Feline acromegaly



Feline AcromegalyTanya Schoeman BVSc(Hons)MMedVet(Med) Dipl ECVIM-CACape Animal Medical Centre, 78 Rosmead Avenue, Kenilworth, Cape TownAbstractFeline acromegaly is more common in cats than once thought. This article emphasises the importance of being open to this diagnosis, particularly in diabetic cats. Some cats do not demonstrate the physical changes associated with this disease. Although these changes remain important disease markers, they are not required to pursue the diagnosis of acromegaly. In addition, acromegaly can cause significantly diminished quality of life from insulin resistance and poorly regulated DM, as well as concurrent problems (eg, congestive heart failure).DefinitionHypersomatotropism 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 the pars distalis of the anterior pituitary. 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 that 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. SignificanceAcromegaly 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 under diagnosed. 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. Pathogenesis and clinical signsAlthough 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 is approximately 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 5.8kg 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 glucose control should alert clinicians on the possible presence of hypersomatotropism.Most described cats have been domestic short hair cats, although a range of other breeds has 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 that has a range of anabolic and catabolic effects on a cat. One of the most noticeable effects of excess GH is that A growth hormone–induced postreceptor defect ininsulin action at the level of target tissues is thought to explain why most cats withacromegalyhaveconcurrentdiabetesmellitus.it decreases insulin sensitivity through a post-receptor defect in insulin action at the level of target tissues A growth hormone–induced postreceptor defect ininsulin action at the level of target tissues is thought to explain why most cats withacromegalyhaveconcurrentdiabetesmellitus. 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). Some cats will show the classic enlargement of extremities, body size, jaw, tongue, and forehead that is characteristic of acromegaly in people.Gross necropsy findings in acromegalic cats may include a large expansile pituitary mass, hypertrophic cardiomyopathy with marked left ventricular and septal hypertrophy (early) or dilated cardiomyopathy (late), hepatomegaly, renomegaly, degenerative joint disease, lumbar vertebral spondylosis, adrenocortical hyperplasia, and (most commonly) diffuse enlargement of the pancreas with multifocal nodular hyperplasia.Neurological signs (blindness, seizures, circling) due to a gradually expanding pituitary tumour can rarely occur. This is however uncommon as the tumours 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). Hypertension is an irregular finding. The question whether cardiovascular complications are genuinely more common in acromegalic cats compared to age matched controls is still under investigation.It has been shown that when a more proactive approach is chosen 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. Diagnosis1. Clinical picture No one single test proves without doubt that acromegaly is present. Suspicious clinical signs include polyuria, polydipsia, polyphagia, weight gain, upper respiratory stridor, broad facial features, prognathia, organomegaly and clubbed paws. Particular attention should be paid 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 clinical signs are not consistently present, one could argue that a screening test for acromegaly should be run in every diabetic feline. Acromegaly should definitely be considered in any diabetic cat with insulin resistance (requiring a dose of >1.5 IU/kg).2. Endocrine testing Feline growth hormone (fGH; serum and plasma) and IGF-1 (serum) have been shown to be useful screening tests, although both false positive and false negative results have been reported when using either test. A suggested growth hormone cutoff value of 10 ng/mL was shown to result in an acceptable specificity of 95% and sensitivity of 84% when using the fGH assay recently developed at the Royal Veterinary College in London. Feline GH also appeared relatively stable, allowing overnight transport of unseparated samples. Unfortunately fGH determination is currently not commercially available (although this should change soon). Documenting an elevated IGF-1 concentration (>1000 ng/ml) is useful as a screening test, but it merely tells us that further confirmatory 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 after 6-8 weeks. It is important to note that hepatic IGF-1 production is dependent on presence of insulin in the portal circulation, as hepatic IGF-1-production is induced via stimulation of?insulin-dependent hepatic GH-receptors. 