Cushing's is a disease of middle-aged to older cats (7-12 years), and may be caused by a pituitary tumor (90% are adenomas), pituitary hyperplasia, adrenal tumors, adrenal hyperplasia, by non-endocrine tumors (usually lung) or it may be iatrogenic.
Cushing's is a disease of middle-aged to older cats (7-12 years), and may be caused by a pituitary tumor (90% are adenomas), pituitary hyperplasia, adrenal tumors, adrenal hyperplasia, by non-endocrine tumors (usually lung) or it may be iatrogenic. Clinical signs in cats include uncontrolled diabetes: (PU/PD, polyphagia, weight loss), pendulous abdomen, lethargy, thin skin, recurrent infections and poor muscle mass are common. Thin skin is the hallmark of feline hyperadrenocorticism and these cats may develop open wounds just by grooming themselves. Often we see severe insulin resistance and this often predates the diagnosis of Cushing's by several months. Cushing's should always be on the differential with cats that need very high doses of insulin. The thin skin is another feature of the disease. This also occurs in the dog but it seems to be more pronounced in the cat perhaps due to later recognition.
Changes expected in the bloodwork are non-specific but include hypercholesterolemia, hyperglycemia, mild leukocytosis and erythroid regeneration (nrbcs). The serum alkaline phosphatase and alt will be elevated. In cats this is not a steroid effect; it is due to concurrent lipidosis or possibly pancreatitis. Decreased T4 and T3 caused by "euthyroid sick syndrome" and attenuated response to TSH stimulation caused by overcrowding of pituitary thyrotrophs by adrenocorticotrophs. Overt diabetes mellitus may result from the insulin antagonism caused by hypercortisolemia in about 85% of cats with hyperadrenocorticism. Urinalysis changes include glucosuria, possibly a low urine specific gravity and a secondary bacteruria.
In order to get the adrenals to suppress in the cat, the "Low-dose dexamethasone test" requires 0.1mg/kg dexamethasone sodium phosphate IV and sample plasma at times 0,2,4,6 and 8 hours after injection. Because cats may escape suppression earlier than 8 hours, so the plasma should be sampled at more frequent intervals than in dogs. Normal cats and cats with non-adrenal illnesses will consistently show cortisol suppression at this dose. However, unlike dogs, it may not suppress cats with pituitary dependent HA. Thus, we can't use it to discriminate between adrenal tumors and PDHA in cats. Rather, the feline "High-dose dexamethasone test", i.e. administering 1.0mg/kg dexamethasone IV and sampling at times 0,2, 4, 6 and 8 hours will differentiate PDHA from adrenal tumors in most cases. In the rare cat who doesn't suppress even at this dose, endogenous ACTH levels, abdominal ultrasound, CT or MRI are required to confirm the location of the tumour. There is controversy about the definitive test with some endocrinologists saying that ACTH stimulation test is the test of choice in cats. The majority of cats have pituitary dependent HA.
Ultrasound is very helpful. It can be used together with endocrine tests to provide a diagnosis of PDHA. With PDHA, one will see 2 normal or enlarged adrenal glands. With adrenal tumors there will be atrophy of the contralateral gland. In cats, adrenal calcification is a normal aging change unlike in the dog where calcified adrenals on radiography are cause for concern.
1. Control the diabetes with as much insulin as is required. This is important, not only from the perspective of glycemic control, but also because the immunosuppressive effects of glucocorticoids predispose an already prone individual to infections.
2. op-DDD (Lysodren): 25 mg/kg BID for 10 days. Check an ACTH stimulation test and if the values are below 5mcg/dl, then reduce the frequency of administration to once weekly. Retest ACTH stimulation after 4 weeks.
Note: when performing an ACTH stimulation test in cats, collect plasma at time 0, administer 2.2 units of porcine ACTH gel/kg IM (Repository Corticotropin injection USP) and collect plasma again at 1 and 2 hours post injection or administer 0.25 mg synthetic ACTH/cat IM (Cortrosyn) and collect plasma again at 30 minutes and 1 hour after injection. It is important that the reference laboratory being used has established feline reference ranges.
1. Metyrapone, which blocks adrenal conversion of 11-deoxycortisol to cortisol may be used at 65mg/kg PO q12h. Clinical improvement is expected within 5 days of initiation of therapy. Monitor blood glucose closely as diabetic cats will be prone to becoming hypoglycemic rapidly.
