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Feline Acromegaly

by Chelsea Sonius
Spring 2011


Introduction

Feline acromegaly is an endocrine disease caused by chronic, excess secretion of growth hormone (GH) from the pituitary gland.  It is a slowly progressive disease that affects many organ systems and nearly always results in diabetes mellitus that is difficult to control with standard insulin therapy regimes.  Often, uncontrolled diabetes is the first sign that makes veterinarians suspect acromegaly, however, there is often many other clinical signs and syndromes that result from excessive GH secretion.  For example, kidney, cardiac, and neurological disease may result, especially as the disease progresses.  Historically, acromegaly has been considered a "rare" disease in cats, but recent statistics indicate that acromegaly is likely underdiagnosed in the feline patient. (1)  Further, with new and improved technology, veterinary professionals have the potential to become more successful at managing and treating patients with acromegaly.  This means that the diagnosis and treatment of cats with acromegaly will likely be more prevalent in the daily veterinary practice.  The aim of this paper is to provide current information regarding the background, diagnosis, and treatment of feline acromegaly.

Physiology of Growth Hormone and its Role in Diabetes Pathogenesis

Growth hormone is produced and secreted from the anterior portion of the pituitary gland.  The pituitary gland is an endocrine gland that resides in the brain and is responsible for the secretion of several hormones that control a variety of homeostatic and metabolic functions in the body.  GH is one of these hormones; it is responsible for growth regulation and plays a role in regulating the metabolism of protein, fat, and glucose.  In cats without acromegaly, GH secretion remains under the control and regulation of the hypothalamus, a structure in the brain that is responsible for regulation of the pituitary gland.  The hypothalamus acts to send excitatory signaling molecules (Growth Hormone Releasing Hormone) or inhibitory signaling molecules (Somatostatin) to the cells of the pituitary gland, which results in modulation and regulation of blood GH levels.  Under normal circumstances, regulation and subsequent secretion of GH occurs in a pulsatile fashion, which is imperative for proper growth and metabolic regulation.  In patients with acromegaly the secretion of GH is not controlled, and excess GH is secreted from the pituitary and delivered throughout the body.  This excess GH results in disturbances in growth and metabolism, and can result in serious deleterious consequences as the disease progresses.

In the feline patient, the most common cause of acromegaly is a tumor of the cells that produce GH.  The cells that produce and secrete GH are called somatotrophs, and the tumor that arises from these cells is termed a "somatrophic adenoma".  These tumor cells produce excessive amounts of GH by causing an elevation in the frequency, duration, and amplitude of GH secretion. (3)  Further, these tumor cells are likely no longer responsive to the normal regulatory mechanisms of the hypothalamus. (2) 

GH mediates its effects on the body both directly and indirectly.  The direct effects of GH are mediated by the effects of GH itself on tissues, while the indirect effects of GH are mediated through a hormone called Insulin-like Growth Factor 1, commonly referred to as IGF-1.  IGF-1 is produced by the liver in response to circulating GH.  IGF-1 is responsible for the majority of the growth promoting effects of GH.  It acts to increase bone and cartilage production, as well as increase protein synthesis and cellular proliferation of soft tissues, resulting in growth and expansion of soft tissues.  These growth promoting and tissue building effects are referred to as the "anabolic" effects of GH.  Anabolism is a termed used to describe the build up or synthesis of molecules, tissues and creation of energy stores within the body.  The result of these anabolic effects is an increase in size or synthesis of biomolecules within the body.

Conversely, catabolism is a term used to describe the breakdown of tissues or molecules and the release of energy from storage pools within the body.  Along with the anabolic effects previously discussed, GH is also responsible for catabolic effects within the body.  These catabolic effects are mediated directly by GH itself, rather than through a secondary molecule such as IGF-1 as described above.  The primary catabolic effects mediated by GH are fat and carbohydrate storage breakdown.  The breakdown of storage carbohydrates leads to a net increase in blood glucose levels.

GH is also an insulin antagonist and insulin sensitivity modulator, meaning that it blocks or counteracts the effects of insulin.  Insulin is also a key hormone involved in glucose and fat metabolism, and is responsible for mediating entry of blood glucose into cells.  In the presence of insulin, glucose can enter liver and muscle cells and be converted to glycogen, the primary storage carbohydrate.  Through complicated metabolic pathways that are yet to be entirely worked out, excess GH can lead to decreased insulin sensitivity and subsequent insulin resistance, there by leading to decreased ability to convert blood glucose to the storage form.

