Introduction

Hyperadrenocorticism (HAC) is an important differential diagnosis for cats with diabetes mellitus. While there are similarities to canine HAC, there are also key differences. In addition to pituitary-dependent (PDH) and adrenal-dependent hyperadrenocorticism (ADH), sex steroid-producing adrenal tumours cause HAC and are more common in cats than dogs.

Most, but not all, cats with HAC have concurrent diabetes mellitus. Up to a third of cats with HAC have extreme skin fragility. Infections of the skin and nail beds, urinary, respiratory and gastrointestinal tract secondary to cortisol-induced immune suppression are also common.

Cats also respond differently to dogs to adrenal function tests including ACTH-stimulation and dexamethasone suppression tests.

Approximately 80% of feline HAC cases are due to PDH. Adenomas cause 90% of PDH cases and 50–60% of ADH cases, the rest are carcinomas.

Clinical Presentation

Hyperadrenocorticism occurs in older cats (mean age ∼10 years.) There is no breed predisposition and males are slightly overrepresented (54%). Diabetes mellitus occurs concurrently in 80% of cases.

Table 1. Clinical findings from reported cases of feline HAC

About 50% of cats with diabetes mellitus and HAC have insulin resistance, but it is less severe than in cats with hypersomatotropism (acromegaly). Cats with HAC more commonly present with weight loss, while weight gain is common in acromegaly. Alopecia is typically bilaterally symmetrical, may involve the thoracic, ventral abdominal, flank and limb regions and is patchy or generalized. Failure of hair regrowth after clipping is common. Secondary skin and nailbed infections are common as well as opportunistic bacterial and fungal infections including urinary, respiratory tract and oral cavity infections.

Diagnosis

Haematology & Biochemistry

Changes on CBC are non-specific such as a stress leukogram and mild anaemia. On serum biochemistry, hyperglycaemia (85%), hypercholesterolaemia (35%), mild to moderate increases in ALT (30%) and/or urea (30%) are the most frequent findings. Since cats have no glucocorticoid-induced isoenzyme of ALP, elevations of ALP (17%) only occur secondary to diabetes. Total thyroxine is normal or decreased (sick euthyroid syndrome). Cats with diabetes have glucosuria, and most maintain urine concentrating ability and have USG>1.020.

Urine Cortisol to Creatinine Ratio (UCCR)

Protocol: Two home-collected morning urine samples on consecutive days. The UCCR has high sensitivity but low specificity for diagnosis of HAC in cats. It is used as a rule-out screening test due to the high predictive value of a negative result. UCCR results do not vary with age, gender, neuter status or breed, but hyperthyroid cats have significantly higher values.

Low-Dose Dexamethasone Suppression Test (LDDST)

Protocol: 0.1 mg/kg dexamethasone IV, serum cortisol measurements at 0, 4 and 8 h.

In healthy animals, hypothalamic secretion of corticotropin-releasing hormone is suppressed for at least 24 h after dexamethasone administration, thereby suppressing pituitary ACTH secretion and adrenal cortisol secretion. Using this protocol, 4 and 8 h serum cortisol levels in healthy cats will be suppressed to <∼40 nmol/L. Cats with HAC are resistant to pituitary suppression and have an 8-h cortisol above the reference range. Overall, the LDDST in cats has high sensitivity and moderate specificity for the diagnosis. Cats with well or poorly controlled diabetes mellitus, without HAC, have comparable LDDST results to healthy cats.

Adrenocorticotropic (ACTH) Stimulation Test

Protocol: 5 µg/kg or 125 µg/cat of cosyntropin (synthetic ACTH) IV, serum cortisol measurements at 0 and 1 h. Healthy cats do not show cortisol level increases above the reference range. However, as few as one third of cats with HAC show positive test results. Thus, with its poor sensitivity and only moderate specificity, the ACTH stimulation test should not be used as an initial diagnostic screening test.

Discrimination Between PDH and ADH

High-Dose Dexamethasone Suppression Test (HDDST)

Protocol: 1 mg/kg dexamethasone IV and serum cortisol measurements at 0, 4 and 8 h. Suppression of >50% of baseline cortisol at 4 or 8 hours is suggestive of PDH but only occurs in approximately 40–50% of PDH cats.

UCCR with High Dose Oral Dexamethasone Suppression for Diagnosis and Discrimination

Protocol: Home collection of two morning urine samples on consecutive days followed on day two by administration of 0.1 mg/kg oral dexamethasone at 8 am, 4 pm and midnight, then collection of a third urine sample the next morning (day 3). If the UCCR of the first two urine samples (averaged) is within reference range, then HAC is excluded, while an elevated result is consistent with HAC. Suppression occurs if the UCCR of the third urine sample is <50% of baseline and this result is consistent with PDH. Less than 50% suppression means that differentiation between ADH and PDH cannot be determined.⁷

Endogenous ACTH Measurement

Plasma endogenous ACTH levels are expected to be increased in cats with PDH and decreased in cats with ADH. Because endogenous ACTH values in affected cats may fall within the reference range, this test cannot be used as a screening test for HAC.

