Cushing Disease (Pituitary-Dependent Hyperadrenocorticism) in Animals

Serum biochemical abnormalities associated with hypercortisolemia in dogs include the following:

• increased serum alkaline phosphatase (ALP) activity

• increased serum alanine aminotransferase (ALT) activity

• hypercholesterolemia

• hyperglycemia

• decreased BUN concentration

Hypercholesterolemia is due to steroid stimulation of lipolysis.

ALP activity is increased in dogs with hypercortisolemia primarily because of the induction of a specific hepatic isoenzyme (corticosteroid-ALP [C-ALP], found only in dogs). Some of the increase in ALP activity also comes from hepatic glycogen deposition and vacuolization impinging on the biliary system.

Cats lack the glucocorticoid-induced C-ALP isoform. ALP activity can be elevated in some cats with hyperadrenocorticism that have concomitant diabetes mellitus.

Increased serum ALT and aspartate aminotransferase (AST) activity is due to hepatocellular necrosis, glycogen accumulation, and swollen hepatocytes. Decreased serum phosphorus concentration can result from increased urinary excretion due to polyuria.

Abnormalities noted on the biochemical profile can also include hyperglycemia due to increased gluconeogenesis and decreased peripheral tissue use through insulin antagonism. Approximately 10% of dogs with hyperadrenocorticism have concurrent diabetes mellitus. In contrast, almost 80% of cats with hyperadrenocorticism have concurrent diabetes mellitus, often with insulin resistance.

In dogs and cats with hyperadrenocorticism, CBC abnormalities are nonspecific and can include evidence of RBC regeneration (erythrocytosis, nucleated RBCs) and a stress leukogram (leukocytosis characterized by mature neutrophilia, eosinopenia, and lymphopenia). Basophilia is occasionally evident.

Many dogs with hyperadrenocorticism show evidence of urinary tract infection (positive results of bacteriological culture of urine) without pyuria (WBCs in urine), bacteriuria, and proteinuria resulting from glomerulosclerosis. In cats, polyuria/polydipsia is the result of concurrent diabetes mellitus; because glucose contributes to the refractive index, however, urine specific gravity measurements usually remain > 1.020.

In dogs, cortisol-induced interference with ADH binding results in hyposthenuria, and central diabetes insipidus can occur as a result of pituitary tumor enlargement.

The LDDST is the screening test of choice for canine hyperadrenocorticism. It is a good screening test for hyperadrenocorticism when the dog has no concurrent medical conditions (eg, diabetes mellitus) or when only dermatological abnormalities are observed.

Only 5%–8% of dogs with PDH exhibit suppressed cortisol concentrations at 8 hours (ie, show false-negative results). Thirty percent of dogs with PDH exhibit suppression at 3 or 4 hours, followed by escape of suppression at 8 hours; this pattern is diagnostic for PDH, making further testing unnecessary.

The major disadvantage of the LDDST is the lack of specificity in dogs with nonadrenal illness: > 50% of dogs with nonadrenal illness have a positive LDDST result. In such cases, the patient should be allowed to recover from the nonadrenal illness before being retested for hyperadrenocorticism with an LDDST.

Another option, particularly in cats, is to perform an oral LDDST using the UCCR as the discriminator:

• Morning urine is collected for a baseline measurement on days 1 and 2.

• On day 2, after urine collection, three doses of dexamethasone (in cats, 0.1 mg/kg; in dogs, 0.01 mg/kg) are administered at 6-hour intervals, and a urine sample is collected for UCCR measurement the next morning.

• After analysis of the first two UCCRs has shown elevation in urine cortisol concentration to confirm the diagnosis of hyperadrenocorticism, the two samples can be combined into a single "pre" or baseline sample.

A decrease in the UCCR by 50% after the administration of oral dexamethasone confirms the diagnosis of pituitary-dependent hyperadrenocorticism. However, lack of suppression does not confirm a diagnosis of adrenal-dependent hyperadrenocorticism; therefore, further testing using endogenous ACTH or ultrasonography may be needed.

The ACTH stimulation test is a shorter, simpler dynamic test for the diagnosis of various disorders, including iatrogenic hyperadrenocorticism and spontaneous hyperadrenocorticism of adrenal or pituitary origin. To screen for the diagnosis of naturally occurring hyperadrenocorticism, this test has a slightly lower diagnostic sensitivity (approximately 80%–85%) than the LDDST, but a much higher specificity.

In one study, only 8 of 59 (14%) of dogs with nonadrenal disease had an exaggerated response to ACTH stimulation (10); therefore, an ACTH stimulation test is preferred for dogs with clinical signs of hyperadrenocorticism and concurrent medical conditions such as renal disease or diabetes mellitus. Adrenal tumors can be particularly difficult to diagnose using an ACTH stimulation test; however, an ACTH stimulation test is the test of choice for diagnosing iatrogenic hyperadrenocorticism.

