The main cause of feline acromegaly is adenoma of the somatotroph cells of the anterior pituitary gland, which secretes excessive amounts of growth hormone (GH). Recent studies in humans have shown that in these adenomas there is an over-expression of cyclin B2 gene (CCNB2); however, the factor triggering this over-expression is still not clear. Studies in murine models have shown that the so-called high mobility group A (HMGA) proteins play a role in the activity of ccnb2 in pituitary tumours; evidence that there is an analogous aetiopathogenic mechanism in the cat is lacking.
Although pituitary adenoma seems to the main cause of acromegaly in the cat, it has recently been hypothesized that some acromegalic subjects have hyperplasia of the somatotroph cells. This may be an independent pathological process or a stage preceding the development of the adenoma.
In human medicine pituitary adenomas are recognized to secrete various different hormones, including GH, prolactin, thyroid-stimulating hormone and the alpha subunit of glycoprotein hormones. A single case of a double pituitary adenoma has been described in a cat with hypercortisolism and diabetes mellitus, in which immunohistochemical studies showed both a somatotroph and a corticotroph adenoma.
Although progestins seem to induce the secretion of GH also in breast tissue of the cat, no cases of acromegaly caused by the production of GH in mammary tissue have yet been described in this species. Mammary secretion of GH does, however, have a local effect involving insulin-like growth factor I (IGF-I) and can cause enlargement of one or more of the mammary glands. This enlargement can be found in young females at the time of their first oestrus or be a consequence of administration of exogenous progestins.
CLINICAL SIGNS
Acromegaly is a disease that usually affects castrated male cats between 6 and 15 years old and is the result of overexposure of tissues not only to GH, but also to IGF-I.
The clinical signs are due to both catabolic and anabolic effects of GH, to the anabolic effects mediated by IGF-I, and in some cases to the space-occupying effects of the tumour. Most of the signs seem to be related to the marked insulin resistance caused by GH. It seems that hyperinsulinaemia is induced by a reduction in the number of insulin receptors and a deficiency of insulin kinase activity. Indeed, almost all subjects with acromegaly have poorly controlled diabetes mellitus because of the strong insulin resistance induced by GH.
The most frequent symptoms reported by owners are polyuria, polydipsia, markedly increased appetite, weight increase, sometimes limping, increased size of the limbs and more marked facial features. Furthermore, inferior prognathism and widened interdental spaces may be seen during the clinical examination (Fig. 1). Some subjects may develop a systolic murmur which, with progression of the disease, can lead to congestive heart failure. Indeed, a chronic excess of GH causes accumulation of collagen in the myocardium. Sometimes there may be respiratory stridor, which is the result of increased thickness of the tissues of the oropharynx and, in particular, of the soft palate. The appearance of neurological signs, such as circling, mydriasis and visual impairment may be the consequence of an increase in the size of the pituitary adenoma.
LABORATORY TESTS
The typical laboratory findings are hyperglycaemia, glycosuria without ketones in the urine and an increase in total proteins. Persistent hyperphosphataemia, not associated with azotaemia, is probably due to increased renal reabsorption of phosphate. Hyperphosphataemia can, however, often be found in the context of renal impairment, characterized by azotaemia, urine with a low specific gravity and proteinuria as a consequence of the chronic excess of GH and the poor control of diabetes mellitus. There may also be a moderate erythrocytosis due to the anabolic effects of GH and IGF-I on the bone marrow.
DIAGNOSIS
There are some difficulties in assaying feline GH; in fact, the hormone can only be measured by heterologous (that is, species-specific for dogs and sheep) radioimmunological assays. Furthermore, a high value may be the result of an isolated pulse of secretion in a non-acromegalic subject; thus three to five blood samples, each taken 10 minutes apart, should be collected for the GH assay.
The serum levels of IGF-I are fundamental for making a diagnosis of acromegaly. The concentration of IGF-I is GH-dependent and, given the fact that IGF-I is bound to transport proteins, its levels are less subject to fluctuations. Furthermore, feline IGF-I can be measured using an assay for human IGF-I; for this reason many laboratories carry out this test, providing results in a reasonably short time. For assays of IGF-I it is important that the serum or plasma sample is sent to and arrives at the laboratory frozen. Values above 1000 µg/L are usually considered indicative of acromegaly; nevertheless, false negatives can occur, particularly in cats with diabetes mellitus still not being treated with insulin. Contrariwise, high levels of IGF-I have been observed in cats with insulin-resistant diabetes mellitus. In the case of suspected acromegaly in a diabetic subject, IGF-I should not be measured at the time the diabetes is diagnosed (because of the risk of false negatives), but at least 1 month after starting insulin therapy.
Once the diagnosis has been confirmed, it can be useful to examine the pituitary gland by computed tomography or magnetic resonance imaging. In most cats the hypophyseal tumour can be visualised by either computed tomography or magnetic resonance imaging after administration of a contrast agent. It is, however, important to emphasize that the lack of a visible hypophyseal mass does not exclude acromegaly, as a mass may not be evident in the early phases of the disease.
TREATMENT
The treatment of choice in humans is surgical asportation of the adenoma. Trans-sphenoidal hypophysectomy in cats is currently performed at the University of Utrecht. Only two cases of cryohypophysectomy have been described: this treatment decreased the insulin-resistance and lowered the plasma levels of IGF-I. Both these management strategies require further study since the number of animals treated so far is extremely limited.
The most frequently used treatment in cats is radiotherapy, administered in a variety protocols, which has led to improvements in insulin-resistance and neurological signs in some cases.
Somatostatin analogues are used in the clinical care of humans and have been shown to have good efficacy in lowering levels of IGF-I and GH, as well as decreasing the size of the tumour in patients with acromegaly. Of four cats treated with ocreotide, a somatostatin analogue, only one had a reduction in plasma levels of GH.
Prolonged-release somatostatin analogues, administered as a single dose every 30 days, have recently been introduced into clinical use for humans. A preliminary test should be carried out to determine the potential efficacy of these substances: acromegalic subjects who have a favourable response to an intravenous administration of ocreotide could be candidates for treatment with a prolonged-release formulation of this somatostatin analogue.
A GH receptor antagonist, pegvisomant, has been shown to be effective in humans; however, species-specific antagonists would be necessary for use in veterinary medicine and these are not currently available.
PROGNOSIS
The short-term prognosis of cats with acromegaly is relatively good, provided that the diabetes mellitus is kept under control; often very large quantities of insulin are needed in order to achieve such control (doses of 10 U/cat every 12 hours are frequently needed and there are published case reports of insulin doses of >50 U/cat every 12 hours).
The most frequent complications, such as congestive heart failure and neurological symptoms due to expansion of the pituitary tumour, generally lead to death or euthanasia within 1 or 2 years.
Suggested readings
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