Hyperadrenocorticism (Proceedings)

"Cushing's syndrome," or hyperadrenocorticism (HAC), refers to the clinical signs associated with the presence of excess glucocorticoids in the body, either from exogenous administration or endogenous production. There are three different forms of hyperadrenocorticism. Iatrogenic hyperadrenocorticism is caused by the exogenous administration of glucocorticoids. "Cushing's disease," or pituitary-dependent hyperadrenocorticism (PDH), refers to excess cortisol production due to a pituitary tumor. Hyperadrenocorticism can also be caused by an adrenal tumor (AT).

Approximately 85% of all naturally occurring HAC is pituitary-dependent. The remaining 15% are caused by adrenal tumors. Of dogs with PDH, about 85% are caused by adenomas arising from the pars distalis (anterior lobe); 15% are caused by adenomas in the pars intermedia (intermediate lobe). The majority of dogs with PDH have microadenomas that are not visible to the naked eye. Other dogs have macroadenomas that can be seen with CT or MRI. In addition to HAC, these tumors can cause neurologic signs, but typically not until >10 mm in diameter (~15%).

Dogs with PDH secrete a much larger amount of ACTH than normal dogs. This excess stimulation from ACTH then stimulates the secretion of excess cortisol from BOTH adrenal glands. This continued stimulation causes bilateral adrenomegaly.

Dogs with AT usually secrete excessive cortisol from one adrenal gland. Half of the adrenocortical tumors are adenomas, and the other half are adenocarcinomas. Since the hypothalamus and pituitary gland detect high levels of cortisol in the blood, CRH and ACTH secretion are dramatically decreased. Since the contralateral adrenal gland requires stimulation from ACTH to secrete cortisol, cortisol secretion from that adrenal gland decreases, and the gland becomes atrophic. However, the AT autonomously secretes cortisol and does not require stimulation from ACTH.

Clinical signs and clinicopathologic and radiographic abnormalities

Dogs with iatrogenic hyperadrenocorticism have very low levels of ACTH in their blood due to inhibition from the exogenous glucocorticoid. This ACTH deficiency causes bilateral atrophy of the adrenal glands.

The classic signs of HAC are panting, polyphagia, polydipsia, and polyuria. They also may have recurring skin infections or urinary tract infections. Testing for HAC is rarely, if ever, indicated in patients that do not have clinical signs. The vast majority of dogs with HAC do not have clinical signs of illness, such as vomiting, anorexia, or diarrhea. The exception is dogs with pituitary macroadenomas, or metastatic adenocarcinoma. Unless either of these is suspected, clinically ill dogs should generally not be tested for hyperadrenocorticism. Non-adrenal illness interferes with endocrine testing, and treatment for hyperadrenocorticism is rarely recommended in dogs that are clinically ill.

Physical examination of patients with HAC often reveals the characteristic pot-bellied appearance. Dermatologic changes such as alopecia (or slow hair re-growth), thin skin, pigmentation, comedones, and dermatitis may be present.

Clinicopathologic abnormalities frequently found in dogs with naturally-occurring HAC include: increased ALP, ALT, cholesterol, and glucose (mild unless diabetic—5%); "stress" leukogram (neutrophilia, monocytosis, and lymphopenia); and isosthenuria (USG <1.020). Increased ALP and cholesterol are so common in these patients that it is very unlikely that a patient has HAC if they do not have at least one of these findings.

About 50% of patients have a urinary tract infection at diagnosis of HAC. Because cortisol decreases the inflammatory response and causes isosthenuria, many of these patients will NOT have an active sediment. Therefore, a urine culture should be performed in all patients diagnosed with HAC, regardless of whether they have an active sediment.

Radiographs in dogs with HAC usually reveal hepatomegaly. An adrenal tumor may be seen, if present. Half of all adrenal tumors are mineralized. Mineralization does NOT predict whether a tumor is an adenoma or adenocarcinoma. Thoracic radiographs may reveal metastasis from a tumor. Abdominal ultrasound may reveal bilaterally enlarged adrenal glands (PDH) or one large adrenal gland (AT) and a very small contralateral gland. Metastasis may also be found with ultrasound (most frequently in the liver).

