Managing problematic patients with Cushings syndrome (Proceedings)

Hyperadrenocorticism is a common endocrinopathy in middle to older aged dogs. Common clinical signs to make the clinician suspicious of hyperadrenocorticism include polyphagia, polyuria/polydipsia, pyoderma, pot bellied appearance, and persistent urinary tract infections.  Physical examination findings include hepatomegaly,truncal obesity,muscle wasting,panting,bilaterally symmetrical alopecia,thin, hyperpigmented skin, calcinosis cutis, and lipid deposits. 

On routine bloodwork, the clinician can see these CBC changes with hyperadrenocorticism:  erythrocytosis, neutrophilia with a left shift, stress leukogram, mature neutrophilia, monocytosis, eosinopenia, and lymphopenia.  Chemistry profile changes include:  hyperglycemia (mild), elevated liver enzymes (both SAP and ALT, although SAP may be very high), elevated cholesterol, and lipemia.  Urinalysis may reveal:  low specific gravity and an active sediment suggesting a urinary tract infection.

Dogs get hyperadrenocorticism in 2 ways:  pituitary tumors (85%) and adrenal tumors (15%).  Both produce an excess of cortisol that causes the disease entity.  Diagnosing hyperadrenocorticism presents a challenge to the veterinarian.  Three screening tests are available.  The urine cortisol:creatinine ratio is very sensitive (100%) although not specific.  Therefore if the urine cortisol:creatinine ratio is positive, another screening test will be necessary in order to diagnose the disease.  The practitioner should have the owner collect the first morning urine for 3 days in a row.  They should be measured separately, but within the same reagent group.  If all are in the normal range, hyperadrenocorticism is virtually ruled out.  A second screening test for hyperadrenocorticism is the low dose dexamethasone suppression test.  It is sensitive (89-92%) but with a decrease in specificity (75%).  It is least specific in animals with concurrent disease.  The practitioner measured cortisol before and 4 and 8 hours after administration of 0.01 mg/kg dexamethasone. The low dose dexamethasone suppression test is can differentiate between pituitary and adrenal-dependent disease.   A third screening test for hyperadrenocorticism is the ACTH Stimulation Test.  It is less sensitive  (75-83%) than the low dose dexamethasone test but it is more specific (85%).  It is more specific in animals with concurrent disease. The practitioner measures cortisol before and 60 min after injection of 5 ug/kg synthetic ACTH (cortrosyn).  Aldosterone can also be measured in cases of potential aldosterone secretion abnormalities.

The practitioner should determine whether the patient has pituitary  or adrenal dependent disease.  This will direct therapy choice as well as help predict cost of treatment, explain potential neurologic disease, predict time of resolution of signs, and mitigate owner frustration with therapy (hopefully).  Differentiating tests include the low dose dexamethasone suppression test with the 4 hour time point showing suppression in the face of a unsupressable cortisol at the 8 hour time point.  An endogenous ACTH concentration can be evaluated.  Adrenal tumors  have low endogenous ACTH levels (<10 pg/ml).  Some pituitary tumors will have have very high levels of ACTH.  The problem with the endogenous ACTH measurement as a sole test is that there is significant overlap between ACTH in normal animals and those with pituitary dependent disease.  Also mishandling of the plasma sample will result in artificially low ACTH levels, leading the practitioner to erroneously conclude the presence of an adrenal tumor.  Abdominal ultrasound can be very helpful in identification of an adrenal tumor or bilateral adrenal hyperplasia.  The practitioner should be cautious in interpreting results of an abdominal ultrasound in that adrenal masses may be nonfunctional, may be a pheochromocytoma, or the animal may have pituitary-dependent disease as well as an adrenal tumor.  Bilateral adrenal hyperplasia may also occur in animals with concurrent non-adrenal disease.

Medical treatment of hyperadrenocorticism includes trilostane (Vetoryl) and mitotane (Lysodren).  Ketoconazole and deprenyl (anipril) have also been advocated, but are substantially less effective than trilostane or lysodrem. Surgical options include adrenalectomy and hypophysectomy, although there are few surgeons in the US doing this presently.

Lysodren is a DDT derivative.  It kills adrenocortical cells with a preference for the cortisol producing ones (zonae fasciculata and reticularis).  The induction phase consists of administering 35-50 mg/kg PO q.d. x 5-7 d.  The maintenance phase is 35-50 mg/kg PO divided twice per week.  The practitioner works with the 500 mg tablet size or may have it compounded.  Owners should be discharged with instructions to call the veterinarian if any of the danger signs including loss of appetite, lethargy, vomiting, diarrhea, or “just aint right” occur.  The practitioner should also send home at least 2 doses ofprednisone at 0.5 mg/kg to be given if the animal becomes ill from the mitotane.  Side effects of mitotane include:  adrenal cortical destruction producing a glucocorticoid-deficient addisonian or a full-blown addisonian.  Often  the adrenocortical deficiency is reversible.  Another side effect is liver toxicity.  This often resolves once off Lysodren, but it can't be used again. 

