Abstract
The two most common endocrine disorders in cats are diabetes mellitus and hyperthyroidism. Each of these conditions has been described as the most common endocrine disorder in geriatric cats of North America and each, separately, has been described as one of the most common conditions in geriatric cats of North America. It would seem that all other endocrine disorders of cats are uncommon-to-rare. Acromegaly, in cats, is a relatively uncommon endocrine disorder and hyperadrenocorticism is even less common. However, there is interest in their clinical signs, diagnosis and treatment.
Acromegaly
Pathophysiology
Acromegaly is a condition that results from chronic exposure to excess growth hormone (GH). This disease is well described in people and is almost always the result of a GH secreting adenoma of the somatotropic cells of the pituitary pars distalis. Much less commonly, a small percentage of people have had excess hypothalamic growth hormone stimulating hormone (GHRH) that causes hyperplasia of pituitary GH-producing cells and secondary acromegaly. The classic symptoms of acromegaly in people include overgrowth of connective tissue, bone and viscera. These individuals can become extremely tall and large if the condition develops before closure of long bone growth plates. If the condition develops after growth plate closure, enlargement of some bones (involving the jaw, forehead, and fingers for example) will still occur.
The Veterinary Medical Teaching Hospital at the University of California has never diagnosed a dog with naturally occurring acromegaly caused by a pituitary tumour. This would suggest that the disease must be quite uncommon or rare in dogs. In contrast, a number of cats with naturally occurring acromegaly have been diagnosed. Like their human counterparts, each of these cats had an adenoma of GH-producing cells within the pituitary pars distalis. Chronic GH hypersecretion has both catabolic and anabolic effects. The anabolic effects are probably mediated by insulin-like growth factor (IGF)-1 (IGF-1; also called somatomedin C). These actions can cause organomegaly as well as proliferation of bone and cartilage. The catabolic effects of chronic excesses in GH are primarily attributed to its insulin antagonistic actions. Growth hormone induces a post-receptor defect in glucose transport leading to hyperinsulinism and down regulation of insulin receptors which, in turn, leads to diabetes mellitus. The diabetes can become quite insulin resistant.
Clinical signs
Acromegaly typically occurs in older male domestic cats (mean age, 10 years). Owner concerns are usually the result of poorly controlled diabetes mellitus or growth of the pituitary tumour. Poorly controlled diabetes causes polydipsia, polyuria and polyphagia, despite insulin therapy. In fact, these signs continue regardless of insulin doses that would otherwise be quite excessive. In addition to diabetes, there are alterations in conformation caused by the excesses in GH. These conformational alterations are insidious in onset and often not noted by owners. They may, however, be obvious to a veterinarian during the initial physical examination, may not be recognised until months later, or may not occur. Conformational changes include an increase in body size, enlargement of the abdomen and head, and weight gain. Weight gain in a cat with poorly-regulated diabetes mellitus can be caused by chronic insulin overdose, or could be due to acromegaly. However, some cats with diabetes mellitus and acromegaly have been described with weight loss. With time, prognathia inferior, degenerative arthropathies, and organomegaly, especially of the heart, kidney, liver and tongue can develop. Congestive heart failure and renal failure develop late in the course of the disease and are the cause of death for many cats with acromegaly.
Pituitary tumours cause clinical signs by compression and/or invasion of structures (usually the hypothalamus and/or thalamus) dorsal to the pituitary. Common signs include stupour, somnolence, poor appetite and then anorexia. More worrisome but less common signs include adipsia, temperature deregulation, circling, seizures, and changes in behaviour. Peripheral neuropathy causing weakness, ataxia and a plantigrade stance may develop as a result of poorly-controlled diabetes mellitus.
Clinical pathology
Concurrent, poorly controlled diabetes mellitus is responsible for most of the abnormalities identified on a serum biochemical panel and urinalysis. The abnormalities include hyperglycaemia, glycosuria, hypercholesterolaemia, and mild increases in alanine transaminase and alkaline phosphatase activities. Ketonuria is an infrequent finding. Persistent hyperphosphataemia without concurrent azotaemia may be noted and is believed to be caused by GH-induced renal phosphate retention. Mild erythrocytosis, found in some cats with acromegaly, may be caused by the anabolic effects of GH or IGF-I on the bone marrow. Persistent hyperproteinaemia (total serum protein as high as 9.5 mg/dl) without a monoclonal spike on protein electrophoresis may also be found. Renal failure is a possible sequela of acromegaly and, if present, will be associated with azotaemia, isosthenuria and proteinuria.