Definitive diagnosis

Diagnosis of HAC requires compatible clinical signs, clinicopathologic abnormalities, and specific endocrine tests. Specific tests for the diagnosis of HAC can be divided into SCREENING and DIFFERENTIATING tests. Screening tests, which help to identify patients with HAC, include the ACTH-stimulation test, low dose dexamethasone suppression test (LDDS), and urine cortisol:creatinine ratio (UCCR). Differentiating tests determine whether a patient with HAC has PDH or an AT. These include the LDDS, HDDS, endogenous ACTH, abdominal ultrasound, and the MRI and CT.

Screening tests for naturally-occurring HAC

While the UCCR is a very sensitive test (up to 99%), it is not very specific and may be positive in patients with other disease. This test is often useful to rule-out HAC. A negative test almost always rules-out the diagnosis of HAC. However, a positive test result requires confirmation with another screening test. The UCCR is most useful in patients in which there is a low index of suspicion for the disease.

The LDDS is a very useful test. It is very sensitive (~95%), and more specific than the UCCR (but less so than the ACTH stimulation test). This test is probably most frequently used in clinical practice because of its sensitivity and ease of administration. Briefly, a serum pre-sample (0 hr) is collected from the patient immediately prior to administration of 0.01 mg/kg dexamethasone, IV. Another sample is drawn at 4 hrs and another sample at 8 hours.

For DIAGNOSIS, not differentiation, of HAC, the clinician need only look at the 0 hr and the 8 hr samples. Remember—the dog must first be diagnosed with HAC before its etiology is determined. The 4-hr sample is not used for diagnosis. Although reference values vary with the laboratory, a dog is considered to have a normal response if the 8 hr cortisol sample is <1.4 µg/dL. A cortisol concentration greater than 1.4 ug/dL is consistent with the diagnosis of hyperadrenocorticism.

The ACTH stimulation test is the least sensitive, but most specific, of the three tests. Sensitivities as low as 60% have been reported. The test is less likely than the LDDS or UCCR to have a false positive result. The recommended protocol requires the collection of a pre-ACTH serum sample, prior to administration of 5 µg/kg (up to 250 µg) of synthetic corticotrophin, IV or IM. A post-serum sample is then collected 1 hour later. Cortisol values of <17 µg/dL are NOT diagnostic for HAC; values from 17-22 µg/dL are in the grey zone; and values >22 µg/dL are consistent with the diagnosis of HAC.

Differentiation tests

After diagnosing a patient with HAC with one of the above methods, one must determine whether the HAC is PDH or caused by an AT. This information is necessary for proper treatment of the disease. It is NOT possible to completely rule out a pituitary tumor without imaging of the abdomen and/or brain. However, it IS possible to rule it in.

The LDDS is most frequently used because of its ability to screen and differentiate. After the HAC has been diagnosed with an 8 hr sample >1.4 µg/dL, several criteria for differentiation can be evaluated.

The LDDS is consistent with PDH if: the 4 hr cortisol sample is <1.4 µg/dL; the 4 hr cortisol sample is <1/2 baseline; or the 8 hr cortisol sample is <1/2 baseline. It is important to realize that some patients with PDH do not suppress at either time point. In fact, over half of the dogs that don't suppress actually have PDH!

The HDDS is very similar to the LDDS and has a slightly increased chance of picking up a dog with PDH. The protocol is the same as the LDDS, except that the dexamethasone dose is 0.1 mg/kg, IV. The HDDS is consistent with PDH if: the 4 hr OR 8 hr cortisol sample is <1.4 µg/dL; or the 4 hr OR 8 hr cortisol sample is <1/2 baseline. Again, all dogs with PDH do NOT suppress with the HDDS. Approximately 50% of dogs that do not suppress have PDH.

Although clinically useful, the endogenous ACTH concentration is somewhat difficult to obtain due to the lability of the hormone. A blood sample must be drawn into a plastic EDTA tube and centrifuged immediately. The plasma should be separated and frozen immediately, until reaching the diagnostic lab. Intuitively, high ACTH levels are consistent with PDH, and very low levels are consistent with ADH. Unfortunately, since ACTH is secreted episodically by the pituitary, it is possible for a dog with PDH to have a low ACTH value. So, although a high value is diagnostic for PDH, a low value does NOT rule it out.

Imaging studies are often helpful in the differentiation of PDH from AT. An abdominal ultrasound that reveals bilaterally enlarged adrenal glands is consistent with a diagnosis of PDH. If there is one very large adrenal gland and a very small contralateral gland, the dog has an AT.