2. Recently, trilostane, a steroid synthesis inhibitor, has been reported for the treatment of PDHA.
Op-DDD, metyrapone or aminoglutasamine may be used to stabilize the patient prior to adrenalectomy. While the challenge is very real to stabilize these patients prior to surgery, adrenalectomy (unilateral for adrenal tumour or bilateral for PDHA) offers the best success.
Post-operatively, cats may develop sepsis, pancreatitis, thromboembolism, wound dehiscence, adrenal insufficiency and hypoglycemia. For patients who had a unilateral adrenalectomy, prednisolone 2.5mgPO q12h should be started in the evening after surgery, continued for several weeks before tapering. For bilaterally adrenalectized cats, lifelong mineralocorticoids will be required. Pituitary tumour enlargement may be treated safely and effectively with external beam radiation therapy.
There are several reports of cats with progesterone secreting adrenal gland tumours. Progestins have a similar structure to cortisol and can mimic the effects of glucocorticoids in cats resulting in the signs of hyperadrenocorticism by suppressing the hypothalamic-pituitary-adrenal axis. When insulin resistance is being evaluated in a cat, HAC, acromegaly and progesterone excess should be considered. If a diagnosis of HAC cannot be confirmed by measurement of cortisol during an ACTH response test or dexamethasone suppression test, adrenal sex hormone assays should be considered. Medical treatment using aminoglutethimide, a drug capable of inhibiting steroid hormone synthesis may be effective short-term; adrenalectomy is the recommended long-term therapy.
This condition is more common than Cushing's in the cat and may readily be misdiagnosed as renal insufficiency. The clinical signs are similar to those in the dog and include lethargy, weakness, inappetence/anorexia, vomiting, diarrhea, PU/PD. On physical examination, the patient is depressed, dehydrated, has a slow capillary refill time, weak pulses (signs of dehydration and electrolyte imbalance), hypothermic and bradycardic. The major differentials are renal insufficiency, shock and urethral obstruction.
Laboratory findings show hyperkalemia, hyponatremia, hypochloremia, hyperphosphatemia (rarely hypercalcemia), and prerenal azotemia with a concurrent low urine specific gravity (caused by medullary washout). The CBC may show a lymphocytosis and eosinophilia with a mild, non-regenerative anemia. The diagnosis is made, after initiating treatment, using the ACTH stimulation; a lack of response is diagnostic for hypoadrenocorticism.
Treatment consists of fluid therapy, glucocorticoids and mineralocorticoids. Florinef is administered at 0.1 to 0.2 mg PO q12h or DOCP at 1 mg/lb. IM or SQ every 21-28 days. Cats seem to due better on supplemental prednisolone especially in terms of eliminating GI side effects. Prednisolone also seems to be needed more in cats receiving DOCP, as DOCP has no glucocorticoid activity. Prednisolone doses are low: 1.25 to 2.5 mg once a day or q48h.
There is also an atypical form of hypoadrenocorticism that cats get probably more frequently than the form described above. This is a glucocorticoid-deficiency state in which electrolyte disturbances are not present at the time of initial presentation. Hence, the cats appear in a similar state and may be thought to have renal or gastrointestinal disease but on evaluation of the minimum database, the characteristic hyperkalemia and hyponatremia are absent. Iatrogenic secondary hypoadrenocorticism is similar but has low endogenous ACTH. Atypical Addison's responds to oral prednisolone therapy.
Conn's syndrome is a rare but recently reported condition in the cat and is caused by a unilateral neoplasm of the adrenal cortex producing excess mineralocorticoids. Cats present with systemic hypertension, muscle weakness from hypokalemia, and polyuria. This is a condition usually seen in geriatric cats and can be mistaken for renal insufficiency. Treatment consists of potassium supplementation and control of hypertension. Some require very high doses of IV and oral K supplementation to resolve the hypokalemia. Doses as high as 60-80 mEq of KCl/liter of fluids may be required in some cats. The first clinical clue to the hypertension may be retinal detachment. Blood pressures are in 200-280 systolic range. Amlodipine is indicated to reduce the hypertension and doses are titrated to effect. The diagnosis is made by documenting elevated serum aldosterone levels. Urinary fractional excretion of potassium may be very elevated. On ultrasound, a unilateral adrenal mass is found. These tumours are usually benign and surgery can be curative. If surgery is declined, then amlodipine and potassium supplementation will help to control the clinical signs. Spironolactone, a potassium-sparing diuretic works by antagonizing aldosterone receptors (2-4 mg/kg/d). Interestingly, almost all of the cats have had other endocrine disorders (esp. hyperthyroidism). It has also been seen with insulinoma, so this may be a feline example of multiple endocrine neoplasia (MEN). Given the recent number of case studies in the literature, It is recommended that primary hyperaldosteronism should be considered as a differential diagnosis in middle-aged and older cats with hypokalaemic polymyopathy and/or systemic hypertension and should no longer be considered a rare condition.
