Canine hyperadrenocorticism

Introduction

Canine hyperadrenocortisolism is a relatively common condition which may occur either spontaneously or via an iatrogenic route. The spontaneous etiologies include hypersecretion of endogenous glucocorticoids from a functional adrenal tumor or hypersecretion of corticotropin or corticotropin-like substances from an idiopathic functional pituitary tumor, whilst exogenous glucocorticoid administration can lead to iatrogenic disease. Approximately 85% of dogs with spontaneous hypercortisolism have pituitary-dependent hyperadrenocorticism (PDH), which results from excessive corticotropin secretion arising from either a microadenoma or a macroadenoma of the pituitary gland 1. Approximately 90% of all pituitary tumors are functional, with the hypersecretion of corticotropin resulting in bilateral adrenal hyperplasia.

The hypothalamic-pituitary-adrenal axis 

The adrenal cortex is composed of three distinct anatomical regions, the zona glomerulosa, zona fasiculata and zona reticularis, with glucocorticoids being produced in the zona fasiculata under the control of the hypothalamic-pituitary-adrenal (HPA) axis. The hormone corticotropin (or adrenocorticotropic hormone, ACTH) is secreted by the adenohypophysis of the pituitary gland, with the primary function of stimulating the adrenal cortex. Secretion occurs in a pulsatile manner and is stimulated by stress, but is normally controlled by the negative feedback of serum glucocorticoid levels. Corticotropin in turn is controlled by release of corticotrophin releasing hormone (CRH), secreted by the hypothalamus, again in a pulsatile manner 23. CRH secretion is inhibited by glucocorticoids and stimulated by serotonin and epinephrine.

Diagnosis

Since diagnosis of canine hyperadrenocorticism can be complex and none of the screening tests are 100% accurate, an integrated approach to the diagnosis is required. Signalment, history, clinical findings, screening tests and specific assays for the hypophyseal-adrenal axis should all be considered carefully in a collective manner to avoid misdiagnosis and to ensure concomitant disorders are not overlooked.

Signalment, history and clinical signs 

Hyperadrenocorticism typically affects middle-aged to old, small breed dogs, with no apparent gender bias. Whilst any breed can develop the disease, Poodles, Dachshunds and Terriers appear to be at increased risk. The clinical signs are generally slow to develop and progress, and many owners consider the early stages as part of the normal aging process of their dog. Various cutaneous changes, as shown in Table 1, are often significant.

 

 

These include the classic textbook appearance of generalized bilateral symmetrical truncal alopecia (Figure 1), often accompanied by hyperpigmentation (Figure 2). Thinning of the skin (Figure 3) and calcinosis cutis are also commonly seen (Figure 4) and suppression of the immune system can contribute to chronic dermatitis and furunculosis (Figure 5). Other systemic signs are also commonly encountered, as set out in Table 2 4. It is important to question an owner about recent corticosteroid administration (topical, oral, and injectable) to rule out a possible iatrogenic cause for hyperadrenocorticism before attempting to diagnose the spontaneous form of the disease.

 

General health profile findings

If a dog is suspected of having hyperadrenocorticism after collecting the signalment, history and performing a physical examination, then blood and urine sampling (hematology and biochemistry panels, plus urinalysis and culture) is indicated. Routine laboratory findings in dogs with hyperadrenocorticism are shown in Table 3. 

                                

Diagnostic tests 

A presumptive diagnosis of hyperadrenocorticism is often made from the clinical signs, physical examination and routine laboratory findings, but diagnosis should be confirmed by a hormonal assay 567. Various tests are available to assess the HPA axis.

Low-dose dexamethasone suppression test (LDDST).

Many clinicians consider the LDDST as the diagnostic test of choice for canine hyperadrenocorticism, largely because it has a 90-95% sensitivity for dogs with PDH 8. However, the specificity can be low, therefore in animals suspected of having non-adrenal disease it is best to wait until the dog has recovered from the concurrent illness prior to testing for hyperadrenocorticism. To perform the test dexamethasone sodium phosphate is administered at 0.01 mg/kg intravenously, and serum cortisol concentrations are determined at 0, 4 and 8 hours afterwards. If the dexamethasone fails to adequately suppress circulating cortisol concentrations at both 4 and 8 hours (with levels remaining > 1 µg/dL or > 30 nmol/L) then hyperadrenocorticism can be confirmed in a dog with compatible clinical signs, although this does not determine the underlying cause. However, if there is initially suppression of cortisol levels at 4 hours post-dexamethasone (levels < 1 µg/dL or < 30 nmol/L) followed by a demonstrable increase in cortisol by 8 hours, this identifies PDH as the cause of the hyperadrenocorticism, with approximately 30% of dogs with PDH showing this “escape pattern” 5679.