Diagnosis
Once conformational alterations are recognised in a poorly-controlled diabetic cat, a tentative diagnosis of acromegaly can be made. Since these signs are inconsistent, however, additional tools have been used to aid in the diagnosis of acromegaly. These include ruling out other causes of insulin resistance in diabetic cats, such as hyperadrenocorticism. It must be emphasised, once again, that there are numerous explanations for diabetes which seems difficult to control. Only a small percentage of those cats have acromegaly or hyperadrenocorticism. When various causes for poor control have been eliminated, one may obtain a pituitary computed tomography or magnetic resonance scan. This is typically an expensive diagnostic aid and a thorough evaluation should be first completed. Noting a pituitary tumour in a cat shown not to have hyperadrenocorticism is considered strongly suggestive of acromegaly. Administration of a positive contrast agent is usually necessary to visualise a pituitary mass. It is assumed that as our index of suspicion increases, a greater percentage of these cats with acromegaly will have GH and/or IGF-1 concentrations that are within reference ranges and may not have a pituitary mass large enough to be seen on imaging scans. Provocative testing will be necessary to confirm a diagnosis.
Definitive diagnosis of acromegaly currently requires documentation of increases in serum GH or IGF-1 concentration. In cats with acromegaly, baseline GH concentrations are typically abnormally increased (normal concentration 1.5 to 7.9 ng/ml). Unfortunately, measurement of GH concentration in cats is not readily available commercially, and, when available, may take some time before results are obtained. In North America, serum IGF-I concentrations are commercially available and can be used as a diagnostic aid. Abnormally increased serum IGF-I concentrations would suggest acromegaly, although values in the high normal range do not rule acromegaly out. We have had several acromegalic cats with IGF-I values in the high normal range (ie, 50 to 75 nmol/L). Studies on the sensitivity and specificity of GH and IGF-1 assay results in cats are not yet available, yet it is likely that GH assays are also not perfect.
Acromegaly vs hyperadrenocorticism
Among the many causes for apparent or poor control of diabetes mellitus are hyperadrenocorticism and acromegaly. Clinical signs, however, differ dramatically when comparing these two disorders. Hyperadrenocorticism is a debilitating disease that results in progressive weakness, weight loss and cachexia. Further, dermal and epidermal atrophy causes the skin to become extremely fragile, thin, easily torn and ulcerated (ie, feline fragile skin syndrome). Many cats with hyperadrenocorticism have tremendous abdominal enlargement. Further, many diabetic cats have neither of these conditions. Rather, they are overdosed with insulin, have chronic hyperglycaemia secondary to glucose counter-regulation, have weight gain secondary to the anabolic actions of insulin and are believed, incorrectly, to be insulin resistant.
Treatment
A successful therapy for acromegaly caused by pituitary or hypothalamic neoplasia has yet to be established in the cat. Potential therapeutic modalities include radiation therapy, medical therapy and hypophysectomy Radiotherapy is currently considered the most effective treatment. Response to cobalt teletherapy ranges from no response to dramatic response characterised by shrinkage of the tumour, correction of hypersomatotropism, resolution of insulin resistance and, in some cats, reversion to a subclinical diabetic state. Typically, tumour size, plasma GH, and serum IGF-I concentrations are decreased and insulin-response is improved after cobalt teletherapy. Hypersomatotropism may recur 6 to 18 months after treatment. Disadvantages of radiotherapy include limited availability, expense, extended hospitalisation, frequent anaesthesia and unpredictable outcome.
The long-acting somatostatin analog SMS 201–995 (octreotide; Sandoz, East Hanover, NJ, USA) inhibits GH secretion in human beings, non-human primates, dogs and rodents and has been used successfully for the treatment of acromegaly in human beings. Unfortunately, octreotide has been unsuccessful in lowering serum GH concentration or improving insulin sensitivity in the small number of acromegalic cats in which it has been used. Dosages have ranged from 10 to 200 μg/cat given SC two to three times daily. The reason for this ineffectiveness in cats is not understood; GH-secreting somatotroph adenomas of cats may lack the somatostatin receptors for the somatostatin analogs.
