- Top of page
- Materials and Methods
This retrospective study indicates that trilostane is a viable, well-tolerated, medical treatment option for management of cats with HAC.
Clinicopathologic data were in agreement with previous studies, with the exception of an increased serum BUN concentration found more commonly in this study (7/15, 47%) than in prior reports (7/32, 22%). Imaging studies of the kidneys in 4/7 of these cases identified changes consistent with chronic kidney disease (CKD). Given the catabolic effect of cortisol, concurrent muscle atrophy could have underestimated the degree of azotemia in these cats. In addition, although dietary history was not always recorded, at least 9 were consuming a diabetic diet, which is high in protein and can result in an increased BUN.
Endocrinopathies in association with DM include acromegaly, which might be difficult to distinguish from PDH in the absence of skin fragility syndrome. Measurement of IGF-1 was not performed in any of these cats; however, 8/15 of the cats in this case report were presented with skin fragility syndrome and had cortisol function testing results consistent with HAC. A prospective study evaluating plasma ACTH precursors in cats with PDH revealed that most cats had increased concentrations of plasma ACTH precursors, compared with healthy cats, or cats with DM with or without acromegaly. Precursor measurement might aid in differentiating PDH from acromegaly in conjunction with IGF-1 levels and clinical signs, if a suspected cushingoid cat does not have fragile skin.
In assessing tumor differentiation, 10 were consistent with PDH based on LDDST. This was somewhat unexpected, as many cats with PDH will not suppress 4 hours after dexamethasone administration and a few will suppress at 8 hours. If combined with sonographic results of bilateral adrenomegaly, findings were consistent with PDH in 1 additional case. One had an adrenal tumor based on left unilateral adrenomegaly, with an atrophied contralateral AG. The remaining case identified unilateral adrenomegaly, with a normal-sized contralateral gland.
This study demonstrated clinical sign improvement in cats with HAC, consistent with previous studies. As expected, dermatologic signs resolved more slowly than clinical signs of PU/PD and lethargy. ACTH stimulation monitoring led to an improvement in results of tested cases.
The reduction in insulin dose seen in this study was in contrast to the previous report of 3 diabetic cats treated with trilostane for HAC, in which there was insufficient information to conclude if insulin requirements were reduced. This is most likely secondary to a small sample size as 52% (11/21) of cats with long term follow up available that were treated successfully for HAC by means other than trilostane (other medical or surgical) had resolution of their DM. Other treatments included mitotane, metyrapone, or adrenalectomy (bilateral or unilateral). In dogs, treatment is expected to alleviate insulin resistance, but resolution of DM is rare. The difference is likely secondary to reversible glucocorticoid-induced peripheral insulin resistance. Although dogs can develop transient DM secondary to an insulin antagonistic disorder (like HAC), these dogs are typically diagnosed with DM first. It is unknown which disorder develops first; given the multifactorial etiology of DM and the common finding of immune-mediated destruction of the pancreatic islet cells in dogs, resolution of DM is not expected. Cats often have a relevant population of residual functional beta cells at the time of DM diagnosis. Once the cause of insulin antagonism is addressed therapeutically, beta cell function should improve, depending on the chronicity.
Trilostane doses in this study were lower when compared to previous studies with a mean initial dose of 4.3 mg/kg once daily (in 13), 3.3 mg/kg twice daily (2), and final dosages of 2.7 mg/kg once daily (8), 5.6 mg/kg twice daily (7), compared to a mean initial dose of 5.8 mg/kg once daily (5), and final dosages of 5.4 mg/kg once daily (2), 7 mg/kg twice daily (3) previously reported. That study extrapolated the dose from a study of 78 dogs treated with once daily trilostane. Dogs weighing less than 5 kg received 30 mg trilostane once daily. Studies using trilostane in cats have not been performed, necessitating extrapolation. The 1st case report published using trilostane in a cat with PDH started with 30 mg once daily and increased the frequency to 30 mg twice daily for complete skin lesion resolution. Studies in dogs have demonstrated equal to superior efficacy in using twice daily trilostane therapy.6 [18-20]
In our study, 13/15 cases were initially started on a once daily therapy and 5 switched to twice daily therapy. Administration frequency changed because of increased ACTH stimulation test results in conjunction with persistent clinical signs. All those cases were diabetic and receiving twice daily insulin. Cats on twice daily insulin likely benefit from twice daily trilostane based on both drugs' duration of action and ease of owner administration/compliance. As the pharmacokinetics and pharmacodynamics of trilostane remain unknown in cats, testing protocols and dosages should be optimized before making definitive recommendations.
