support for Dr. Borin-Crivellenti was provided by the São Paulo Research Foundation (FAPESP; process No. 2013/0027-6).
Presented in part as an abstract at the American College of Veterinary Internal Medicine Forum, Nashville, Tenn, June 2014.
Akaike information criterion
Area under the curve
Corticosteroid-induced alkaline phosphatase
Mineralocorticoid- and glucocorticoid-deficient hypoadrenocorticism
Receiver operating characteristic
Advia 2120i, Siemens Healthcare Diagnostics, Tarrytown, NY.
Cobas 6000 c501, Roche Diagnostics, Indianapolis, Ind.
Immulite, Diagnostics Products Corp, Los Angeles, Calif.
R, version 3.2.3, The R Foundation for Statistical Computing, Vienna, Austria. Available at www.R-project.org. Accessed Dec 11, 2015.
2. Boag AM, Christie MR, McLaughlin KA, et al. Autoantibodies against cytochrome P450 side-chain cleavage enzyme in dogs (Canis lupus familiaris) affected with hypoadrenocorticism (Addison's disease). PLoS One 2015; 10: e0143458.
3. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979–1993). J Am Vet Med Assoc 1996; 208: 85–91.
4. Thompson AL, Scott-Moncrieff JC, Anderson JD. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985–2005). J Am Vet Med Assoc 2007; 230: 1190–1194.
5. Lifton SJ, King LG, Zerbe CA. Glucocorticoid deficient hypoadrenocorticism in dogs: 18 cases (1986–1995). J Am Vet Med Assoc 1996; 209: 2076–2081.
6. Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000–2005). J Am Vet Med Assoc 2007; 231: 413–416.
7. Bovens C, Tennant K, Reeve J, et al. Basal serum cortisol concentration as a screening test for hypoadrenocorticism in dogs. J Vet Intern Med 2014; 28: 1541–1545.
8. Seth M, Drobatz KJ, Church DB, et al. White blood cell count and the sodium to potassium ratio to screen for hypoadrenocorticism in dogs. J Vet Intern Med 2011; 25: 1351–1356.
9. Dorner JL, Hoffmann WE, Long GB. Corticosteroid induction of an isoenzyme of alkaline phosphatase in the dog. Am J Vet Res 1974; 35: 1457–1458.
10. Teske E, Rothuizen J, de Bruijne JJ, et al. Corticosteroid-induced alkaline phosphatase isoenzyme in the diagnosis of canine hypercorticism. Vet Rec 1989; 125: 12–14.
11. Wiedemann AL, Charney SC, Barger AM, et al. Assessment of corticosteroid-induced alkaline phosphatase as a prognostic indicator in canine lymphoma. J Small Anim Pract 2005; 46: 185–190.
12. Hoffmann WE, Dorner JL. Disappearance rates of intravenously injected canine alkaline phosphatase isoenzymes. Am J Vet Res 1977; 38: 1553–1556.
13. Jensen AL, Poulsen JS. Preliminary experience with the diagnostic value of the canine corticosteroid-induced alkaline phosphatase isoenzyme in hypercorticism and diabetes mellitus. Zentralbl Veterinarmed A 1992; 39: 342–348.
14. Wellman ML, Hoffmann WE, Dorner JL, et al. Comparison of the steroid-induced, intestinal, and hepatic isoenzymes of alkaline phosphatase in the dog. Am J Vet Res 1982; 43: 1204–1207.
15. Wilson SM, Feldman EC. Diagnostic value of the steroid-induced isoenzyme of alkaline phosphatase in the dog. J Am Anim Hosp Assoc 1992; 28: 245–250.
16. Solter PF, Hoffmann WE, Hungerford LL, et al. Assessment of corticosteroid-induced alkaline phosphatase isoenzyme as a screening test for hyperadrenocorticism in dogs. J Am Vet Med Assoc 1993; 203: 534–538.
17. Behrend EN, Kooistra HS, Nelson R, et al. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med 2013; 27: 1292–1304.
18. Lemeshow S, Hosmer DW Jr. A review of goodness of fit statistics for use in the development of logistic regression models. Am J Epidemiol 1982; 115: 92–106.
19. R Core Team. R Foundation for Statistical Computing. R: a language and environment for statistical computing. Vienna, Austria. Available at www.r-project.org. Accessed Dec 11, 2015.
20. Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011; 12: 77.
21. Saito M, Olby NJ, Obledo L, et al. Muscle cramps in two Standard Poodles with hypoadrenocorticism. J Am Anim Hosp Assoc 2002; 38: 437–443.
22. Feldman EC, Nelson RW. Canine hyperadrenocorticism. In: Canine and feline endocrinology and reproduction. 3rd ed. St Louis: WB Saunders Co, 2004; 252–319.
23. Hoffmann WE, Sanecki RK, Dorner JL. A technique for automated quantification of canine glucocorticoid-induced isoenzyme of alkaline phosphatase. Vet Clin Pathol 1988; 17: 66–70.