Trans-sphenoidal selective adenoma removal or hypophysectomy have been curative in about 60% of human beings with acromegaly. This method of therapy has not yet been described in cats with hypersomatotropism, however, transsphenoidal cryotherapy of a pituitary tumour has been described in a cat with acromegaly.
Prognosis
The short- and long-term prognosis for tumour induced acromegaly is guarded to poor. Survival time has ranged from 4 to 42 months (median, 21 months). Growth hormone-secreting pituitary tumours usually grow slowly. Neurological signs associated with an expanding tumour are uncommon until late in the course of the disorder. Diabetes mellitus can usually be somewhat controlled (ie, blood glucose between 200 and 400 mg/dl) with large doses of insulin given twice daily. Severity of insulin resistance often fluctuates in cats with acromegaly; to avoid development of severe hypoglycaemia, insulin doses should not exceed 12 to 15 units per injection. Most cats with acromegaly eventually die or are euthanatised because of development of severe congestive heart failure, renal failure, or neurologic signs from an expanding pituitary tumour.
Hyperadrenocorticism
Hyperadrenocorticism in cats is a syndrome analogous to Cushing's syndrome in humans. The incidence of this condition in cats and humans is rare, whereas it is considered relatively common in dogs. Naturally occurring feline hyperadrenocorticism (in approximately 80% of cats) is usually caused by an autonomously functioning pituitary tumour (usually an adenoma) that, in turn, results in adrenocortical hyperplasia (pituitary dependent hyperadrenocorticism; PDH). Approximately 20% of cats have a functioning adrenocortical tumour. Approximately 50% of cats with adrenal tumour have had an adenoma and 50% a carcinoma.
Clinical signs
Cats with Cushing's syndrome are middle-aged or older (mean, 10 to 11 years). Approximately 70% of the cats are female and no breed predilection has been noted. The most common clinical signs of feline hyperadrenocorticism are polydipsia, polyuria and polyphagia. These signs are frequently observed because the incidence of diabetes mellitus is extremely high. In most cats, hyperadrenocorticism is diagnosed following documentation of insulin-resistant diabetes mellitus. Therefore, polyuria and polydipsia develop as a result of hyperglycaemia and glycosuria rather than from cortisol excess. Consistent with this concept is the low incidence of polyuria, polydipsia and polyphagia in cats receiving exogenous glucocorticoids and the common finding of concentrated urine (>1.020) in most cats with hyperadrenocorticism.
Dermatological signs most notably include extremely fragile, thin, infected and easily bruised skin (‘feline fragile skin syndrome’). These skin problems constitute the second most common set of clinical signs in cats with hyperadrenocorticism. Afflicted cats may also have an unkempt hair coat, patchy and asymmetrical alopecia, muscle wasting, a potbelly (pendulous abdomen with hepatomegaly) and pigmented skin. Some of these cats may be described as ‘listless’ or ‘depressed’ due to muscle weakness or due to the effects of a large pituitary mass.
Clinical pathology and radiography
The CBC from cats with hyperadrenocorticism was not contributory to the final diagnosis. The red and white blood cell counts are usually within normal limits. One-half of the cats tested have had circulating oeosinophils, and 75% had normal lymphocyte counts. Seventy-five to 80% of cats with Cushing's syndrome have had randomly obtained urine specific gravities greater than 1.020. More than 80% of Cushing's syndrome cats have hyperglycaemia, hypercholesterolaemia and a mild increase in alanine aminotransferase; attributed to poorly regulated diabetes mellitus. ‘Steroid-induced’ alkaline phosphatase and ‘steroid hepatopathy’ are unique to dogs.
Radiographically, most (>70%) cats with Cushing's syndrome have hepatomegaly, excellent contrast due to mesenteric fat and a pendulous abdomen. Abdominal ultrasonography is far more valuable and reliable in evaluation of adrenal size and the possibility of adrenal neoplasia.