Monitoring included ACTH stimulation testing 4–6 hours posttrilostane administration, which is similar to the manufacturer's recommendations for dogs under treatment for PDH.1 A 3 hours nadir after trilostane administration in 1 cat was previously reported, justifying similar timing for ACTH stimulation testing as recommended in dogs. Timing of post-ACTH serum cortisol measurements was varied, as cats have a peak serum cortisol response at different times with varying doses of synthetic ACTH.[22-24] Studies that have used the standard- (125 μg/cat) or low-dose ACTH stimulation test (5 μg/kg) have reported peak cortisol responses at 60 minutes in overweight or healthy purpose-bred cats.[25, 26] Guidelines for monitoring dogs receiving trilostane for HAC include an ACTH stimulation test at 10–14, 30, and 90 days later and every 90 days thereafter.1 Clinical signs and cortisol concentrations continue to improve in most dogs within the first month, therefore some authors advocate testing within the first 10–14 days without making adjustments until 30 days of trilostane therapy.[11, 21] Based on this study and previous studies, monitoring via ACTH stimulation testing (5 μg/kg IV) 10–14 days later (4–6 hours after trilostane administration), along with monitoring weight, clinical signs, electrolytes, and glucose is recommended, followed by reevaluations on day 30 and 90, and every 90 days thereafter. It is also important to remember that trilostane therapy in dogs leads to adrenomegaly consistent with diffuse hyperplasia, nodular hyperplasia, or both, likely due to the loss of negative feedback as a result of lowering cortisol production, leading to excessive ACTH production, a direct action of trilostane or its metabolites.[27, 28] To the authors' knowledge, this has not been studied in cats yet.
Duration of treatment was variable. The shortest survival time was 87 days. This case had multiple recurrent episodes of hypernatremia (including at the time of HAC diagnosis) and a declining quality of life. Therefore, euthanasia was elected.
Causes of hypernatremia were not definitively established; however, renal losses of pure water or hypothalamic disorders seem likely. This cat had a diagnosis of PDH, though no advanced imaging was performed and had chronic kidney changes evident on initial ultrasonographic examination, making a renal disorder, hypothalamic disorder, or both a likely cause of the observed hypernatremia.
Nelson's syndrome can occur in humans and some dogs, from rapid enlargement of a pituitary mass after loss of negative feedback from adrenal cortisol production (via surgical or medical treatment). Common clinical signs associated with pituitary tumors in cats are blindness, altered consciousness, lethargy, and anorexia. In this study, no cats had any reports of blindness; however, the shortest surviving case was lethargic, anorexic, and adipsic. Advanced diagnostic imaging was only performed in 1 cat in this series. That cat had evidence of a pituitary macroadenoma, surviving 750 days on trilostane, and ultimately was euthanized and diagnosed with small cell lymphoma of the gastrointestinal tract based on necropsy examination, with clinical signs of anorexia and weight loss at the time of euthanasia.
Adverse effects of trilostane administration in dogs with HAC include adrenal necrosis, hypoadrenocorticism, and hyperkalemia. RF and weight loss are important adverse effects in cats. Weight loss was reversible upon decreasing the dose of trilostane. RF was determined to be the most likely cause of death; however, it was not clear whether it was a direct effect of the trilostane or owing to a concurrent disorder, as RF is common in older cats and occurs in conjunction with HAC and DM. A prospective study comparing renal function of dogs diagnosed with PDH and treated with trilostane or transsphenoidal hypophysectomy demonstrated an important decline in GFR 1 year after treatment, with increased GFRs noted before treatment, with no development of azotemia.
In our study, common complications were weight loss and UTIs. UTIs could be secondary to DM, CKD, HAC, or all the three. Another complication was the development of azotemia, which could be secondary to progression of CKD as most (2/3) had evidence of chronic kidney changes on initial ultrasonographic examination. This was progressive in 1 case, being the ultimate cause of euthanasia after 570 days of trilostane therapy.
Manufacturers do not recommend trilostane therapy if hepatic disease, renal insufficiency, or both is present. A direct relationship with trilostane therapy causing weight loss was not identified. Other important complications include anorexia, lethargy, recurrent pancreatitis, recurrent hypernatremia, lymphoma, and seizures. Existence of these complications highlights the need for diligent monitoring of these cats. Their comorbidities make direct causation from trilostane nearly impossible to prove. Recognizing signs of hypocortisolemia in cats is important, with signs of lethargy, anorexia, and weight loss reported. Clinicopathologic findings of hypocortisolemia can be more difficult to determine, as the classic electrolyte abnormalities associated with hypoaldosteronism are not present or may not actually reflect a lack of aldosterone; however, hypoglycemia or absence of a stress leukogram may increase hypocortisolism suspicion, illustrating how important it is to perform an ACTH stimulation test.[32, 33]
There are several study limitations. The retrospective nature and small sample size make sweeping claims regarding the efficacy of trilostane therapy in cats with HAC difficult. As HAC is infrequently diagnosed, prospective studies remain unlikely.
In conclusion, through retrospective analysis, trilostane ameliorates clinical signs of HAC in cats, is well tolerated long term, and can lead to improved glycemic control in the majority (67%) of cases.