Acromegaly has been studied in the last several years with an increased level of interest as it has been discovered that ¼ to 13 of cats with diabetes may have unrecognized acromegaly. This condition is usually caused by an adenoma in the pars distalis of the anterior pituitary gland that secretes excessive growth hormone (GH). Less commonly, pituitary hyperplasia is suspected to result in acromegaly. Insulin-like growth factor 1 (IGF-1) is produced in the liver in response to the GH. GH has catabolic and diabetogenic effects, while IGF-1 has anabolic effects.
The characteristic signs of acromegaly are insulin resistance, believed to be caused by a GH-induced post-receptor defect in the tissues; most are middle-aged to older, neutered male mixed breed cats. Physical changes consisting of prognathism and a broad face, large thickened limbs with clubbed paws and organomegaly may be present but subtle. Upper respiratory stridor associated with structural changes may be seen. Organomegaly refers to hypertrophy of the heart and enlargement of the kidneys in particular.. In addition, arthropathies occur and, in some cases, there may be neurological signs from intracranial tumour expansion.
Classic signs of diabetes: PU/PD with polyphagia are present despite increasing doses of insulin. Uncharacteristic of diabetes, however, is concurrent weight gain. There are two populations of acromegalic cats: those who have been diabetic for some time and then deteriorate while the second group consists of those cats who appear to be acromegalic from the beginning of their diabetes.
Differentials that need to be considered when dealing with an insulin resistant or uncontrolled diabetic cat include treatment compliance or comprehension failure, inappropriate insulin handling, resistance associated with concurrent, uncontrolled inflammatory or infectious conditions, neoplasia or hyperadrenocorticism.
Diagnosis is suggested by measurement of increased IGF1 levels or imaging studies of the pituitary gland. If possible, GH measurements should be included. It must be noted, however, that no single antemortem test is 100% reliable as there may be false positives and negatives in any of them. GH is secreted in a pulsatile fashion. This may result in false negatives, i.e., normal GH values in an acroegalic cat and, important from a therapeutic perspective, may intermittently allow marked hypoglycemia to occur as a result of large insulin doses. IGF-1 is secreted continuously and is, therefore, theoretically more reliable. Contrast enhanced CT or MRI studies are very useful for diagnosis as well as for treatment planning, should radiation or stereotactic radiosurgery be a consideration.
There are several therapeutic options. Conservative treatment with high doses of insulin as needed may be used, however the risk is that iatrogenic hypoglycemia may occur if the insulin dose is too high for the GH surge at the time. Thus, should this form of treatment be the one chosen, the client and veterinary team needs to work closely together to ensure that the client is able to assess blood glucose levels and trends.
Medical therapeutic options are of three kinds in humans. Somatotropin analogues (octreotide, followed by longer-acting lanreotide) or more recent, long acting, once a month agents have been developed. In about 50% of humans, GH and IGF-1 secretion is controlled. Octreotride has not been effective in cats.
Pegvisomant is a GH-receptor antagonist that is used in humans but also has not been effective in cats. It isn't known whether it binds to cat GH receptors.
The third type of drug are dopamine antagonists such as bromocriptine and L-deprenyl (Selegiline). 70% of humans respond well to them but neither have been properly evaluated in cats.
Currently the best treatment option is radiation therapy with either 39 to 54 Gray (Gy) administered either once weekly for 4-5 weeks; Monday through Friday in 2.7 or 3.0 Gy fractions or twice or three times weekly. By reducing the bulk and function f the pituitary mass, neurological signs associated with mass as well as insulin resistance improve. Adjustment of insulin doses is not straightforward as resolution of insulin resistance can occur immediately or months after radiotherapy.
Hepatic IGF-1 hyperproduction does not always resolve, so while diabetic management may become significantly easier or diabetes may resolve, the anabolic effects (polyphagia, bone growth, organomegaly, etc.) may still cause problems.
Stereotactic radiosurgery is being evaluated at Colorado State University. This involves use of a gamma knife to reduce the tumor mass. Cryotherapy is another technique that has been attempted in a small number of cats.
