The Basics: What Is Hypersomatotropism or Acromegaly?

Hypersomatotropism represents the excess production of growth hormone (GH). Most cases of feline acromegaly are caused by a functional benign pituitary tumour originating from the acidophilic cells. In addition rare cases of pituitary hyperplasia have been reported. This is in contrast to the situation in dogs, where it occurs as a consequence of dioestrus induced GH production by the mammary gland. Acromegaly refers to a clinical syndrome as a result of the hypersomatotropism, which includes the physical changes which occur in the patient when exposed to the excess GH over a longer period of time. However, these classical acromegalic features take time to appear and are therefore not consistently present in our feline patients. Technically it is therefore better to use the term hypersomatotropism (overactivity of somatotrophs or GH producing cells), which might or might not result in the complete syndrome of acromegaly. Admittedly, both terms are however often used interchangeably, with acromegaly being the more popular term.

Why Worry About Acromegaly?

Acromegaly was previously thought to be rare and therefore usually featured only infrequently or sparsely during the basic training of veterinarians. This has changed very recently in light of studies revealing that its prevalence amongst diabetic cats is higher than expected. Since that time, screening diabetic cats for acromegaly or hypersomatotropism has increased and it has become evident that it is a rather common cause for diabetic cats to become diabetic in the first place, as well as being difficult to control once diabetes mellitus (DM) has occurred. Prevalence of acromegaly amongst diabetic cats in North America and the UK was found to be around 1 in 4 diabetic cats seen in primary practice. The disease is therefore likely currently underdiagnosed. The prevalence amongst non-diabetic cats is currently unknown although these cats would be expected to become diabetic in the long-run. On the basis of this high prevalence and the significant clinical implications of missing the diagnosis, it is important for veterinarians to at least consider offering to screen diabetic cats for this disease.

What Does an Acromegalic Cat Look Like?

Although many of the physical changes associated with acromegaly take several months to (more often) years to appear, diabetes mellitus will be one of the very first (or often only) things to be noticed. The youngest cat described to date was 6 years of age, although the average age of an acromegalic cat seems 11 years. Like regular diabetic cats, acromegalic cats are more often male than female. Body condition can range from normal to being overweight and an average body weight of 5.8 kg was found in a large cohort of acromegalic cats. This is of particular interest, since typical diabetic cats with poorly controlled DM would show weight loss. Therefore gaining weight despite suboptimal control should alert clinicians on the possible presence of hypersomatotropism. Acromegalic cats are believed to be less likely underweight. Most described cats have been domestic short hair cats, although a range of other breeds have also been known to suffer from the disease. The insulin requirements of an acromegalic cat will ultimately likely be higher than an average non-acromegalic diabetic. In fact, some acromegalic cats need an extraordinarily high insulin dose and still show a poor response to therapy. A group of 59 acromegalics was found to be treated with an average of 7 IU BID, but with some cats receiving as much as 35 IU BID. The reason for the insulin resistance observed in these patients relate to the excess GH which has a range of anabolic and catabolic effects on a cat. One of the most noticeable effects of excess GH however is that it decreases insulin sensitivity and through this mechanism will cause the, often insulin-resistant, DM. Polyuria and polydipsia are often reported due to uncontrolled diabetes mellitus, as well as polyphagia. Interestingly, the polyphagia can be reported to be extreme, possibly related to both the indirect effect of uncontrolled diabetes, compounded by the direct effects of GH on appetite. In fact, the polyphagia can be so extreme that owners perceive it to be one of the main, or even the main quality of life affecting signs.

GH induces the production of a peptide called insulin-like growth factor-1 (IGF-1), predominantly by the liver. Acromegalic cats will therefore also have excess circulatory IGF-1, which has additional anabolic effects. As a result, after long-term exposure to excess GH and IGF-1, patients can suffer from excessive tissue growth and deformations of internal and/or external organs, which may include broad facial features, big (so-called 'clubbed') paws, cranial abdominal organomegaly and prognathia inferior (protrusion of the mandible).

