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ISU Student Experience

Canine Hyperadrenocorticism

Written by: Donnielle R.


Introduction

Hyperadrenocorticism (HAC) or Cushing’s syndrome is defined as an overproduction of glucocorticoids either endogenously or exogenously.7 There are two types of endogenous overproduction. The first, Adrenal- Dependent Hyperadrenocorticism (ADH) involves a functional adenoma or carcinoma of the adrenal gland.7 The second form, Pituitary- Dependent Hyperadrenocorticism (PDH) involves a tumor on the pituitary gland that over secretes adrenocorticotropic hormone (ACTH).8 Finally, the exogenous form, called iatrogenic HAC, is due to chronic exposure to glucocorticoids that leads to suppressed ACTH levels and adrenal gland atrophy.9

Pathophysiology

The normal adrenocortical axis has a balance of positive and negative feedbacks to maintain normal cortisol levels in the body. When, the body is stressed a positive feedback is sent to the hypothalamus to initiate an increase in cortisol. The hypothalamus releases cortisol releasing hormone (CRH) to the anterior pituitary which triggers the release of ACTH to the adrenal cortex.6 In the adrenal cortex, the zona fasciculata releases cortisol. When, cortisol levels are high they act as a negative feedback on the hypothalamus and the pituitary gland deceasing CRH and ACTH.6 Whereas in, PDH and ADH the tumors do not respond to the negative or positive feedback of the adrenocortical axis thereby disrupting the delicate balance needed to maintain normal cortisol levels in the body.

PDH makes up about 80-85% of HAC cases.8 The tumor on the adrenal gland secretes an excess of ACTH which causes bilateral hyperplasia of the adrenal glands and excessive secretion of cortisol. The pituitary tumor can be found 70% of the time at the pars distalis and 30% of the time at the pars intermedia.

ADH is not as common a form of HAC compared to PDH. Approximately, 15-20% of HAC cases are ADH.7 In ADH, the tumor is usually unilateral and solitary. The contralateral adrenal gland is usually atrophied due to the low ACTH levels caused by the negative feedback of the high cortisol levels on the pituitary gland.7

Predilection and Clinical Signs

 Both forms of endogenous HAC seem to have predilection for older dogs, increased odds past the age of twelve.4 Both types also seem to develop more commonly in overweight dogs.4 However, they differ in the breed and if there is the presence of a sex predilection. ADH tends to occur in middle to large breed dogs and seems to have a predisposition to be in females 60-65% of the time.2,7 Whereas, PDH occurs commonly in small dogs particularly Dachshunds, Beagles, Poodles, Terrier breeds, and Miniature Schnauzers.8 PDH does not seem to have a fondness for any particular sex.

The most common clinical signs of HAC include the following: polydipsia, polyuria, polyphagia, heat intolerance, lethargy, abdominal enlargement (potbellied appearance), muscle weakness, weight gain, panting, alopecia (especially truncal area), and hyperpigmentation. 2,7,9 The polyuria is caused by cortisol interfering with antidiuretic hormones action at the renal tubules.7 Water is not reabsorbed leading to polyuria. As a result, polydipsia is the compensatory mechanism2 Cortisol also increases the appetite leading to polyphagia and weight gain. However keep in mind, 5-10% of patients with HAC have concurrent diabetes mellitus.8 So, these patients may exhibit weight loss instead of weight gain. The potbellied appearance can be caused by one or a combination of the following: catabolic effect of cortisol causing abdominal weakness, hepatomegaly, or fat redistribution to the abdominal mesentery.8 Panting excessively is caused by weakness of the respiratory muscles, decreased respiratory compliance, or pulmonary hypertension.8 Overall, glucocorticoids have a variety of metabolic effects that can cause a variety of issues when in excess.

