The Diagnostic Approach of Hypercortisolism in Dogs and Cats
World Small Animal Veterinary Association World Congress Proceedings, 2006
Hans S. Kooistra, DECVIM-CA
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

Introduction

Hypercortisolism can be defined as the physical and biochemical changes resulting from chronic glucocorticoid excess. In dogs and cats there are two main endogenous forms: the adrenocorticotrophic hormone (ACTH)-dependent form, which accounts for about 85% of the cases, and the ACTH-independent form, which is due to autonomous glucocorticoid-secreting adrenocortical tumour(s). A combination of the two forms may also occur.

ACTH is synthesized from a well-characterized precursor molecule, proopiomelanocortin (POMC), which also gives rise to a number of other peptides that are co-released with ACTH. In the canine and feline pituitary, POMC- producing cells are present in both the anterior lobe (AL) and the pars intermedia (PI). ACTH secretion by the AL is regulated by the hypothalamus and the central nervous system via hypophysiotrophic hormones such as corticotrophin-releasing hormone (CRH) and vasopressin. Glucocorticoids inhibit ACTH release at the level of the AL and the hypothalamus. The POMC producing cells of the PI are resistant to glucocorticoid suppression due to the absence of glucocorticoid receptors on these cells. The dopaminergic influence of the hypothalamus is held responsible for inhibiting the expression of glucocorticoid receptors on PI cells.

Pituitary-dependent hypercortisolism (PDH) or Cushing's disease results from chronic overproduction of glucocorticoids due to excessive secretion of ACTH by the pituitary gland, resulting in hypersecretion of cortisol and in hyperplasia of the adrenal cortices. In dogs and cats, PDH is most often caused by a corticotroph adenoma that may originate in the AL or the PI. One of the functional hallmarks of corticotroph adenomas is that they are less sensitive to the suppressive feedback effects of glucocorticoids.

Adrenocortical tumours (AT) causing hypercortisolism occur in both dogs and cats. Most are unilateral lesions. The left and right adrenal glands are affected about equally. Bilateral tumours occur in about 10% of cases. Histological types range from small well-encapsulated adenomas to large adenocarcinomas with liver and lung metastases (Rijnberk, 1996).

In both dogs and cats, spontaneous hypercortisolism is a disease of middle-aged and older animals. In dogs there is no pronounced sex predilection, whereas in cats the great majority of the reported cases are females. In dogs the disease is seen more often in small breeds such as Dachshund, miniature Poodles and Yorkshire Terriers. Clinical manifestations of dogs chronically exposed to excess cortisol include polydipsia, polyuria, polyphagia, abdominal enlargement, alopecia, panting, muscle weakness and lethargy. The course of the disease is often slowly progressive and often the signs and symptoms are regarded by the owner as a consequence of aging. In cats the cutaneous manifestations are initially less pronounced than in the dog. Polyuria and polydipsia in cats with hypercortisolism may in most cases be the result of concurrent diabetes mellitus. Cats seem to be more susceptible than dogs to the diabetogenic effects of glucocorticoids. Only about 10% of dogs with hypercortisolism develops overt diabetes mellitus.

Among the routine laboratory data a consistent finding is an elevation of the plasma concentration of alkaline phosphatase (AP). In dogs, this is mainly due to the induction of an isoenzyme which has greater stability at 65 degrees Celsius than other AP-isoenzymes and is therefore easily measured by a routine laboratory procedure. In the majority of dogs with hypercortisolism decreased plasma total thyroxine levels are found. In addition, a low plasma urea level, lymphopenia and eosinopenia, an elevated plasma glucose level, and elevated liver values may be found.

Diagnosis

When the physical and biochemical changes fit in with hypercortisolism, diagnostic tests have to be performed to prove chronic glucocorticoid excess. Measurement of the plasma cortisol concentration has little diagnostic value, as the pulsatile secretion of ACTH results in fluctuating plasma cortisol levels that may at times be within the reference range. The diagnosis hypercortisolism should therefore rely on:

1.  Determination of elevated urinary corticoid excretion

2.  Determination of a decrease in sensitivity to the negative feedback effects of glucocorticoids

By determination of the urinary corticoid excretion an integrated reflection of adrenal glucocorticoid secretion is obtained, thereby adjusting for fluctuations in plasma levels. The urinary corticoid (largely cortisol) concentration is related to the urinary creatinine concentration, thus providing the urinary corticoid/creatinine ratio (UCCR), in order to obtain a value independent of the degree of urine concentration. Determination of the UCCR requires little time from the veterinarian, is not invasive (no blood collection), and has a high diagnostic accuracy (Rijnberk et al., 1988). In addition, the test procedure has the advantage of combining a test for basal adrenocortical function and a dynamic test for differential diagnosis (see below).

The UCCR is a very sensitive reflection of adrenocortical cortisol secretion. Therefore, stress during or prior to the urine collection (e.g., urine collection in veterinary practice or during hospitalisation) should be avoided as much as possible, since this activates the pituitary-adrenocortical axis and thus elevates cortisol excretion (van Vonderen et al., 1998). In addition, an elevated UCCR may be found in dogs with non-adrenal illness (Gieger et al., 2003). However, when the physical and biochemical changes point to hypercortisolism a false-positive result is highly unlikely.