Neurological signs (blindness, seizures, circling) due to a gradually expanding pituitary tumour can rarely occur. This is, however, uncommon as the tumors tend to be benign and slow growing. Auscultation may reveal a systolic cardiac murmur or gallop rhythm or respiratory changes due to congestive heart failure or referred upper respiratory stridor (due to an increase in oropharyngeal tissue and thickening of the soft palate). However, whether cardiovascular complications are genuinely more common in acromegalic cats compared to age matched controls is still under investigation. It has, however, been shown that when a more proactive approach is chosen (just as we now adopt with screening for hyperthyroidism) and one screens for acromegaly amongst diabetic cats, a large proportion of cases will in fact look like any other regular diabetic cat. Clinical management of their diabetes will usually, however, prove more difficult than any other regular diabetic cat.

How Do I Prove it to Be Present?

Clinical Picture

No one single test proves without doubt that acromegaly is present. A thorough analysis of the clinical picture is initially warranted, paying particular attention to the presence of signs not typically seen in a regular diabetic, including weight gain despite lack of control and presence of insulin resistance. However, since these atypical signs are not consistently present, the author recommends running a screening-test for acromegaly in every diabetic feline. Acromegaly should definitely be considered in any diabetic cat with insulin resistance.

Endocrine Testing

Measuring serum IGF-1 is a good initial screening test. A GH assay is currently not commercially available (although this should change soon). It should be noted though that both false positive and false negative results have been reported when using either test. Documenting an elevated IGF-1 concentration therefore merely tells us that further testing is required. If the IGF-1 is normal, yet the animal clinically still fits the picture of acromegaly, it will be wise to repeat the IGF-1 measurement at a later stage. It is important to note that hepatic IGF-1 production is dependent on presence of insulin in the portal circulation. This means that in some diabetic cats that have beta-cell dysfunction and therefore hypoinsulinemia, IGF-1 will be lower and presence of acromegaly can be masked when using IGF-1 as a screening test. When we re-test the IGF-1 after 6–8 weeks of exogenous insulin therapy the true IGF-1 value will be detected which might prove higher. Feline GH measurement has proven useful. Specificity and sensitivity of one particular assay and one particular cut-off level proved a reasonable 95% and 84% respectively. Combining IGF-1 and fGH determination will significantly increase diagnostic accuracy, although we have to await the commercialisation of a GH assay.

Intracranial Imaging

After having detected an elevated IGF-1 and/or fGH in a diabetic cat hypersomatotropism becomes a genuine possibility and confirmatory testing is indicated. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) (both pre- and post-contrast) should be offered to assess pituitary size and morphology. If a pituitary enlargement is present, this substantiates the diagnosis and treatment could be considered. Since hyperadrenocorticism can also cause insulin-resistant diabetes mellitus, weight gain despite uncontrolled diabetes mellitus (although weight loss is more common with hyperadrenocorticism) and adrenomegaly and can also be associated with a pituitary tumour on CT or MRI, potential exists for misdiagnosis. Differentiation will be made extra difficult in light of all pituitary-adrenal function tests being vulnerable to rendering false positives in ill and stressed animals. Indeed, urine cortisol:creatinine ratios will often be elevated in acromegalic cats as well. The differentiation will usually be possible though through paying attention to specific clinical differences between the two endocrinopathies; acromegaly: broad facial features, clubbed paws, arthropathy, prognathia inferior, particularly severe insulin resistance; hyperadrenocorticism: frail skin, fur changes, bruising, less severe insulin resistance). Additionally, fGH and IGF-1 results are expected to be different. In some cases a low-dose dexamethasone suppression test (LDDST; often preferred over an ACTH stimulation test in cats) helps deciding if hyperadrenocorticism is likely.

Treatment Options

Choosing the best treatment option will be crucial in achieving the desired effect with complete and permanent diabetic remission being the ultimate reward in well managed cases. In general, options include conservative and proactive approaches.

The Conservative Option

The main aim of treatment is to improve the quality of life of the patient. As such, different pet-owner combinations may require a different treatment option.