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. Combining IGF-1 and fGH determination should significantly increase diagnostic accuracy, although we have to await the commercialisation of a GH assay. Given the potential for both false positives and false negatives with either GH or IGF-1 assessment and the need for confirmatory intracranial imaging, research is currently ongoing to evaluate alternative biomarkers for feline hypersomatotropism. Because hypersomatotropism is associated with tissue growth, serum type III procollagen propeptide (PIIIP), a peripheral indicator of collagen turnover, has recently been shown to be elevated in cats with hypersomatotropism. A PIIIP concentration greater than 8 ng/mL was shown to be 100% specific for a diagnosis of hypersomatotropism, with a sensitivity of 75%.Serum ghrelin, an endogenous ligand of the GH secretagogue receptor and therefore susceptible to negative feedback in a state of hypersomatotropism, has thus far not been found useful in differentiating diabetes from hypersomatotropism-induced diabetes, despite such suggestions in human hypersomatotropism.The glucose suppression test (measuring GH before and after administration of glucose) is a gold standard test in the diagnosis of human hyperso-matotropism, although little?evidence in favour of its use in feline hypersomatotropism has as yet been published.3. Intra-cranial 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. Intracranial imaging (with contrast enhancement) has been proven useful in confirming the presence of hypersomatotropism, with MRI probably more sensitive than CT.If a structural pituitary abnormality is documented, this provides further circumstantial evidence for the presence of hypersomatotropism, especially if?there are concurrent increases in frontal bone thickness and/or evidence of soft tissue accumulation in the nasal cavity, sinuses and pharynx.However, the demonstration of a pituitary tumour as such does not provide differentiation from a non-functional pituitary tumour or pituitary dependent hyperadrenocorticism (PDH), especially because pituitary tumours are a relatively common type of brain tumour in the cat.Cases with a negative CT and/or MRI have also been documented, with the diagnosis eventually being confirmed on post mortem examination. Cases with subtle (microscopic) acidophilic hyperplasia or microadenoma, instead of?obvious (macroscopic) adenoma, might more likely show negative intracranial imaging.In conclusion, pituitary imaging is too expensive and too invasive (sedation or anaesthesia needed) to be considered suitable as a screening test, and is ideally used as an attempt to confirm the disease or for preradiation or pre-surgical planning. Refinement of our hormonal assessment methods and increasing availability of assays probably constitutes the best way to improve the diagnosis of?hypersomatotropism. Differential diagnosisSince 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. Interestingly, 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. TreatmentThe 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. Treatment options for hypersomatotropism consist of medical treatment, surgical options, radiotherapy or palliative treatment. When definitive treatment is instituted, clinicians and owners need to be vigilant for rapid changes in insulin demands should the treatment prove effective. Iatrogenic hypoglycemia is frequently encountered and home blood glucose measurement should be considered. should be considered.Medical treatmentIn contrast to the situation in human hypersomatotropism, medical treatment options aimed at inhibiting the pituitary have not proven very successful in the cat thus far. Previously tested dopamine agonists and somatostatin analogues, including long-acting formulations such as lanreotide and sandostatin, have not resulted in detectable clinical improvement.Nevertheless, a novel somatostatin analogue Pasireotide (Novartis) has been tested recently in a phase 2 clinical trial 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. (Stijn Niessen, DVM, PhD, DipECVIM, personal communication, 2012). However, somatostatin treatment was also associated with gastro-intestinal side effects in a significant number of cats, including diarrhoea, rendering this not a miracle solution, especially when considering its considerable expense and the fact that the pituitary tumour is left in place. Surgical treatmentHypophysectomy 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 tumour, as well as fast and complete normalisation of GH levels with a high chance of achieving diabetic remission. After decades of this procedure being available only in the Netherlands, transphenoidal hypophysectomy has in recent years become available also in the United Kingdom (London), United