Diagnosis

A complete blood count usually reveals a stress leukogram (eosinopenia, lymphopenia, neutrophilia without a left shift), a regeneration response (nucleated red blood cells, erythrocytosis), and occasionally a basophilia.2 A chemistry panel reports an increased ALP in 85-95% of HAC patients.7 Other results include an increased ALT, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hypophosphatemia, and decreased BUN.2,7 A urinalysis commonly shows a decreased urine specific gravity (<1.020) and proteinuria secondary to protein losing glomerulopathy.8 Also, 60-80% of HAC patients have a urine protein: creatinine ratio greater than 1.0. Finally, 40-50% of HAC patients have a concurrent urinary tract infection. However, the normal symptoms of pyuria, hematuria, or stranguria are absent due to anti-inflammatory properties of glucocorticoids.7

HAC patients are at increased risk of developing pulmonary thromboembolism (PTE) due to their hypercoagulable state.7 So, when taking thoracic radiographs signs of PTE may be present such as hypovascular lung fields, pulmonary effusion, right-sided cardiomegaly, and alveolar pulmonary infiltrates.8 In the case of ADH, pulmonary metastasis can be present in thoracic radiographs if the tumor is a carcinoma. Abdominal radiographs will show hepatomegaly in 80-90% of HAC patients. Also, there is the possibility of visualizing the adrenal tumor since about 50% are calcified.7

Abdominal ultrasound can also be helpful in diagnosing a HAC patient. With ADH, the unilateral adrenal tumor can have an irregular or rounded shape with mixed echogenicity. The contralateral adrenal gland will appear atrophied or can be normal size and shape.7 In PDH, the patients typically have bilaterally, symmetrical adrenomegaly with normal echogenicity.

There a variety of endocrine screening tests to diagnose HAC. Some are able to just diagnose HAC while others can differentiate between ADH and PDH. The urine cortisol: creatinine ratio reflects cortisol secretion over several hours.7 The test is sensitive enough to differentiate a normal dog from a HAC dog. However, the test is not specific. Dogs with moderate to severe non adrenal disease can also have elevated ratios.2 So, if this test is used results should be considered along with results from a different endocrine screening test. Another test is the ACTH stimulation test. HAC patients will have an exaggerated cortisol response to ACTH.7 It is considered the gold standard for diagnosing iatrogenic HAC.7 However, it is not considered a good test for differentiating between ADH and PDH. For, it only has 61% sensitivity in diagnosing ADH and 80% sensitivity in diagnosing PDH.9 The low dose dexamethasone suppression test (LDDST) can be used as a diagnostic and a differential test. A dog with HAC will not demonstrate a decrease in cortisol after the administration of dexamethasone.9 The test is very sensitive in diagnosing a HAC dog. However the specificity is between 40-50% because results can be affected by a concurrent nonadrenal illness.7 Even considering this, “the 2012 ACVIM Consensus Statement considers the LDDST the screening test of choice unless iatrogenic HAC is suspected.”7 As a differential test, the LDDST uses three criteria to differentiate PDH from ADH. The criteria are the following; at 4 hour post dexamethasone administration the cortisol levels have to be less than 1.0ug/dl or less than 50% the baseline cortisol levels or at 8 hours cortisol levels should be less than 50% baseline and greater than 1.4ug/dl.8 The criteria is successful in separating out 65% of dogs with HAC.8 However, 30-40% of PDH dogs and 100% ADH dogs do not meet the criteria.

Two other tests are available for differentiating between ADH and PDH. The first is a high dose dexamethasone suppression test (HDDST). It works under the theory that a high dose of steroid can suppress autonomous ACTH secretion from a pituitary tumor. However, in an ADH patient no suppression will be noticed because ACTH is already suppressed via the negative feedbacks of the high cortisol levels from the adrenal tumor.2 The only exception to this theory are the dogs with a pituitary macroadenoma.2 In this form of PDH, the HDDST does not suppress the ACTH levels being secreted by the tumor.  The second test is an endogenous ACTH test. A patient with PDH can have normal to elevated ACTH levels. While, an ADH patient will have low to undetectable levels of ACTH.7 Overall, there are a variety of tests to diagnose and differentiate HAC. The advantages, disadvantages, and possible outlying results must be considered when deciding which test to utilize when making a diagnosis of HAC.

