Unusual feline endocrinopathies (Proceedings)

Hyperadrenocorticism (Cushing's disease)

While less commonly seen than in their canine counterparts, cats can suffer from an excessive production of cortisol by the adrenal glands. 85% of the cases of feline hyperadrenocorticism are due to a pituitary tumor whereas 15% stem from an adrenal tumor. Progesterone-secreting adrenal tumors have been documented a handful of cats.

Clinical presentation

Hyperadrenocorticism (HAC) is a disease of middle-aged to older cats. There is no breed predilection but females appear to be over-represented (70% of cases). 80% of cats with hyperadrenocorticism have concurrent diabetes mellitus. Cortisol often causes insulin resistance in cats so frequently hypercortisolemia from hyperadrenocorticism leads to overt diabetes mellitus. It was long believed that the typical signs of polyuria and polydipsia seen in cats with HAC were actually manifestations of the secondary diabetes mellitus; however, cats with only HAC who had not yet progressed to diabetes mellitus have been described as displaying these same clinical signs. Hyperadrenocorticism still is most frequently diagnosed in cats that have poorly controlled diabetes mellitus. Other clinical signs frequently seen in cats include generalized muscle wasting, pendulous abdomen, thin, inelastic skin, lethargy, and unkempt hair coats.

Clinical pathology

Hyperglycemia is typically found in feline HAC. Other changes that may be noted on a biochemical panel include hypercholesterolemia and an increase in alanine transaminase (ALT). Because cats do not have the steroid-induced isoenzyme of alkaline phosphatase (ALP), elevations in this enzyme are less commonly seen and, when present, are due to concurrent diabetes mellitus and hepatic lipidosis most likely.

Diagnostic imaging

Plain radiographs are of little value in the diagnosis of feline HAC. Abdominal ultrasound may be of benefit in examining the adrenal glands. In published reports of naturally occurring HAC in cats, ultrasound reveals bilaterally enlarged adrenal glands in approximately ⅔ of cases. Unilateral enlargement of an adrenal gland is suggestive of an adrenal tumor. MRI has been proven useful in documenting pituitary tumors in cats.

Endocrine testing

Specific testing of the pituitary-adrenal axis is necessary to diagnose HAC. Unfortunately, there is no one perfect test. Clinicians usually rely on a combination of appropriate clinical signs in conjunction with multiple supporting test results before establishing a diagnosis of feline HAC. There are two tiers to testing; first it is necessary to confirm the diagnosis of HAC, secondly it must be determined whether the HAC is pituitary-dependent (PDH) or due to an adrenal tumor (AT).

Urinary cortisol:creatinine ratio

There is an obvious benefit to tests that require only a single sample of urine (although obtaining this sample in a cat is usually much more challenging than for a canine patient). The urinary cortisol:creatinine ratio (UCCR) is theoretically useful as an assessment of cortisol secretion over time. However there are many challenges to using this test in the feline patient. Unfortunately in cats, only 18% of cortisol is eliminated in the urine versus 70% in dogs. Furthermore, relatively minor stress such as that associated with handling can activate the hypothalamic-pituitary axis in cats, leading to cortisol secretion. Therefore, urine for this test should always be collected at home to ensure greater accuracy. Other disease processes, most notably hyperthyroidism, have been shown to increase the UCCR in cats. Because of these issues, the UCCR is suitable as a screening test for HAC but is not specific enough to serve as a confirmatory test.

ACTH stimulation test

Despite limitations in both sensitivity and specificity, the ACTH stimulation test is frequently used in the diagnosis of HAC in cats. The cortisol response in greater and more prolonged following intravenous administration. The currently recommended protocol for ACTH stimulation testing in cats is 125 µg/cat IV with samples being taken for cortisol measurement at baseline, 60 minutes and 90 minutes post-administration. This dose has been shown to be sufficient even in obese cats.

Low-Dose Dexamethasone Suppression (LDDS) Test

Because the response to dexamethasone is more variable in cats, a ten-times higher dose (0.1 mg/kg IV) is recommended. The protocol is otherwise similar to that for dogs with samples being collected at baseline, 4 hours and 8 hours post-dexamethasone administration. Little or no suppression is found in 70% of cats with pituitary-dependent HAC. Cats with adrenal tumors reportedly do not suppress on a LDDS.

High-Dose Dexamethasone Suppression (HDDS) Tes

Once it has been established that a cat is suffering from HAC, the source must then be determined. In a HDDS, the cat receives 1.0 mg/kg dexamethasone IV with samples taken at baseline, 4 hours and 8 hours post-dexamethasone administration. Suppression is defined as a post-sample (at either 4 or 8 hours) that is either less than the reference range or <50% of the baseline value. Suppression at either time is consistent with PDH. Lack of suppression can be seen with either PDH or AT.