Several hypotheses have been made to explain the mechanism of insulin antagonism by GH.  One likely cause of GH mediated insulin resistance is due to persistent hyperglycemia caused by the catabolic effects of GH.  This persistent hyperglycemia leads to elevations in insulin levels, termed hyperinsulinemia.  In response to persistent increases in circulating insulin, the body decreases the production of insulin receptors that are found in cells, a process termed insulin-receptor down regulation.  With down=regulation of insulin receptors, there is less capability for insulin to mediate its effects on glucose metabolism, despite the fact that there is an elevation in circulating insulin.  In this way, excess GH can contribute to decreased insulin responsiveness and decreased insulin sensitivity. (4) 

Additional mechanisms have also been hypothesized and studied, many of which include complicated signaling pathways that occur following insulin receptor binding, which is beyond the scope of this paper.  In short, however, it appears that GH and insulin share many of the same post-receptor cellular signaling pathways, and excess GH may directly modulate or interfere with these signaling pathways leading to decreased insulin sensitivity and insulin resistance. (4) 

As briefly discussed above, one of the primary findings in feline patients with acromegaly is diabetes mellitus that is difficult to manage by standard insulin therapy regimens.  Diabetes mellitus is a very common endocrine disorder in cats which results when there is insufficient insulin action in response to elevations in blood glucose.  Commonly this is caused by inadequate production of the insulin hormone by cells of the pancreas.  Patients with inadequate insulin production often respond very well to insulin administration for control of diabetes, as exogenous insulin therapy corrects the insulin deficiency.  However, diabetes can also be caused by an inability to properly utilize insulin.  In such cases, insulin administration may not be sufficient for diabetes management. (5)  In patients with acromegaly, diabetes is often caused by decreased responsiveness and utilization of insulin, as discussed above.  It follows then, that cats with acromegaly and concurrent diabetes often cannot be sufficiently managed with standard insulin therapy protocols.

Acromegaly is not the only disease condition that can cause insulin-resistant diabetes mellitus, however.  Many other underlying diseases and disorders can cause decreased effectiveness of insulin, such as hyperthyroidism, dental disease, urinary tract infection, gastrointestinal diseases, cancer, and various other diseases.  Further, there may also be other underlying causes contributing to an apparent insulin resistance; for example, the cat may simply be getting underdosed or may not be receiving his/her injections properly. (1)  It becomes apparent then, that while insulin-resistant diabetes should be a red flag to cause suspicion of acromegaly, the clinician should also consider all of these additional underlying conditions that could be contributing. 

Clinical Presentation of Acromegaly in Cats

Acromegaly tends to occur in middle age to geriatric patients, with the average age of onset in two separate studies being 10 and 11 years old. (2,6)  Acromegaly also tends to be more prevalent in the male population, with 20 of 23 cats in one population of patients with acromegaly being males in one study and 15 of 17 in an additional study. (2,3) 

In the early stages of acromegaly the catabolic effects of GH often predominate, and the cat often presents and displays signs very similar to a typical diabetic cat.  The most common early signs of acromegaly are increased eating (polyphagia), increased drinking (polydypsia), and increased urination (polyuria).  In one study, 100% of owners of cats with confirmed acromegaly reported increased drinking and urinating, and 16/17 owners reported an increase in appetite. (6)  Because of the very similar initial presentation of acromegaly and diabetes mellitus, it is easy to see how a diagnosis of acromegaly could initially easily be confused for a diagnosis of diabetes mellitus.  The cat may show an initial weight loss, as well, which is also commonly seen in cats with non-acromegaly diabetes mellitus.  However, as the disease progresses, the cat will often begin to gain weight.  This is in contrast to most patients with uncomplicated diabetes mellitus who typically do not gain weight, but rather show varying amounts of weight loss throughout the course of disease.

As the disease progresses, the anabolic effects mediated by IGF-1 may become more apparent.  As discussed above, IGF-1 is responsible for the growth promoting effects of GH such as bone, cartilage, and soft‐tissue growth.  Cats may begin to develop enlarged facial features and their mandible (lower jaw bone) may begin to protrude past their maxilla (upper jaw bone).  14 of 17 cats displayed broad facial features on presentation, and 8 of 17 cats displayed a protrusion of the mandible. (6)  The cat may also show a generalized weight gain, and on physical examination the veterinarian may find that the cat has abdominal distention and/or enlarged organs such as the liver or kidney (15/17 cats from the study above). (6) 

It should be noted, however, that because this is a fairly slowly progressive disease, these changes are often difficult for owners to recognize.  For example, the study described above reported that on physical examination by the veterinarian, 14 of 17 cats were noted to display broad facial features, a change reported by only one of the owners. (6)  It should also be noted that in some patients the aforementioned physical findings are not present or obvious to either the owner or the veterinarian.  A lack of obvious physical findings such as these cannot be used to rule out acromegaly in patients displaying other signs and symptoms consistent with an underlying growth hormone disorder.