Diagnostic Imaging

Protocol: Ultrasonography and bilateral measurements of adrenal length and height of cranial and caudal poles. Most cats with PDH have bilaterally symmetrical adrenal gland enlargement. However, in some adrenal size falls within reference ranges or adrenomegaly is unilateral. Adrenal calcification can be an incidental finding on abdominal radiographs in healthy cats. Cats with ADH have a unilateral adrenal mass or adrenomegaly. The uninvolved adrenal is atrophied or may be of normal size. Bilateral adrenocortical adenomas and bilateral tumours of different functional type (e.g., phaeochromocytoma) occur occasionally. The adrenal glands of hyperthyroid cats are approximately 20% larger than healthy cats. Diabetes mellitus does not cause adrenal gland enlargement in cats, but acromegaly does.

Computed Tomography or Magnetic Resonance Imaging (Brain)

Approximately 50% of PDH cases are pituitary macroadenomas that can be detected using CT or MRI.

Treatment

Trilostane

Usually causes a reduction, but not resolution, of clinical signs and insulin doses if diabetic, as well as improved ACTH stimulation test results. Doses used for treatment of feline HAC range from 10 to 30 mg per cat orally SID to BID; however, lower starting doses of 1–2 mg/kg/day have been suggested more recently. A 2–4 h post-trilostane ACTH stimulation cortisol measurement of 50–150 nmol/L is recommended. Adverse effects include anorexia, lethargy, weight loss, pancreatitis and hypoadrenocorticism. Trilostane is mostly well tolerated and is the most efficacious drug currently available for treatment of feline HAC.

Mitotane

Not recommended for therapy since it is far less effective than trilostane, clinical signs often progress and ACTH stimulation test results remain unchanged.

Adrenalectomy

Unilateral adrenalectomy is the treatment of choice for feline ADH. Bilateral adrenalectomy is curative for PDH but is associated with a relatively high complication rate due to poor wound healing, immunocompromise and skin fragility.

Hypophysectomy

Microsurgical transsphenoidal hypophysectomy for PDH is an increasingly reported curative treatment for PDH. Complications included oronasal fistula, soft palate dehiscence, transient reduction in tear production and recurrence of HAC due to pituitary remnants.

Radiation

Radiation therapy for PDH generally involves multiple fractionated treatments. Availability of a gamma knife or a stereotactic capable linear accelerator can reduce this to a single treatment.

Prognosis

Trilostane is the medical treatment option with the longest reported survival times. Cure can be achieved with adrenalectomy or transsphenoidal hypophysectomy if immediate surgical complications do not occur. For cats with pituitary macroadenomas, neurological signs usually improve after radiation, and some, but not all, have improved signs of HAC after radiation therapy, and reduced insulin requirements or diabetic remission. Cats with diabetes mellitus may have reduced insulin requirements or diabetic remission if they respond to treatment for HAC.

Sex Steroid-Secreting Adrenal Tumours

Tumours may secrete one or more adrenal sex steroids (e.g., progesterone, oestradiol or testosterone), alone or in combination. Typical clinical presentations include clinical signs of HAC, diabetes mellitus and behaviour change (aggression). Some adrenal tumours in cats co-secrete aldosterone and adrenal sex steroids (e.g., progesterone and aldosterone). These cats can present with clinical signs of HAC as well as behaviour changes and signs of hyperaldosteronism such as weakness and hypertension. Alternatively, overproduction of sex steroids can result in presentation with signs of oestrus or virilisation of neutered males (e.g., urine spraying, aggression, skin thickening and penile spines).

Diagnosis

Diagnosis is on the basis of high basal and post-ACTH stimulation sex hormone levels, detected on adrenal sex steroid panels and adrenal imaging. Serum cortisol levels are usually low due to lack of enzymes within the adrenal tumour to convert progesterone to cortisol, or hypothalamic-pituitary-adrenal axis suppression of cortisol by sex steroids. Adrenalectomy of the neoplastic gland is curative with regression of clinical signs over weeks to months

References

1.  Boland L, Barrs VR. Peculiarities of feline hyperadrenocorticism: update on diagnosis and treatment. J Feline Med Surg. 2017;19:933–947. doi: 10.1177/1098612X17723245.

2.  Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract. 2013;43:319–350.