Endogenous ACTH level

Endogenous ACTH concentrations (eACTH) can be used to distinguish between PDH and AT once the diagnosis of HAC has been determined. In cases of PDH, eACTH levels are elevated as that is the signal for the adrenal glands to secrete cortisol. Conversely, an AT autonomously secretes cortisol in the absence of stimulation from the pituitary, thus eACTH concentrations are low.

Treatment

HAC is a much more debilitating disease in cats than it is in dogs and treatment is usually less successful.

Trilostane

A limited number of cats have been treated with trilostane. Trilostane reversibly inhibits 3 -hydroxysteroid dehydrogenase which results in decreased production of cortisol. In 5 cats with HAC, 3 of which had concurrent diabetes mellitus, trilostane was found to reduce clinical signs in all 5 cats. Little is known about the pharmacodynamics of trilostane in cats; the appropriate dose and frequency of administration still need more examination.

Surgery

Despite a >30% mortality rate, adrenalectomy has long been considered the treatment of choice for HAC in cats. For cats with AT, unilateral adrenalectomy is performed versus a bilateral adrenalectomy for cats with PDH. All cats will require glucocorticoid and potentially mineralocorticoid supplementation post-operatively. Cats with bilateral adrenalectomy will require supplementation for life. Post-operative complications are frequent, often fatal and include pancreatitis, sepsis, thromboembolism, and hypoadrenocorticism. Following surgery, resolution or marked reduction in clinical signs is apparent within a few months. Diabetes mellitus fully resolves in about half of the cases.

Transsphenoidal hypophysectomy

Transsphenoidal hypophysectomy has been described for the treatment of PDH in 7 cats. Two cats died within a month of surgery, although the authors felt the deaths were due to unrelated causes. 5 of the 7 cats achieved remission following the procedure with 1 cat experiencing a relapse 19 months post-operatively. In the 4 cats with concurrent diabetes mellitus, 2 had resolution of the DM. Transsphenoidal hypophysectomy is currently only available at a very limited number of referral institutions.

Other therapies

A variety of other treatment protocols including mitotane, ketoconazole and metyrapone have been tried in cats with HAC with varying success. Most treatments have been used in too few of cats to draw any conclusions or have not shown consistent responses.

Prognosis

The prognosis for HAC in cats must be considered guarded. However early reports on trilostane and transsphenoidal hypophysectomy both suggest these options may prove beneficial in the management of this disease.

Acromegaly

Acromegaly in cats is due to excessive production of growth hormone by a pituitary adenoma. This is a similar etiology as to humans but unlike dogs who normally develop acromegaly secondary to ectopic growth hormone production from the mammary gland. Acromegaly is becoming increasingly recognized in the cat.

Growth hormone (GH) stimulates the secretion of insulin-like growth factor (IGF). The clinical signs in acromegaly arise from the catabolic and diabetogenic effects of GH and the anabolic effects of IGF. Additionally, the pituitary tumor may cause signs related to its being a space-occupying mass.

Clinical presentation

Acromegaly is typically diagnosed in older, castrated male mixed-breed diabetic cats. The question of whether an individual cat may suffer from acromegaly typically only arises after the cat is determined to suffer from insulin resistance. Clinical signs are consistent with poorly controlled diabetes mellitus and include polyuria-polydipsia and polyphagia. One aspect of acromegaly is that unique in a poorly controlled diabetic is a history of weight gain. Many morphologic changes may be evident upon examination of the acromegalic cat. Often the disease is so insidious in onset, the owner does not detect a change in their cat's appearance. Prognathism, widened interdental spaces and diffuse soft tissue growth of the tongue may be noted. These changes may lead to respiratory stridor. Any of the internal organs may be subject to excessive growth. Hypertrophic cardiomyopathy and subsequent heart failure sometimes develops in cats with acromegaly. Lameness due to proliferative changes leading to a progressive degenerative arthropathy has been described.

Clinical pathology

Findings on routine bloodwork are consistent with poorly controlled diabetes mellitus. Hyperglycemia, glucosuria, hypercholesterolemia, elevated ALP, elevated ALT and elevated BUN are frequently reported.

Imaging

There are no pathognomonic findings of acromegaly on imaging of either the thorax or abdomen. Enlargement of affected organs such as heart, kidneys or liver may be noted. Imaging of the brain by either CT or MRI should be performed to look for a pituitary mass.