Treatment

Surgery is an option for ADH. A unilateral adrenalectomy can be performed. However the risk of intraoperative and postoperative complications are high. Intraoperative complications occur in 15% of patients.7 Postoperative complications including pneumonia, sepsis, renal failure, and hypoadrenocorticism occur in 50% of patients.7 If a PDH patient has a macroadenoma that is causing neuroglial signs radiation is an option.2 Radiation is an effective method with low morbidity, but may take several months for PDH signs to abate.2

Medical management is an option for both ADH and PDH. Two main drugs are used to medically manage HAC. The first is mitotane. Mitotane selectively destroys the cells of the adrenal cortex resulting in necrosis and atrophy. 7,2 Mitotane can sometimes stop the growth or decrease the size of adrenal tumors.7 ACTH stimulation tests are performed to determine when to switch from an induction to a maintenance dose and to monitor for hypoadrenocorticism. After a maintenance dose is established, an ACTH stim should be performed every three to six months.8 The second drug is called trilostane. Trilostane is a competitive inhibitor of 3-beta hydroxysteroid dehydrogenase which reduces the synthesis of cortisol, aldosterone, and adrenal androgens.5 Ten to fourteen days after initial prescription of the drug and after any increase in dose cortisol levels should be checked with an ACTH stim test.5,7

Other drugs are available to treat HAC besides the main two. For example, ketoconazole is sometimes used in patients that cannot tolerate mitotane at a high enough dose to control HAC.9 Ketoconazole inhibits enzymes responsible for the synthesis of cortisol.9 Another medicine available is selegiline hydrochloride. It downregulates ACTH secretion by increasing dopamine levels. However, its’ efficacy is questionable and use contended.7,9 So, there are a variety of treatment options to consider when deciding what route to take in treating HAC.

Prognosis

The prognosis of HAC patients varies depending on what study is analyzed. In one study, medical management with trilostane increased survival time when compared to no treatment at all.3 Another study comparing survival time using mitotane vs. trilostane concluded no significant difference.1 Median survival for dogs that underwent a unilateral adrenalectomy was 992 days from discharge.7 Overall, the prognosis varies in survival time, but treatment does seem to prolong survival time.

The variance in prognosis and survival time is probably a direct effect of concurrent diseases and complications common to HAC patients. Approximately, 15-20% of PDH patients exhibit neurological signs due to their pituitary tumor increasing in size.8 86% of untreated HAC dogs and 40% of treated PDH dogs are hypertensive.7,8 Pulmonary thromboembolism is a rare complication that can occur in HAC dogs.8 Also, 5-10% of dogs with HAC additionally have diabetes mellitus.7,8

In conclusion, HAC is an endocrine disease that presents in a variety of ways. The two main forms, ADH and PDH, have a plethora of similarities but also distinct differences that can help in differentiating them. Treatment options abound and the advantages, disadvantages, and exceptions must be considered when choosing a treatment plan. Finally, prognosis varies depending upon the type of HAC diagnosed, treatment, and presence of concurrent diseases.


References:

  1. Arenas, C., Melian, C., Perez-Alenza, M.D. (2014). “Long Term Survival of Dogs with Adrenal-Dependent Hyperadrenocorticism: A Comparison Between Mitotane and Twice Daily Trilostane Treatment.” Journal of Veterinary Internal Medicine 28: 2, p. 473-480.
  2. Kahn, C. M., Line, S. (2010) The Merck Veterinary Manual Tenth Edition. Merck & Co., Inc. p. 497-500.
  3. Nagata, N., Kojima, K., Yuki, M. (2017). “Comparison of Survival Times for Dogs with Pituitary-Dependent Hyperadrenocorticism in a Primary-Care Hospital:  Treated with Trilostane versus Untreated.” Journal of Veterinary Internal Medicine 31: 1, p. 22-28.
  4. O’Neill, D.G., Scudder, C., Faire, J.M., Church, D.B., McGreevy, P.D., Thomsen, P.C., Broodbelt, D.C. (2016). “Epidemiology of Hyperadrenocorticism Among 210,824 Dogs Attending Primary-Care Veterinary Practices in the UK from 2009 to 2014.” Journal of Small Animal Practice 57:7, p. 365-373.
  5. Plumb, D.C. (2015). Plumb’s Veterinary Drug Handbook Eighth Edition. Wiley Blackwell.
  6. Reece, W. O., Erickson, H.H., Goff, J.P. Uemura, E.E. (2015). Duke’s Physiology of Domestic Animals Thirteenth Edition. Wiley Blackwell, John Wiley and Sons, Inc. p. 635-637.
  7. Rothrock, K. (2015). “Hyperadrenocorticism, Adrenal-Dependent.” Associate Database-VIN. Accessed July 22, 2017 at http://www.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=306

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