Diagnosis—screening tests
Diagnosis—discrimination testing
Complete evaluation of cats suspected of having a rare disease, such as Cushing's syndrome, is often recommended. However, the only consistent and reliable therapy to date is surgical removal of one or both adrenals. Therefore, discrimination testing may be interesting and informative, especially to a surgeon, but treatment of these cats is best accomplished with surgery.
Lack of suppression, either on a percentage basis (>50% of baseline) or using absolute values (>1.0μg/dl), is consistent with a diagnosis of Cushing's syndrome but should not be thought to confirm a diagnosis of adrenocortical tumour. Diagnosis of an adrenal tumour is usually suspected on abdominal ultrasonography. Suppression, using both percentage decrease and an absolute decrease on 0.1 and/or 1.0 mg/kg dexamethasone testing, is documented in a few cats with PDH but not in those with adrenocortical tumours. Again, most cats with hyperadrenocorticism fail to suppress absolute plasma cortisol concentrations after receiving either of the two dexamethasone doses.
Treatment
Hyperadrenocorticism is remarkably debilitating in cats. Although therapy is difficult and the prognosis guarded, an attempt is usually made to control the disease because of the deteriorating clinical condition of afflicted cats. Adrenalectomy, unilateral in cats with adrenal tumour or bilateral in cats with PDH, has provided our best results.
When o, p′-DDD was administered to clinically normal cats, only 50% had adrenocortical suppression. Several Cushing's syndrome cats treated with o, p′-DDD at doses of 50 mg/kg/day (divided BID) failed to demonstrate any improvement, including two cats treated daily for longer than 90 days. Even doubling the dose has not improved the response seen in our treated cats.
The response to ketoconazole (30 mg/kg/day divided BID) has also been inconsistent, at best. While monitoring ketoconazole administration to five cats with hyperadrenocorticism, three responded moderately well but not completely, one had no response, and one developed severe thrombocytopaenia, necessitating withdrawal of therapy.
Reports of four hyperadrenal cats treated with metyrapone have been published. One cat demonstrated transient reduction in baseline and ACTH-stimulated cortisol concentrations, amelioration of clinical signs, and underwent subsequent successful adrenalectomy. The dose for which the best results were described was 65 mg/kg BID orally. It is important to point out that this cat was also diabetic and suffered from a severe hypoglycaemic reaction after metyrapone treatment was initiated. Successful resolution of hypercortisolism should reduce insulin antagonism and reduce or eliminate the need for exogenous insulin in some cats. Appropriate monitoring, anticipating this effect, should minimise the risk associated with this beneficial side effect. Unfortunately, metyrapone is not consistently available.
Adrenalectomy procedures are well described elsewhere. If discrimination tests are not performed or are not conclusive, the surgeon must be prepared to make decisions during the procedure regarding removal of one or both adrenals. Eight of the cats we have treated were diagnosed as having PDH and had both adrenal glands surgically removed. Two cats undergoing surgery for Cushing's syndrome were diagnosed as having adrenocortical tumours and had their adrenal tumours removed (one adenoma and one adenocarcinoma). These two cats were among the three longest-living cats following surgery (12 and >30 months, respectively).
Post-operative complications contributing to death or euthanasia include sepsis, pancreatitis, thromboembolic phenomena, wound dehiscence and adrenal insufficiency. Sepsis was identified in 50% of our most recently treated cats, causing most of the problems we encountered with morbidity and mortality. Preoperative medical management of the Cushing's syndrome and administration of anticoagulants may be extremely beneficial in preventing many of these complications. Two of our cats that survived bilateral adrenalectomy, subsequently (2 and 14 months later, respectively) developed signs caused by large pituitary masses.
Prognosis
Hyperadrenocorticism must be considered a serious disease with a guarded to grave prognosis. The deleterious effects of chronic hypercortisolism on skin fragility as well as on immune and cardiovascular function are frequently responsible for the death of untreated cats. Medical therapies have had limited success, and surgery has been difficult to perform owing to the debilitated condition of these cats. The longest-surviving cats are those that have had an adrenocortical adenoma or carcinoma removed surgically. The most important determinant of long-term prognosis in cats undergoing adrenalectomy is the ability of the owner and clinician to successfully manage the iatrogenic adrenal insufficiency. An Addisonian crisis has occurred in several of our cats months after surgery and was believed to be responsible for the death of several cats.