Endocrine testing

Ideally growth hormone would be measured in cases of suspected feline acromegaly. Unfortunately there is not a currently available assay. Furthermore, GH is released in a pulsatile fashion so solitary measurements are unreliable as the sole diagnostic. IGF-1 can be measured as an indicator of serum GH concentrations over a 24-hour period. Increased IGF-1 levels have been documented in other disease states, most notably diabetes mellitus. However, the increase in IGF-1 in diabetics is fairly modest whereas the increase in acromegalics is usually much more pronounced.

Treatment

Treatment options include procedures aimed at removing/destroying the pituitary mass and medical management of the hormonal abnormalities. Procedures that have been used to treat the pituitary mass in acromegaly include transsphenoidal cryotherapy, traditional radiation therapy, stereotactic radiosurgery and linear-accelerator-based modified radiosurgery. A 2009 report in JVIM (Sellon et al) discussed treatment of 11 cats with pituitary tumors with linear-accelerator-based modified radiosurgery. 7/11 cats were diagnosed with acromegaly and 2 were diagnosed with PDH (these 9 cats all were poorly controlled diabetics). 7/11 total cats (5/9 diabetic cats) had improved clinical signs following treatment. Traditional radiation therapy has also been shown to be beneficial in some, but not all, cats with pituitary tumors. Many cats still require insulin therapy post-treatment.

Octreotide, a somatostatin analogue, is effective in 60-70% of humans with acromegaly for inhibiting growth hormone. In one study, a single intravenous injection of octreotide was found to reduce GH concentrations in acromegalic cats but not in normal cats. Other studies have not shown any effect on GH. The drug has been examined for clinical efficacy in controlling diabetes mellitus secondary to acromegaly in cats. L-deprenyl, a monoamine-oxidase inhibitor was used in one cat to prolong dopamine activity in the brain. No clinical improvement was noted.

Hyperaldosteronism

Primary hyperaldosteronism (PHA), also known as Conn's disease, was first described in humans in 1955 and in cats in 1983. In humans, PHA was initially an infrequent diagnosis, but is now recognized as the most common cause of endocrine hypertension, the most frequent cause of secondary hypertension. Similar to early under recognition in human hypertension, because blood pressure is not currently minimum database for routine physical examination in healthy and diseased cats and aldosterone is not routinely measured in all cases of feline hypertension, cats may also experience PHA more commonly than is currently reported.

Aldosterone physiology

The main function of aldosterone is regulation of systemic blood pressure and homeostasis of extracellular fluid volume.. Aldosterone increases secretion of potassium and hydrogen and reabsorption of sodium and chloride in the distal nephrons of the kidneys. Thus, increased aldosterone levels cause an increase in sodium concentration, increasing extracellular fluid volume.

The adrenal gland is comprised of two portions, the inner medulla and the outer cortex. The cortex is divided into three zones, the outermost zona glomerulosa, the middle zona fasciculata and the innermost zona reticularis. Aldosterone is secreted by the zona glomerulosa of the adrenal cortex. The zona glomerulosa is the only zone containing the enzymes which dehydrogenate 18-hydroxycorticosterone to aldosterone. In contrast, the zona glomerulosa has very low concentrations of CYP17 (previously named 17α-hydroxylase), the enzyme necessary for cortisol and androgen synthesis. Aldosterone production in the zona glomerulosa of the adrenal cortex is controlled regulated by the renin-angiotensin system (also called the renin-angiotensin-aldosterone system, RAAS) and potassium levels. When the body experiences decreased renal blood flow, renin, angiontensin II, and aldosterone are increased, resulting in increased sodium retention, increased extracellar fluid volume, and lower potassium (via loss in the urine). Once homeostasis is restored, renin production is reduced and aldosterone level declines. In primary hyperaldosteronism (PHA), excess aldosterone causes systemic hypertension. The increased urinary loss of potassium may result in profound hypokalemia. As potassium shifts extracellularly, hydrogen ions move intracellularly. Metabolic alkalosis may result from increased urinary loss of hydrogen ions in addition to the intracellular shift.

Clinical Presentation

Cats diagnosed with PHA are usually geriatric. There does not appear to be any sex or breed predilection. Weakness due to hypokalemic myopathy is the most common presenting complaint for cats with PHA. followed by cervical ventroflexion is often seen. The weakness may manifest with an acute onset or be more insidious in nature. Hypokalemia in cats with PHA can also result in the lethargy and depression described in cats with hyperaldosteronism. Clinical signs from systemic hypertension such as blindness may be seen at initial presentation. Other consequences of systemic hypertension include cardiac hypertrophy and renal damage. Additional presenting complaints include polyuria-polydipsia, weight loss, diarrhea and polyphagia. Cats may have a palpable abdominal mass.