Dogs with adrenal sex steroid excess could have a negative ACTH stimulation test and a negative LDDST, because serum cortisol concentrations are normal as a result of excess cortisol precursors. Documentation of increased concentrations of cortisol precursors, such as progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, and estrogens, can require dynamic adrenal testing using the ACTH stimulation test and measurement of both sex steroid concentrations and cortisol concentration.

After a diagnosis of hyperadrenocorticism has been confirmed, differentiation of pituitary-dependent versus adrenal-dependent disease might be necessary. Although most dogs with hyperadrenocorticism have PDH, in atypical cases (eg, anorectic dogs with hyperadrenocorticism), a differentiation test is appropriate. In particular, differentiation of PDH (often macroadenomas) from adrenal tumors is often necessary in large breeds.

The HDDST works on the principle that autonomous ACTH hypersecretion by the pituitary can be suppressed by supraphysiological concentrations of steroids. Dogs with autonomous cortisol-producing adrenal tumors have maximally suppressed ACTH production via the normal feedback mechanism; therefore, administration of dexamethasone, no matter how high the dose, cannot suppress serum cortisol concentrations. In dogs with PDH, however, the high dose of dexamethasone is able to suppress ACTH and, hence, cortisol secretion. One important caveat is that dogs with pituitary macroadenomas (15%–50% of dogs with PDH) do not suppress ACTH on the HDDST.

Measurement of endogenous plasma ACTH concentrations is the most expedient way to discriminate between PDH and adrenal tumors. Dogs with adrenal tumors have low to undetectable ACTH concentrations; in contrast, dogs with PDH have normal to increased ACTH concentrations.

Researchers have found that the addition of the protease inhibitor aprotinin to whole blood in EDTA tubes inhibits degradation of ACTH. Samples can be collected, spun in a centrifuge, and kept for up to 4 days at < 4ºC. Furthermore, new point-of-care diagnostic endocrine testing (Truforma, Zomedica) now offers ACTH testing on freshly drawn plasma samples.

Diagnostic imaging of the pituitary and adrenal glands can be accomplished via abdominal radiography, ultrasonography, CT, or MRI. Abdominal ultrasonography is a more sensitive way to identify and differentiate pituitary hyperadrenocorticism from adrenal tumors (compare images of normal adrenal glands with pituitary hyperadrenocorticism and abnormal adrenal gland with adrenal tumor). In addition, ultrasonography can demonstrate liver metastasis or invasion into the vena cava in dogs with adrenal carcinomas.

Normal adrenal glands, ultrasonograms, dog

Image

Courtesy of Dr. Deborah Greco.

Adrenal tumor, ultrasonogram, dog

Image

Courtesy of Dr. Kristina Miles.

CT or MRI of the brain and abdominal cavity in dogs that do not suppress on the HDDST can demonstrate unilateral adrenal enlargement, pituitary macroadenoma, or pituitary microadenoma.

Most cases of hyperadrenocorticism are treated with the adrenal enzyme inhibitor trilostane. Dogs with atypical or sex steroid hyperadrenocorticism and those with calcinosis cutis respond better to mitotane than to trilostane.

Trilostane, now FDA approved, is the treatment of choice for dogs with hyperadrenocorticism, with the exception of those with calcinosis cutis or atypical hyperadrenocorticism. Trilostane should be administered at a starting dosage of 1–3 mg/kg, PO, given with food every 12 hours, to achieve a decrease in glucocorticoid secretion from the adrenal glands. Mineralocorticoid insufficiency, which is reversible, also can occur in animals receiving trilostane; in addition, a few cases of adrenal necrosis with permanent adrenal insufficiency have been reported after trilostane administration.

Monitoring the effects of trilostane treatment can be difficult; however, most clinicians use the ACTH stimulation test to maintain post-ACTH cortisol concentrations in the normal range. Once-daily treatment with trilostane can be associated with transient hypoadrenocorticism, which can be difficult to identify in routine testing. Another option for monitoring is to determine pre-trilostane or 3-hour-post-trilostane cortisol concentrations. Pre-trilostane or 3-hour-post-trilostane cortisol concentrations ≤ 138 nmol/L or 62 nmol/L, respectively, are associated with excellent control, as documented by owners' observations of their pets' clinical signs (11).

Dogs with PDH can be treated with the adrenolytic agent mitotane (o,p′-DDD), beginning with an induction dosage of either 25–50 mg/kg, PO, every 24 hours or 12.5–25 mg/kg, PO, every 12 hours for 7–10 days.

Medical treatment of adrenal tumors is difficult because they tend to be resistant to the effects of mitotane. Dogs with adrenal-dependent hyperadrenocorticism require up to 4 times the usual dose of mitotane used to treat PDH to respond, and the clinical response tends to be less favorable, compared with surgical management. Cats have a poor response to trilostane or mitotane.