MRI and CT can help diagnose PDH and give an indication of how large the tumor is. Tumors greater than 10 mm may cause neurologic signs (dullness, altered mental status, anorexia, etc.). Brain imaging will differentiate a macroadenoma from a microadenoma, and help identify patients that may benefit from radiation therapy. The indications for an MRI or CT are: 1. Evaluation of a neurologic dog with HAC; 2. Discriminating PDH from AT (if macroadenoma is present); 3. Identification of patients for radiation therapy. If PDH has been diagnosed by other methods and the dog does not have neurologic signs, imaging of the brain is only indicated if the owner is willing to pursue radiation therapy if a large macroadenoma is present.

Iatrogenic HAC

A dog with iatrogenic HAC generally shows clinical signs of HAC while receiving glucocorticoids. However, if the steroid is suddenly discontinued, the atrophied adrenal glands will be unable to respond to stress, and clinical signs of hypoadrenocorticism may occur due to cortisol deficiency. Since exogenous glucocorticoids suppress ACTH secretion and may cause adrenal atrophy, an ACTH stimulation test is used to identify a patient with iatrogenic HAC. The test is performed as described above, except that the corticotrophin is given IV. A dog with iatrogenic HAC should have a flat-line response, generally with both baseline and 1 hr post-stimulation values of <1 µg/dL.

It is important to note that glucocorticoids can also inhibit the adrenal response to ACTH; some will do so for up to a month. These patients often have decreased, but not baseline, responses (post ~2 µg/dL – 5 µg/dL). Usually, careful questioning of the owner will reveal steroid administration, which may include topical steroids. Additionally, some steroids, such as prednisone, can interfere with the cortisol assay and falsely elevate the value. Thus, there should be at least a 24-48 hr "washout" period after administration of short-acting steroids, and longer for longer-acting steroids.

Treatment

Adrenal tumor

Treatment of adrenal tumors depends on the presence of metastasis and invasion of adjacent structures. Ideally, ATs are surgically removed. However, if the mass is surgically non-resectable due to the invasiveness of the tumor, an unsuitable anesthetic candidate, or owner choice, medical therapy may be attempted. Mitotane and trilostane have both been used in these cases. Mitotane is preferable if metastasis is present. Response is variable, although much higher doses may be required than with PDH.

Pituitary-dependent hyperadrenocorticism

Possible treatment modalities for PDH include hypophysectomy, medical (mitotane, trilostane), and radiation therapy. Since hypophysectomy is only performed in Europe, it will not be discussed further in these notes.

The goal of medical therapy is to decrease cortisol secretion from the adrenal cortex, thus decreasing the changes associated with HAC. The goal of radiation therapy is to shrink a pituitary tumor, either because of current neurologic signs of a macroadenoma, or to help prevent growth of the tumor. Radiation therapy does NOT usually decrease cortisol secretion, so medication must be used in addition.

Medical therapy

Mitotane and trilostane are the drugs currently recommended for medical treatment of PDH. Deprenyl and ketoconazole have also been recommended in the past. Deprenyl increases dopamine concentrations in the intermediate lobe, which decreases ACTH secretion from that lobe. However, since the majority of pituitary tumors in dogs (80-85%) arise from the anterior lobe, and dopamine does not affect ACTH secretion from the anterior lobe, the efficacy of deprenyl is less predictable and more controversial than the efficacy of mitotane and trilostane. Ketoconazole inhibits the synthesis of cortisol; however, due to its side effects and lesser efficacy, it is no longer a drug of choice for PDH.

Mitotane is a chemotherapeutic drug that induces adrenocorticolysis. Management of PDH using mitotane consists of two different phases—induction and maintenance. During the induction phase, mitotane is usually given for 7-10 days at a dose of 50 mg/kg/day, divided. When the dog shows any decrease in clinical signs (drinking, urinating, appetite) or signs of cortisol deficiency (vomiting, diarrhea, lethargy), the dog is given an ACTH stimulation test. The recommended target post-stimulation cortisol concentration range is 2-5 µg/dL. Once induction is complete (achieved the recommended post-stim cortisol), the maintenance phase may be initiated. The dog is given about 50 mg/kg/week, divided. The more the dose is divided (2, 3, or 4 times per week), the less likely the patient is to have side effects associated with drug administration itself. An ACTH stimulation test is performed 1 month after starting the maintenance phase, then once every 3 months, and when clinical signs of HAC or hypoadrenocorticism appear.