Monitoring Lysodren therapy should occur after the induction phase.  An ACTH-stimulation test should be performed the morning after the last dose of Lysodren during the induction phase.  Ideally the cortisol should be within the normal range pre- and post- ACTH injection.  The practitioner should also perform bloodwork to evaluate the liver.  Clinical signs of the animal should be discussed with the owner. In cases where the ACTH-stimulation test results do not agree with the resolution (or non resolution) of clinical signs reported by the owner, the clinical signs should be believed.  

Trilostane if a competitive 3B-OH steroid dehydrogenase inhibitor that inhibits the conversion of pregnenolone to progesterone in the adrenal gland.  This blocks the formation of the end products of progesterone including cortisol and aldosterone.  Trilostane can be compounded but recently a manufactured product has become available (Vetoryl).  The drug must be given daily.  The recommended dose is 1.5-3 mg/kg, with the lower dose given bid considered safer and more efficacious.  Side effects of trilostane are similar to those of lysodren and prednisone should be sent home with the owner similarly to that done with lysodren therapy. 

Side effects of trilostane include glucocorticoid, mineralocorticoid or glucocorticoid + mineralocorticoid  deficiency.  Complete adrenal necrosis has been reported.  Over time adrenal glands will get enlarged and irregular, but no problems with this have been noted.  Investigators have reported elevations of 17 OH progesterone which indicates that trilostane has other actions that those expected based on just its pharmacology.

Trilostane therapy should be monitored 7-10 days after initiation.  An ACTH-stimulation test measuring cortisol is performed 4-6 hours after the morning dose of trilostane is given.  Results of the ACTH-stimulation are ideally a cortisol in the normal range pre- and post- ACTH with little stimulation.  A sodium/potassium level should be measured as well.  This often decreases with trilostane treatment.

Which therapy should the practitioner choose to treat hyperadrenocorticism.  In comparing trilostane and lysodren, both are as efficacious in controlling clinical signs and in the longevity of the treated animals.  Both are sold commercially and cost is approximately the same.  Some considerations are that trilostane must be given every day while lysodren can be given 2-3 times per week in a stabilized animal.  Lysodren should not be given to animals with liver disease.  Animals treated with trilostane should be monitored carefully since they can become glucocorticoid/mineralocorticoid deficient even after longterm stable treatment.  The effects of adrenal gland hyperplasia/metaplasia by trilostane have not been fully investigated.  Trilostane is the only effective medical therapy for use in feline hyperadrenocorticism.  Cats respond well to 5 mg bid.

There are no studies comparing trilostane and lysodren for treatment of cortisol-producing adrenal tumors.  Trilostane may be more effective in controlling the excess cortisol levels produced by a functional adrenal tumor than lysodren.  Lysodren may kill metastatic tumor cells.

Atypical cushing's disease

Patients sometimes present with the constellation of clinical signs compatible with canine cushing's disease without concurrent elevation of plasma cortisol levels.  Instead, plasma levels of cortisol precursors or androgens are elevated.   “Atypical Cushing's” has been used to describe  the syndrome in these patients.  It been hypothesized that these ‘atypical' cases may involve a relative deficiency in some of the enzymes critical to the synthesis of cortisol. 21-β hydroxylase and 11-β hydroxylase have been investigated as enzymes that are deficient in the synthesis pathway. It has been suggested that without the requisite enzymes the steroid synthesis pathway is blocked, resulting in abnormal increases in plasma concentrations of active cortisol precursors or sex hormones.  This has been seen in dogs with adrenal dysfunction, PDH, and non-cortisol secreting adrenal tumors (ATs). In these cases, neither ACTH stimulation, measuring cortisol, nor low dose dexamethasone tests will be diagnostic for CCS.   Thus, a patient can present with clinical signs strongly suggestive of CCS, but without supportive diagnostic results on routine endocrine screening tests.  These patients can be diagnosed using the extended adrenal panel.  The results of these panels must be interpreted with caution.  To make the diagnosis of atypical cushing's disease, there must be a significant increase of at least 2 precursor/sex hormones along with appropriate patient clinical signs.  These cases may be treated with trilostane or mitotane. 

And what about the patient with concurrent diabetes mellitus and hyperadrenocorticism?

Yikes!  These patients can be a true challenge.  Diagnosis of diabetes mellitus is usually made first since it is easier to diagnose.  Hyperadrenocorticism is usually suspected if the diabetes mellitus is not controlled with insulin doses climbing over 1.5 U/kg.  At this point concurrent disease, including hyperadrenocorticism is suspected.  Patients should be tested for hyperadrenocorticism with the ACTH-stimulation test as it is the most specific in dogs with concurrent disease and the chances of getting a false positive result are lessened.  ACTH-stimulation testing should proceed as previously described.  The diabetic patient should be fed regularly and have its usual dose of insulin.  Blood glucose should be checked to make sure the animals is in some sort of regulation.  If the animal is profoundly hyperglycemic, hypoglycemic or ketotic, ACTH-stimulation testing should be postponed until the animal is under better glycemic control or false-positive test results could occur.

If the diagnosis of hyperadrenocorticism is made, treatment should be instituted as described above.  The practitioner is reminded that control of the cortisol will reduce the insulin antagonism that has been present.  To compensate for this, the insulin dose should be decreased by 25% before therapy for hyperadrenocorticism is instituted. 

References are available upon request.