Corticotropin (ACTH) stimulation test.

This is the best screening method to distinguish between dogs with iatrogenic and spontaneous hyperadrenocorticism. As well as being convenient and quick to perform, it also provides useful baseline information for treatment monitoring when using mitotane or trilostane 567. The preferred method is to take a baseline sample for serum cortisol before intravenous or intramuscular injection of cosyntropin (ACTH) at 5 µg/kg, and then determine serum cortisol an hour later. Affected dogs tend to have an exaggerated response to the cosyntropin administration, with cortisol concentrations rising to greater than 20 µg/dL (> 600 nmol/L). Low-normal baseline results with little to no response to ACTH stimulation is diagnostic for iatrogenic hyperadrenocorticism. This test will identify about 85% of dogs with PDH 56781011, but will not discriminate between PDH and an adrenal tumor if hyperadrenocorticism is present, therefore additional diagnostics, such as an abdominal ultrasound, are required. It is important to note that stressed dogs, or those with significant non-adrenal illness, can have cortisol levels elevated enough to give false positive results with this test. Ideally, a dog should be allowed to recover from its nonadrenal illness before testing is performed. 

Urine cortisol: creatinine ratio. A non-specific screening test that has a high sensitivity (85-99%) and exceptionally low specificity, the urine cortisol: creatinine ratio (UCCR) is used for its negative-predictive value and is really only useful in ruling out hyperadrenocorticism.

Once a diagnosis of hyperadrenocorticism is confirmed it is then important to determine whether the patient has a functional adrenocortical tumor or PDH. Endocrine tests which can help the clinician to differentiate the etiology include the high-dose dexamethasone suppression test and plasma endogenous ACTH concentration. Imaging techniques such as abdominal radiography, abdominal ultrasound or computed tomography/magnetic resonance imaging can also be particularly helpful (Table 4).

 

High-dose dexamethasone suppression test (HDDST).

 

This test may be used when Cushing's disease has been confirmed by means of a LDDST in order to clarify whether a dog has the pituitary or the adrenal form of the disease; a HDDST will identify the cause of the hyperadrenocorticism in approximately 75% of affected dogs. The protocol is identical to the LDDST, but with the dexamethasone administered at 0.1 mg/kg IV. If the cortisol levels are suppressed, the diagnosis is PDH.

Plasma Endogenous ACTH concentration.

Endogenous ACTH concentrations are normal to high in dogs with PDH (> 40 pg/mL or > 8.8 pmol/L) and low (< 20 pg/mL or < 4.4 pmol/L) in those with adrenal tumors. Unfortunately, about 20% of dogs with hyperadrenocorticism will have non-diagnostic results in the “grey” zone, therefore diagnostic imaging or HDDST is required to determine the cause of the hyperadrenocorticism 4. Furthermore, sample handling can be both difficult and costly, so this test is not routinely used and the clinician should discuss sample collection and processing requirements with a local laboratory before proceeding. 

Management

Before embarking on treatment, all concurrent disorders such as urinary tract infections and diabetes should be identified and treated. Although these may not completely resolve until the hypercortisolism is controlled, they can become life-threatening to the patient if ignored. Treatment of any demodicosis or secondary bacterial or Malassezia skin infections is also important, as resolution of these will improve the patient’s quality of life.

Calcinosis cutis (Figure 6) usually resolves with removal of the underlying cause, but frequent bathing in medicated shampoos and hydrotherapy are helpful. Occasionally, the surgical removal of isolated lesions may be recommended if the surgeon feels wound healing would be successful in an individual patient. Calcinosis cutis can also be treated with dimethyl sulfoxide (DMSO) gel once or twice daily until resolved 13. Serum calcium levels should be monitored, as calcium release from the larger nidus in the tissue may elevate levels. More recently the use of minocycline to treat calcinosis cutis has been reported 14. Although an antibiotic, minocycline chelates calcium and directly inhibits collagenolytic enzymes, but it is important to remember that resolution is not immediate and that the skin often looks worse before it looks better.