States (California), and Japan. Analog to the situation in human medicine, success rates are strongly correlated with the experience of the surgeon, as well as the availability of high-quality intensive postoperative care. Post-operatively the cats should be managed with once daily oral prednisolone (0.1 mg/kg/d) or hydrocortisone (0.5 mg/kg/d) and thyroid hormone supplementation. A minority also needs daily DDAVP administration (ADH replacement) in an ocular preparation. The induced diabetes insipidus seems only temporary in nature in most patients, whereas secondary hypocortisolism and secondary hypothyroidism require lifelong supplementation.Glucose concentrations must be very closely monitored, because severe clinical hypoglycemia can ensue in patients as soon as the first week after surgery. A number of cases have been published; all showing diabetic remission rates within 4 weeks after surgery. This further substantiates that early diagnosis and subsequent immediate and effective intervention increases the chance for complete diabetic remission hugely, given that sufficient beta-cell function will still be present. On the basis of these results, 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 dangerous in a particular patient. Radiation therapy 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 tumour. Unfortunately radiotherapy is actually better at reducing the size of the tumour than normalising 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). Other disadvantages with most protocols include the need for several anaesthetics with associated risks and associated hospitalisations and costs, therefore making it unsuitable for a significant proportion of owners and pets. Palliative treatmentRisk-averse owners might opt for the most conservative route. This route ignores the underlying disease mechanism and focuses on gaining more control of the diabetes mellitus and treating possible co-morbidities.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 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. Treating complications and co-morbiditiesNo matter which treatment modality is chosen, acromegaly-associated complications and co-morbidities need to be attended to in order to ensure a maximal quality of life. Analgesia should be provided to all cats in case of arthropathies, while angiotensin converting enzyme (ACE)-inhibitor, diuretic treatment and regular veterinary assessments are required if heart failure occurs. PrognosisWhen left unattended, quality of life will be negatively affected in a chronic and slowly progressive fashion in feline hypersomatotropism. Traditionally a guarded to poor prognosis has been suggested, but advances in the treatment of feline hypersomatotropism, especially in terms of increased availability of hypophysectomy and identification of effective somatostatins, will likely lead to modification of?expected life expectancy and life quality expectations. When effective treatment is initiated early enough, an improved quality of life and even diabetic remission can be achieved.REFERENCES Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract. 2013 Mar; 43(2):319-50. Niessen SJ, Petrie G, Gaudiano F, Khalid M, Smyth JB, Mahoney P, Church DB. Feline acromegaly: an underdiagnosed endocrinopathy? Niessen SJ, Petrie G, Gaudiano F, Khalid M, Smyth JB, Mahoney P, Church DB. J Vet Intern Med. 2007 Sep-Oct; 21(5):899-905. 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. Journal of Veterinary Internal Medicine 2007: 21(5): 892-8. Niessen S.J., Khalid M., Petrie G. & Church D.B. Validation and application of an ovine radioimmunoassay for the diagnosis of feline acromegaly. Veterinary Record 2007; 160(26): 902-907.Niessen S, Feline acromegaly: An essential differential diagnosis for the difficult diabetic. JFMS 2010; 12:15-23 Niessen SJM, Church DB In August, JR (Ed): Consultations in feline internal medicine. Vol 6. Elsevier Saunders, Philadelphia. 2010 pp:304 Berg RI, Nelson RW, Feldman EC, et al. Serum insulin-like growth factor-I concen-tration in cats with diabetes mellitus and acromegaly. J Vet Intern Med 2007; 21(5):892–8Niessen SJ, Forcada Y, Church DB. Serum type III procollagen propeptide: an alternative measure of growth hormone bioactivity in cats with diabetes mellitus and hypersomatotropism. J Vet Intern Med 2012; 26(6):1520 TBC Jensen K, Forcada Y, Glanemann B, et al. Physiology and diagnostic potential of serum ghrelin in cats with diabetes mellitus and hypersomatotropism. J Vet Intern Med 2012; 26b(6):1519Posch B, Dobson J, Herrtage M. Magnetic resonance imaging findings in 15 acromegalic cats. Vet Radiol Ultrasound 2011; 52(4):422–7Niessen SJ, Forcada Y, Jensen K, et al. Routine screening of diabetic cats for acromegaly: overdue or overkill? J Vet Intern Med 2011; 25:1489–90 ................
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