Dogs should be monitored for clinical signs of hypoadrenocorticism, such as anorexia, vomiting, and diarrhea; if such signs occur, mitotane treatment should be discontinued and glucocorticoids administered.

Water consumption can be measured or appetite evaluated to provide an end point for treatment; in dogs, water consumption should decrease to < 60 mL/kg, PO, every 24 hours. Assessing appetite is often a more precise way to monitor mitotane treatment. The dog is fed 75%–80% of its usual ration, and if it doesn't finish a meal, the dog should undergo ACTH response testing.

After 7–10 days of treatment with mitotane or after a decrease in water or food consumption, an ACTH response test should be performed to determine whether cortisol suppression is adequate. Cortisol concentrations measured both before and after the ACTH response test should be in the normal range.

To maintain suppression of cortisol secretion, mitotane is administered at a dosage of 50 mg/kg, PO, every 7 days. Dogs on longterm treatment with mitotane should be examined and tested for ACTH response every 3–4 months. Gradually increasing dosages of the drug are often required to maintain adequate clinical remission.

Adverse effects of mitotane at the recommended dosage include GI irritation (vomiting and anorexia), CNS disturbances (ataxia, weakness, seizures), mild hypoglycemia, and a moderate increase in ALP activity. Clinical signs such as lethargy or ataxia can be alleviated by dividing the daily dose into twice-daily administration. Persistence of CNS signs after mitotane is discontinued suggests an expanding pituitary macroadenoma.

If a dog is showing neurological signs (eg, anorexia, stupor, or seizures) and a large pituitary tumor (macroadenoma) is identified, radiotherapy of the pituitary gland is indicated.

Newer types of radiotherapy (cyberknife, gamma knife) may prove superior to previously available modalities and can treat pituitary tumors in < 3 days with minimal adverse effects. Results of radiotherapy in dogs show that it is an effective method of treatment with a low morbidity rate; however, it can take several months for the clinical signs of PDH to subside.

Radiotherapy of pituitary tumors is associated with a high rate of response; however, most dogs and cats require ancillary trilostane or mitotane treatment for several months after radiation treatment because of residual ACTH secretion.

Dogs treated with radiotherapy do well longterm because the primary disease process (pituitary tumor) has been addressed.

Surgical removal of unilateral adrenal adenomas or adenocarcinomas is indicated in some cases; however, surgical and anesthetic complications (eg, hypotension) can develop secondary to hypoadrenocorticism, which occurs immediately after tumor removal.

The median survival time for dogs with carcinomas treated by surgical excision is 778 days. The metastatic rate is 5% at the time of surgery and 14% longterm. With unilateral adrenalectomy, the mortality rate within 1 month after surgery is 14%–60%; the overall rate of cure for adrenal tumors is approximately 50%.

Bilateral adrenalectomy is the treatment of choice for feline hyperadrenocorticism because cats have a poor response to trilostane or mitotane.

Hypophysectomy is available on a limited basis and has many advantages over conventional treatments, such as rapid reversal of clinical signs and excellent prognosis. Adverse effects of hypophysectomy can include transient diabetes insipidus, infection, and complications arising from rapid reversal of hyperadrenocorticism.

In dogs with PDH that undergo hypophysectomy, 80% achieve remission, and 11% experience recurrence. Thyroid and glucocorticoid support may be needed afterward, and animals may lose the ability to secrete vasopressin, leading to diabetes insipidus as well.

The treatment of iatrogenic hyperadrenocorticism should include a change to an oral, short-acting steroid such as prednisone or prednisolone. Over several weeks, the steroid dosage is tapered (initially, 1 mg/kg, PO, every 24 hours; then 0.5 mg/kg, PO, every 24 hours; then 0.5 mg/kg, PO, every 48 hours) until the adrenal glands can respond to ACTH stimulation. Monthly ACTH stimulation tests should be performed to determine when steroid treatment can be discontinued.

Overall, the prognosis for dogs with PDH is good. Median survival time has been estimated at 2 years with or without medical treatment. However, studies have shown that dogs with early hyperadrenocorticism that have no comorbidities (eg, dermatological signs only) can live much longer when treated with either trilostane or mitotane. The cost of treatment is similar with either trilostane or mitotane because mitotane must be compounded into small doses for most veterinary patients. A recent study of dogs with PDH treated twice daily with low doses of trilostane reported a median survival of 998 days (range 26–1,832 days) (12). Radiotherapy of pituitary tumors that cause PDH and hypophysectomies are associated with a relatively good longterm prognosis (survival time 2–5 years). Median survival time for dogs after unilateral adrenalectomy is approximately 18 months.