In cats with pituitary-dependent hyperadrenocorticism, microsurgical transphenoidal hypophysectomy has been described in 7 cats; in five cats the hyperadrenocorticism disappeared. This may be another possible technique for acromegaly.
Because there are chronic, ongoing changes associated with the effects of the IGF-1, namely possible arthropathy, HCM, renal insufficiency and hypertension, these, along with quality of life must be addressed regardless of form of therapy.
Without treatment, acromegalic cats may suffer neurological damage from the mass effect, iatrogenic hypoglycemia, congestive heart failure, respiratory distress, renal failure or pain from arthropathies.
1. Skelly BJ, Petrus D, Nicholls PK: Use of trilostane for the treatment of pituitary-dependent hyperadrenocorticism in a cat. J Small Anim Pract 44: 269-72 2003
2. Neiger R, Witt AL, Noble A et al: Trilostane Therapy for Treatment of Pituitary-Dependent Hyperadrenocorticism in 5 Cats.. J Vet Intern Med 18: 160-164 2004
3. Kaser-Hotz B, Roher CR, Stankeova S, et al: Radiotherapy of Pituitary Tumors in Cats. J Sm Anim Pract 43:303-307 2002
4. Rossmeisl JH, Scott-Moncrieff JCR, Siems J, et al: Hyperadrenocorticism and Hyperprogesteronemia In A Cat With An Adrenocortical Adenocarcinoma. JAAHA 36:512-517 2000.
5. Boord M, Griffin C: Progesterone Secreting Adrenal Mass in a Cat with Clinical Signs of Hyperadrenocorticism. JAVMA 214: 666-669 1999
6. Lorenz MD, Melendez L: Hypoadrenocorticsm, Proceedings: Western Veterinary Conference 2002.
7. Greco DS: Hypoadrenocorticism in Small Animals, Proceedings: Atlantic City Veterinary Conference, 2002.
8. Moore LE, Biller DS, Smith TA: Use of Abdominal Ultrasonography in the Diagnosis of Primary Hyperaldosteronism in a Cat. JAVMA 217:213-215 2000
9. Rijnberk A, Voorhout G, Kooistra HS et al: Hyperaldosteronism in a cat with metastasised adrenocortical tumour. Vet Q 23:38-43 2001
10. Flood SM, Randolph JF, Geller ARM, et al: Primary Hyperaldosteronism in Two Cats. JAAHA 35:411-416 1999
11. Tidwell AS, Penninck DG, Besso JG: Imaging of adrenal gland disorders. Vet Clin North Am Small Anim Pract 27: 237-54 1997
12. Duesberg C, Peterson ME: Adrenal disorders in cats.. Vet Clin North Am Small Anim Pract 27: 321-47 1997
13. Niessen SJM, Petrie G, Gaudiano F, et al. Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med. 2007; 21(5): 899-905.
14. Berg RIM, Nelson RW, Feldman EC, et al. Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly. J Vet Intern Med. 2007; 21(5): 892-8.
15. Hurty CA, Flatland B. Feline acromegaly: a review of the syndrome. J Am Anim Hosp Assoc. 2005; 41(5): 292-7.
16. Fracassi F, Mandrioli L, Diana A, et al. Pituitary macroadenoma in a cat with diabetes mellitus, hypercortisolism and neurological signs. J Vet Med A Physiol Pathol Clin Med. 2007; 54(7): 359-63.
17. Niessen SJM, Khalid M, Petrie G, et al. Validation and application of a radioimmunoassay for ovine growth hormone in the diagnosis of acromegaly in cats. Vet Rec. 2007; 160 (26): 902-7.
18. Abraham L, Helmond SE, Mitten RW, et al. Treatment of an acromegalic cat with the dopamine agonist L-deprenyl. Aust Vet J 2002; 80: 479-483.
19. Kaser-Hotz B, Roher CR, Stankeova S, et al.. Radiotherapy of pituitary tumours in five cats. J Small Anim Pract. July 2002; 43 (7): 303-7
20. Mayer MN, Greco DS, Larue SM. Outcomes of pituitary tumor irradiation in cats. J Vet Intern Med. 2006; 20(5): 1151-4.
21. Littler RM, Polton GA, Brearley MJ. Resolution of diabetes mellitus but not acromegaly in a cat with a pituitary macroadenoma treated with hypofractionated radiation. J Small Anim Pract. 2006; 47 (7): 392-5.