Zycortal Symposium Proceedings

Aldosterone-to-Renin and Cortisol-to-ACTH Ratios

Due to the time and expense associated with the ACTH stimulation test, investigators have evaluated alternative methods to diagnose hypoadrenocorticism. One strategy uses the feedback principles of the hypothalamic-pituitary-adrenal axis and the renin-angiotensin- aldosterone system. In normal dogs, aldosterone concentrations should increase in response to high renin (or plasma renin activity) concentrations, and when no aldosterone is present. Thus, a low aldosterone and high renin concentration, resulting in a low aldosterone- to-renin ratio (ARR), is inappropriate in a hypovolemic, hyperkalemic patient. Likewise, ACTH stimulates the release of cortisol in normal dogs, and cortisol feeds back to the pituitary to inhibit further ACTH secretion. In hypoadrenocorticism, lack of negative feedback of cortisol on the pituitary gland results in a decreased cortisol-to-ACTH ratio (CAR). Javadi et al (JVIM, 2006) were the first group to evaluate the ARR and CAR in dogs. They compared normal dogs with Addisonian dogs, and found that while there was overlap between aldosterone, renin (plasma renin activity), cortisol, and ACTH, there was no overlap between ARR and CAR. Two later studies (Lathan et al, JVIM, 2014 and Boretti et al, JVIM, 2015) compared CAR between normal dogs, dogs with non-adrenal illness (or diseases mimicking Addison’s), and dogs with Addison’s. There was no overlap between the CAR in dogs with Addison’s vs healthy dogs and dogs with non-adrenal illness in the Lathan study, but there was overlap between two dogs with Addison’s and dogs in the non-adrenal illness category in the larger Boretti study. No dogs with secondary hypoadrenocorticism were included in the former study, and only one dog in the latter. Thus, no conclusions could be made regarding the CAR in dogs with secondary Addison’s. Importantly, even though there was minimal overlap between the CARs of Addisonians and non-Addisonians in all three studies, the ranges for the CARs for each group differed between studies. Due to these inconsistencies, the CAR cannot be recommended for definitive diagnosis of Addison’s at this time. Although definitive diagnosis of Addison’s requires an ACTH stimulation test, the disease can be ruled out by evaluating baseline cortisol values. If the baseline cortisol is >2 µg/dl (>55 nmol/l), the dog is very unlikely to have hypoadrenocorticism. If the baseline cortisol is <2 μg/dl (55 nmol/l), or <3 ug/dl with a very high suspicion of disease, an ACTH stimulation test MUST be run to confirm the diagnosis. A recent study (Gold et al, JVIM 2016) evaluated cut-off values of <2 μg/dl (55 nmol/l) and found that a basal cortisol concentration of <2 μg/dl had a sensitivity of 99.4%, and a concentration <0.19 μg/dl (5.5 nmol/l) had a specificity of 99.1% for the diagnosis of hypoadrenocorticism. The study included 163 dogs with Addison’s, and 351 dogs with non-adrenal illness. Three dogs with non-adrenal illness had baseline cortisol concentrations <5.5 nmol/l, meaning that these patients would have been falsely diagnosed with Addison’s using that cut-off value alone. Thus, further studies are needed to determine whether other diagnostic criteria may help increase the specificity and eliminate false positives, as inappropriately treating a dog with glucocorticoids and mineralocorticoids for life has significant negative financial and medical consequences. Baseline Cortisol

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