Clinical pathology

Other presenting complaints for cats with hyperaldosteronism include polyuria-polydipsia and nocturia. Weight loss, diarrhea and polyphagia are other uncommon presenting complaints for cats with PHA. Cats may have a palpable abdominal mass. Biochemical abnormalities for cats with PHA are consistent with the excessive levels of aldosterone. Moderate to severe levels of hypokalemia are typically seen whereas sodium may be normal or mildly increased. Urinary fractional excretion of potassium is greatly increased due to the effects of aldosterone. Creatinine kinase levels are also usually markedly elevated, secondary to hypokalemic polymyopathy. Cats with PHA may have evidence of renal disease on bloodwork including isosthenuria and elevations in creatinine and BUN. Many cats presenting without azotemia or only mild azotemia with hyperaldosteronism experience progression of their renal disease. Additionally, angiotensin II is damaging to the kidneys.

Aldosterone may have other effects in the body in addition to its effects on electrolytes and the kidneys. Many of the cats diagnosed with hyperaldosteronism had evidence of cardiovascular disease including cardiac murmurs, radiographic evidence of cardiomegaly and/or ventricular hypertrophy noted during echocardiogram; the role of the hyperaldosteronism in the generation or progression of cardiac disease in cats is not known.

Etiology

There are multiple causes for primary hyperaldosteronism in cats. The majority of cases have been attributed to either adrenal adenomas or carcinomas. Of the 23 cases reported in the literature with histopathological examination of the affected adrenal gland(s), eleven cats developed hyperaldosteronism secondary to a unilateral carcinoma and nine cats were diagnosed with an adenoma. Of the nine cats with adenomas, two had bilateral disease. Additionally, there have been three cats diagnosed with bilateral adrenal hyperplasia.

Diagnosis

Increased aldosterone levels are the diagnostic a hallmark of PHA. Measurement of aldosterone levels should be interpreted in light of serum potassium concentrations. Because potassium is a major cause for aldosterone secretion, hypokalemia is a potent suppressor of aldosterone secretion in the normal cat. Therefore if aldosterone levels are in the high normal range, but potassium level is low, PHA should still be considered.

Recently, a reference range for the urinary aldosterone to creatinine ratio (UACR) has been established for cats. The UACR offers advantages over plasma aldosterone concentrations in that it provides a measurement of aldosterone concentration over time (the time over which the urine is made) and large volumes of blood are not required for analysis. The usefulness utility of the UACR in cats with spontaneously occurring PHA needs further examination.

In cats with elevated aldosterone and hypertension, plasma renin activity should be measured in order to differentiate primary from secondary hyperaldosteronism. In primary hyperaldosteronism, plasma renin activity is minimal, reflecting the autonomous secretion of aldosterone by the adrenal(s) gland(s). In humans, the aldosterone to renin ratio (ARR) is used as the primary screening test for PA. Unfortunately, measurements of renin activity are not widely available through veterinary laboratories and clinicians often must interpret aldosterone levels in the absence of a documented renin activity level. Primary hyperaldosteronism is often confirmed retrospectively following surgical removal of an adrenal tumor with a subsequent dramatic decline in aldosterone levels.

Imaging of the adrenal glands is frequently performed in veterinary patients with PHA. Ultrasound findings in cats with PHA include adrenal masses, adrenal calcification, and changes in echogenicity. Computed tomography and MRI has have also been used to improve imaging of the adrenal glands in these cats. However, the finding of an enlarged adrenal or adrenal mass does not mean that it is producing excessive aldosterone. Adrenal masses in the cat are often incidental findings known as incidentalomas; other adrenal masses in cats can be attributed to hyperadrenocorticism (cortisol-secreting), pheochromocytomas and progesterone-secreting tumors.

Treatment and prognosis

For cats with unilateral disease, surgical removal of the affected adrenal gland remains the treatment of choice. Surgery appears to be curative for both adenomas and carcinomas, with signs of hypokalemia and hypertension resolving without further treatment. Cats who survive the immediate post-operative period often had survival times of many years. Interestingly, cats with carcinomas appear to have a similarly good prognosis as to those with adenomas following surgery.

Cats also do well with medical management. Medical management consists of spironolactone therapy, potassium supplementation and anti-hypertensives as needed. Spironolactone is an aldosterone antagonist which binds to the aldosterone receptors in the distal convoluted tubules. Reported survival times for cats treated medically often range from many months to years.