Risk-averse owners might opt for the most conservative route. This route consists of dealing with the consequences of the hypersomatotropism only, which mainly focuses on the secondary diabetes mellitus. Twice daily or sometimes even more frequent long-acting insulin injections might help reduce the levels of polyuria and polydipsia in some cases. However, obtaining good glycemic control often proves impossible using this approach and high doses of insulin will be needed. Nevertheless, if more definitive treatment options are not available or declined, it remains an option to explore. Finding the appropriate insulin dose is an empirical process; dosage increases are implemented until satisfactory clinical improvement is achieved according to improvement in fructosamine, a series of blood glucose curves and clinical signs associated with the diabetes mellitus. Sometimes more intense insulin therapy is required to bring the diabetes under control. This could include a period of continuous intravenous insulin infusion or the use of more intense subcutaneous insulin regimes including using combinations of long-acting insulin twice daily and short-acting insulin preparations (soluble insulin) at the time of each meal, as well as feeding four to five times daily to limit blood glucose undulations.

The Proactive Options

More proactive treatment options focus on controlling the hypersomatotropism itself. Treatment modalities include medical treatment, radiotherapy or hypophysectomy.

Radiotherapy

The primary aim of the radiotherapy is to reduce GH production to levels that are no longer clinically significant whilst at the same time reducing the size of the tumor. Unfortunately radiotherapy is actually better at reducing the size of the tumor than normalizing excess hormone secretion. Nevertheless, it can lead to improved control of the diabetes mellitus and even diabetic remission in a proportion of patients. A significant disadvantage is the fact that the treatment's effect is impossible to predict in terms of degree (no response, partial response, complete response), time of onset (within weeks, after a year or never) and duration (temporary or permanent). However, disadvantages also include, with most protocols, the need for several anaesthetics with associated risks, associated hospitalizations and costs, making it unsuitable for a significant proportion of owners and pets.

Hypophysectomy

Hypophysectomy is the treatment of choice in many human acromegaly sufferers as well as many of our feline patients. It will result in instant near complete removal of the pituitary tumor, as well as fast and complete normalisation of GH levels with a high chance of achieving diabetic remission. Both experience with and access to transsphenoidal hypophysectomy in acromegalic cats is currently limited, yet increasing rapidly. Whereas Utrecht University in the Netherlands used to be the only institution offering this modality, the author's Acromegalic Cat Clinic in London is now also performing such procedures with good success. The clinic has operated on 13 cats thus far; 11 survived the operation; nine became non-diabetic within one week to one month and two saw their insulin requirements reduce by 85%. Postoperatively the cats are being managed with once daily oral hydrocortisone and thyroid hormone supplementation. A minority also needs daily DDAVP administration (ADH replacement) in an ocular preparation. On the basis of these results, in the author's clinic, hypophysectomy has become the treatment of choice for feline acromegaly, unless the tumor is rather large or there are specific reasons for the procedure to be too hazardous in a particular patient.

Medical Treatment Using Pituitary Inhibitors

Using somatostatins to inhibit GH secretion by the pituitary tumour has proven very effective in humans suffering from acromegaly, but has previously proven ineffective in cats. Previously tested dopamine agonists and somatostatin analogues, including long-acting formulations such as lanreotide, have not resulted in detectable clinical improvement. Nevertheless, a novel somatostatin analogue Pasireotide (Novartis, Basel) has been tested in the author's Acromegalic Cat Clinic and found to be effective, leading to insulin dose reduction in all cats, decreases in IGF-1 and even diabetic remission in 25% of cases when using a once monthly preparation. However, somatostatin treatment was also associated with gastrointestinal side effects in a significant number of cats, including diarrhoea, rendering this not a miracle solution, especially considering its considerable expense and the fact that the pituitary tumour is left in place.

Taking Care of Complications and Comorbidities

No matter which treatment modality is chosen, acromegaly-associated complications and comorbidities need to be attended to in order to ensure a maximal quality of life. Analgesia should be provided to in case of arthropathies, angiotensin converting enzyme (ACE)-inhibitor, diuretic treatment and regular veterinary assessments are required if heart failure occurs.

References

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

2.  Niessen SJ, Petrie G, Gaudiano F, Khalid M, Smyth JB, Mahoney P, Church DB. Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med. 2007;21(5):899–905.

3.  Berg RI, Nelson RW, Feldman EC, Kass PH, Pollard R, Refsal KR. Serum insulin-like growth factor-I concentration in cats with DM and acromegaly. J Vet Intern Med. 2007;21(5):892–898.

4.  Niessen SJ, Khalid M, Petrie G, Church DB. Validation and application of an ovine radioimmunoassay for the diagnosis of feline acromegaly. Vet Rec. 2007;160(26):902–907.