In the second approach the sensitivity of the hypothalamic-pituitary-adrenocortical system to feedback suppression is tested by administering a synthetic glucocorticoid in a dose that discriminates between healthy dogs and dogs with hypercortisolism. For this purpose, the potent glucocorticoid dexamethasone is used, because dexamethasone is not measured in the cortisol assay. In this so-called dexamethasone screening test or low-dose dexamethasone suppression test (LDDST), 0.01 mg dexamethasone per kg body weight is administered intravenously. Blood for cortisol measurement is collected 8 h after dexamethasone administration. In healthy dogs the plasma cortisol concentration is still depressed (< 40 nmol/l) at this time, whereas in animals with hypercortisolism the plasma cortisol concentration remains high or may have escaped from initial suppression. In case of adrenocortical tumours the cortisol excess may be only moderate, which may pose diagnostic problems.

Another popular test to screen for the presence of hypercortisolism is the ACTH stimulation test. In principle, this test has been designed to diagnose hypoadrenocorticism (Addison's disease) and to distinguish between iatrogenic and spontaneous hypercortisolism in dogs (Feldman and Nelson, 1996; Rijnberk, 1996a). The sensitivity of the ACTH stimulation test differs in dogs with a functional adrenocortical tumour and those with PDH. About 85% of dogs with PDH will have an exaggerated cortisol response to ACTH, while only 55% of dogs with a functional adrenocortical tumour will have such a result. The main advantages of the ACTH stimulation test are its simplicity and the short duration of the test. However, the diagnostic accuracy for hypercortisolism of this test is less than that of the UCCR and the LDDST. Therefore, this test is no longer recommended in the diagnostic approach of dogs with hypercortisolism (Feldman, 2005).

Differentiation between PDH and Adrenocortical Tumour

Once the diagnosis of hypercortisolism has been made it is necessary to distinguish between pituitary-dependent hypercortisolism (PDH) and hypercortisolism due to adrenocortical tumour. Differentiation of the cause of hypercortisolism is necessary to provide a more accurate prognosis and instigate a suitable treatment protocol.

Despite a decreased sensitivity to suppression by glucocorticoids, the ACTH secretion of most dogs with PDH can be suppressed with a 10-fold higher dose of dexamethasone (0.1 mg/kg), resulting in decreased cortisol secretion. The autonomous hypersecretion by adrenocortical tumours will not be influenced by the high dose of dexamethasone. Two procedures are used, one employing plasma cortisol as a reflection of adrenocortical secretion and the other the urinary corticoid/creatinine ratio (UCCR). In both, a greater than 50% decline from baseline values is regarded as diagnostic for PDH (Galac et al., 1997).

This high-dose dexamethasone suppression test (HDDST) does not require a second test procedure when for the diagnosis of hypercortisolism the UCCRs are used. After collection of two basal urine samples the owner is asked to administer dexamethasone tablets in a dosage of 0.1 mg dexamethasone/kg body weight at 8-hourly intervals. When the UCCR in the third urine sample is 50% lower than the mean of the first two ratios, the diagnosis of PDH is justified (Galac et al., 1997).

Also the LDDST may have value in distinguishing dogs with PDH from those with a functional adrenocortical tumour. When the plasma cortisol concentration is not only measured at 8h but also after 3 or 4 h after intravenous administration of 0.01 mg dexamethasone/kg, those dogs with decreases of the plasma cortisol concentrations >50% of the basal concentration either at 3, 4 or 8 h can be regarded as pituitary-dependent (Rijnberk, 1996b). In these cases the HDDST does not need to be performed.

When suppression is less than 50% in the HDDST, either performed with plasma cortisol or UCCR, there is about equal chance the hypercortisolism is due to either adrenocortical tumour or pituitary ACTH excess that is extremely resistant to dexamethasone suppression (Feldman et al., 1996). In these cases, differentiation between the two forms of hypercortisolism should rely on measurements of endogenous ACTH and ultrasonography of the adrenals. In the great majority of dogs with functional adrenocortical tumour the basal ACTH values are completely suppressed. When an adrenocortical tumour is found on ultrasonography it is still useful to have ACTH measurements. If the plasma ACTH levels are not low, further studies are warranted, as there might be co-existent PDH (Van Sluijs et al., 1995; Greco et al., 1999). These further studies may include visualization of the pituitary.

Once the biochemical work-up indicates the presence of PDH, the pituitary is visualized if possible (Van der Vlugt-Meijer et al., 2002). This visualization is imperative in institutions where hypophysectomy or pituitary irradiation are options for treatment. If this is not the case then visualization still gives insight into the prognosis.

References

1.  Feldman EC and Nelson RW. In: Canine and Feline Endocrinology and Reproduction 2nd edn, 1996: 187-265.

2.  Feldman EC et al. JAVMA 1996; 209: 772-775.

3.  Feldman EC. Proceedings ACVIM Forum 2005. 669-671.

4.  Galac S et al. Vet Q 1997; 19: 17-20.

5.  Gieger TL et al. JVIM 2003; 17: 154-157.

6.  Greco DS et al. JAVMA 1999; 214: 1349-1353.

7.  Rijnberk A et al. Vet Rec 1988; 122: 178-180.

8.  Rijnberk A. In: Clinical Endocrinology of Dogs and Cats, 1996a: 61-93.

9.  Rijnberk A. In: Clinical Endocrinology of Dogs and Cats, 1996b: 205-212.

10. Van der Vlugt-Meijer RH et al. Mol Cell Endocrinol 2002; 197: 81-87.

11. Van Sluijs FJ et al. Vet Q 1995; 17: 113-116.

12. Van Vonderen IK et al. JVIM 1998; 12: 431-435.

Speaker Information
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Hans S. Kooistra, DECVIM-CA
Department of Clinical Sciences of Companion Animals
Utrecht University
Utrecht, The Netherlands


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