 

Trilostane

Trilostane acts by inhibiting cortisol steroidogenesis, as it is a competitive inhibitor of the 3-β-hydroxysteroid dehydrogenase enzyme system. The induction dose is 2-5 mg/kg PO daily (usually divided into two) and is generally well tolerated, although reported adverse effects include lethargy, decreased appetite, anorexia and vomiting. Hypoadrenocorticism can occur with overdosage but should resolve rapidly following discontinuation of the drug. The most serious potential side effect is acute adrenal necrosis, and although deaths are rare, subclinical histopathological evidence of cortical necrosis is more common. The underlying cause of the necrosis is uncertain and cannot be directly explained by the competitive inhibition of steroidogenesis; it may be due to hypersecretion of ACTH, which, as well as increasing the size of the adrenal glands, may also paradoxically result in necrosis and hemorrhage of the tissue. 

Mitotane (o,p’-DDD)

Mitotane can be used because it causes selective necrosis of the zona fasciculata and reticularis of the adrenal cortex, whereas the zona glomerulosa (which produces mineralocorticoids) is relatively resistant 13. The induction dose (administered with food) is 12.5-25 mg/kg q12H for 7 to 10 days 15. The most common side effects seen initially include signs of hypoadrenocorticism, including lethargy, vomiting, diarrhea, anorexia and weakness 16. If such signs occur, therapy should be discontinued, and glucocorticoids administered. Less commonly, disorientation, ataxia, head pressing and acute hepatopathy may be seen 17.
Water consumption or appetite may be measured to provide response to treatment, with the latter being a more precise way to monitor mitotane therapy in many cases. The dog is fed 75-80% of its normal ration, and the owner instructed to observe the point at which the dog fails to finish a meal. If water consumption is used, the owner should be alert for this decreasing to < 60 mL/kg/day. When a reduction in water or food consumption is noted, or after 7-10 days of mitotane therapy, another ACTH response test should be performed to determine whether cortisol suppression is adequate. If this is the case, cortisol levels should be in the normal range both before and after ACTH administration. To maintain suppression of cortisol secretion, mitotane is then administered at a dosage of 50 mg/kg per week. Dogs on long-term treatment should be examined and have an ACTH response test performed every 3-4 months, as incremental doses are often required to maintain adequate clinical remission.

 

Other options

Ketoconazole has a reversible inhibitory effect on glucocorticoid synthesis whilst having minimal effects on mineralocorticoid production, and has been used effectively to manage canine hyperadrenocorticism, although around 33-50% of all dogs treated will fail to respond adequately. The initial recommended dosage is 10 mg/kg q12H for 14 days, although treatment can be initiated at 5 mg/kg q12H for the first seven days to assess drug tolerance, before increasing to 10 mg/kg. The efficacy of the initial 14-day course of treatment is determined by an ACTH stimulation test.

Selegiline (L-deprenyl) hydrochloride is an irreversible monoamine oxidase (type B) inhibitor that increases dopamine levels, which in turn can inhibit ACTH release from the pituitary gland. Treatment is initiated at 1 mg/kg daily, but increased to 2 mg/kg if the response is inadequate after two months. However, only 10-15% of dogs show improvement of clinical signs with this treatment 3.

Radiation therapy of pituitary tumors is associated with a high rate of response, although most dogs require trilostane or mitotane therapy for several months after radiation treatment because of residual ACTH secretion.

Hypophysectomy has been performed successfully in dogs with PDH, but the surgery is technically difficult and not widely available. Thyroid and glucocorticoid support may be needed after surgery, and animals may lose the ability to secrete vasopressin, leading to diabetes insipidus. 

Conclusion

Early recognition of the clinical signs of hyperadrenocorticism should allow the necessary diagnostic tests to be initiated and appropriate therapy commenced if the disease is confirmed. Dogs should be checked 6-8 weeks after starting treatment, at which point there should be a marked improvement, with the most obvious and rapid response being a reduction in water intake, urine output and appetite. The skin and hair coat changes can take longer to resolve – sometimes several months – and the dermatological signs may deteriorate markedly before improving. Re-examination every 3-6 months is recommended for the remainder of the animal's life, as relapses and episodes of overdosage can occur, and regular assessment of adrenal reserve by ACTH stimulation testing is indicated.