Beware of false positives, negatives in canine hyperadrenocorticism testing

Canine hyperadrenocorticism is a commonly diagnosed endocrinopathy in small animal practice.

The diagnosis of canine hyperadrenocorticism using the low dose dexamethasone suppression test or the ACTH stimulation test is usually straightforward, but problems with false positive and false negative test results can be encountered.

The effect of nonadrenal illness on the low dose dexamethasone suppression test and the ACTH stimulation test (resulting in false positive test results) is well described. Adrenal function testing should be reserved for dogs with historical and clinical signs consistent with hyperadrenocorticism. Furthermore, the adrenal function testing of sick animals should be avoided if at all possible, and delayed until after the resolution of the nonadrenal illness if suspicion of hyperadrenocorticism remains.

Adrenal function testing

In practice, we occasionally see dogs with historical and physical examination findings consistent with hyperadrenocorticism but with normal low dose dexamethasone suppression and ACTH stimulation tests. Assuming that other disorders had been excluded, the clinician, until recently, had few options when faced with this dilemma. Waiting three to six months and repeating the adrenal function tests will yield positive test results for hyperadrenocorticism in some of these cases.

Recently, Ristic, Evans and Herrtage (2001 ACVIM Forum Abstract #107) described several dogs with clinical findings consistent with hyperadrenocorticism (such as polyuria, polydipsia, polyphagia, pendulous abdomen, dermatological abnormalities and elevated serum alkaline phosphatase levels), but with normal results on low dose dexamethasone suppression tests and ACTH stimulation tests. Both pituitary-dependent and adrenal tumor cases were described.

Recent cases

All of the cases had elevated post-ACTH serum 17-OH progesterone levels. Treatment with mitotane (Lysodren) resulted in normalization of the 17-OH progesterone levels and resolution of the clinical signs of hyperadrenocortism.

Hill, et al reported on the incidence of elevations of adrenal sex hormones in dogs with pituitary dependent hyperadrenocorticism, adrenal adenocarcinoma and noncortisol-secreting adrenal tumors (2002 ECVIM-CA/ESVIM Congress Abstract; 2003 ACVIM Forum Abstract # 60). Concentrations of testosterone, estradiol, progesterone, 17-OH progesterone and androstenedione were determined before and one hour after administration of ACTH in dogs with pituitary-dependent hyperadrenocorticism, adrenal adenocarcinoma and noncortisol-secreting adrenal tumors.

All of the dogs with adrenal adenocarcinoma, 90 percent of the dogs with pituitary-dependent hyperadrenocorticism and 67 percent of the dogs with noncortisol-secreting adrenal tumors had one or more of the hormones above the reference range after ACTH stimulation.

Dogs with adrenal adenocarcinoma had significantly higher levels of testosterone, progesterone and 17-OH progesterone after ACTH stimulation than the dogs in the other two groups.

These studies show that dogs with hyperadrenocorticism can have elevations of other adrenal hormones besides cortisol. In the case of 17-OH progesterone, it has been shown that such elevations can result in clinical signs of hyperadrenocorticism in dogs with normal low dose dexamethasone suppression test results and a normal post ACTH cortisol concentration. We have seen several such dogs in our practice.

Study findings

Historical and clinical signs of Cushing's disease were present, but the standard tests (low dose dexamethasone suppression test and ACTH stimulation test) for Cushing's disease were negative. All of these dogs had elevated 17-OH progesterone concentrations following ACTH stimulation and bilateral adrenomegaly on abdominal ultrasound examination. Treatment using the standard mitotane (Lysodren) protocol for canine pituitary-dependent Cushing's disease (induction dose followed by maintenance therapy) resulted in resolution of the signs of hyperadrenocorticism in the cases we have seen. Measurement of pre- and post- ACTH 17-OH progesterone levels can be recommended in dogs with historical and clinical signs of hyperadrenocorticism and normal low dose dexamethasone test results and a normal post ACTH cortisol concentration.

Should these results also be normal, the clinician could contemplate measuring other adrenal hormone levels before and after ACTH stimulation.