Mitotane usually is selective in that it only destroys the zona fasciculata and reticularis of the adrenal cortex. Thus, most side effects are due to cortisol deficiency. However, at higher doses, and in patients that are more sensitive to it, mitotane can also destroy the zona glomerulosa. In these cases, the patient may turn into a glucocorticoid and mineralocorticoid-deficient Addisonian. It is IMPERATIVE that owners follow dosing and testing instructions closely, and contact you if the dog shows any signs of hypoadrenocorticism, such as lethargy, inappetence, vomiting, or diarrhea. Whereas HAC is chronic in nature, hypoadrenocorticism can be rapidly fatal. If in doubt, the owner should discontinue mitotane therapy until able to contact a vet. Owners may be given prednisone to use in case of an emergency.

Trilostane is an enzyme inhibitor that decreases production of cortisol, and, to a lesser extent, aldosterone and other steroids. It has been the drug of choice for HAC in Europe and Australia, and was approved in the US at the end of 2008. It is currently the only FDA-approved medication for treatment of pituitary and adrenal-dependent hyperadrenocorticism in dogs. Although enzyme inhibition sounds less "dangerous" than the adrenocorticolysis associated with mitotane, close monitoring is vital with any drug that decreases cortisol secretion. Trilostane has been reported to cause idiosyncratic adrenal necrosis in some dogs after treatment. This may occur at any point after initiating treatment, but is rare.

There is no induction phase involved with the administration of trilostane. Initial recommendations were for a much higher dose, but some of the more current literature and the author recommend starting on a dose of 1-3 mg/kg/24 hrs in order to decrease side effects. An ACTH stimulation test is performed approximately 10 days later. The test MUST be performed 4-6 hours post-pill. (Which typically means that the owners give the pill in the morning.) The target post-stimulation cortisol concentration is 2-6 µg/dL. This range is flexible, depending on clinical response; a dog that is doing well with a post-stimulation value of 1.6 µg/dL may be fine, whereas a dog that has GI signs with a post-stimulation value of 2.1 µg/dL may need his dose decreased. Similar holds true at the upper end of the range. Depending on the ACTH stim results, the trilostane dose may be increased or decreased by 10-25%.

Some dogs don't seem to be well-controlled on once-daily trilostane dosing, likely because the duration of efficacy of trilostane is variable, from 10-18 hrs. In these dogs, the dose may be divided and given BID. In the author's experience, dogs on BID dosing will end up needing a little more than half of the SID dose given twice daily. Dogs on BID dosing appear to have a slightly increase incidence of side effects than dogs on SID dosing. One plausible explanation for this is that production of cortisol and aldosterone is inhibited for the entire day, with no chance to "escape" the inhibition to avoid a crisis.

Each time the trilostane dose is changed, an ACTH stimulation test should be run about 10 days later. After the appropriate dose is determined, the dog should return for an ACTH stimulation test 1 month later, 3 months later, and then every 3-6 months. The dose of trilostane may need to be increased, as patients seem to get more resistant to it with time.

Although mitotane has been the standard treatment of PDH in the US, trilostane is gaining popularity, particularly with recent FDA approval. It is particularly popular among newer graduates. It MUST be stressed that owners still need to be cautioned that this drug can also lead to disastrous consequences if appropriate monitoring is not followed.

One advantage of trilostane is that it simplifies the management of Cushingoid diabetics. Patient response is more predictable than with mitotane. The dose of insulin still needs to be decreased when initiating treatment for HAC. However, the dog may be started on a low dose of trilostane initially to assess how the dog's HAC and DM management are going to respond to treatment. The dose can then be increased slowly, to help prevent a hypoglycemic crisis.

Radiation therapy

As mentioned above, radiation therapy can be used to treat neurologic signs secondary to a macroadenoma. Radiation is also indicated to treat moderately-sized pituitary tumors to prevent them from causing clinical signs later. Radiation does NOT control the secretion of cortisol; this must be achieved with one of the aforementioned medications.

Clearly, the financial, emotional, and time commitments associated with radiation therapy prevent the vast majority of owners from pursuing it. However, CT/MRI should be offered to owners of all dogs with PDH that would consider radiation therapy. As our experience with treatment of HAC increases, patients are living longer, and this extended life span gives the macroadenomas time to grow and cause clinical signs of neurologic disease. One study (Bertoy EH, et al. JAVMA 208:1268,1996) showed that 50% of dogs with PDH had visible tumors at the time of diagnosis. Of these, 25% died within the next year. Of the 50% of the dogs with microadenomas, 40% had macroadenomas a year later. Radiation therapy can shrink and/or inhibit growth of the tumors.