Various other clinical findings have been described in a smaller proportion of feline patients with acromegaly.  Increased respiratory noise was noted on physical examination in 9 of 17 cats. (6)  The current belief is that this is likely caused by the IGF-1 effects on growth of soft-tissue structures in the laryngeal region, resulting increased turbulence of airflow and subsequent noise on inspiration. Some cats also show lameness. (6)  and painful joints. (2)  This too, is likely also caused by IGF-1 mediated effects, wherein increased bone and cartilage growth results in diseased conditions of joints. (2)  As the disease progresses organs such as the kidney, liver, and heart may become affected by the IGF-1 effects, as well.  Cats may or may not show overt signs of organ system dysfunction, and often additional diagnostic tests and modalities are needed to look for the presence of kidney, liver, or cardiac disease.

Finally, the cat may also display signs of neurologic disease.  This clinical finding, unlike the other clinical findings, is not an effect of endocrine/hormone imbalance, but rather a direct effect of either a space occupying lesion in the brain due to the pituitary tumor itself or due to invasion of the tumor into adjacent brain structures.  Cats with neurologic manifestations of acromegaly may show signs such as an abnormal behavior/temperment, an abnormal gait, circling behaviors, or seizure disorders

Diagnosis of Acromegaly in Cats

Once acromegaly is suspected, further investigation is warranted in order to make a diagnosis, however, definitive diagnosis can sometimes prove a challenge to veterinarians.  Current diagnostic modalities utilized in acromegaly diagnosis are endocrine testing and brain imaging.  Other adjunctive modalities such as routine blood work, radiography, and ultrasonography can also be helpful in providing further support for a diagnosis of acromegaly.

Endocrine testing consists of both GH and IGF-1 level testing, which are often used in combination.  GH has shown to be a somewhat reasonable indicator of acromegaly in cats; however, current testing availability in the US and around the world is limited.  Further, some scientists have made arguments that due to the pulsatile release of GH and its short biological half‐life, it may not be the most reliable test for diagnosis of acromegaly.  IGF-1 testing is more readily available and is often used in conjunction with GH testing.  IGF-1 has a longer biological half-life than GH, and IGF-1 levels can be used as an indicator of the average GH levels over the last 24 hours.  However, some studies have shown that IGF-1 can be elevated in patients with diabetes mellitus alone.  A recent review of acromegaly suggests that when possible, doing both tests in combination will allow for a more confident diagnosis of acromegaly, especially when combined with diagnostic imaging, as discussed below. (2)

The two diagnostic imaging modalities that are utilized to look for pituitary adenomas in patients with suspected acromegaly are Computed Tomography (CT) and Magnetic Resonance Imaging (MRI), both of which are utilized to construct 3-D images of the soft tissue and bony structures of the brain.  A recent study reports that of 16 cats evaluated via a combination of CT and MRI, 15 of 16 cats showed some degree of evidence of pituitary tumor either with CT/MRI alone or in combination. (6)  It should be noted, however, that there are other pituitary tumors/abnormalities that can be seen on MRI/CT that do not cause acromegaly.  Therefore, CT and MRI testing in conjunction with GH and IGF-1 testing is likely the best diagnostic plan for a cat with suspected acromegaly.

Other tests can also be used adjunctively to further support a diagnosis of acromegaly.  Various clinical laboratory findings consistent with diabetes mellitus, renal disease, liver disease, etc. can occur simultaneously with acromegaly.  Further, echocardiography can be utilized to look for concurrent evidence of cardiac disease, and diagnostic imaging modalities such as radiology and ultrasonography can be utilized to look for abdominal organ enlargement. (2)

Treatment Options

Current treatment options for cats with acromegaly aim to either eradicate the pituitary tumor itself or control the endocrine effects of the pituitary tumor hypersecretion.  Multiple publications document that tumor eradication is currently the most effective treatment options for cats.  Several different methods of tumor eradication have been utilized, with radiation therapy likely being the most commonly employed and most readily available.

With radiation therapy the aim is to irradiate and kill the somatrophic tumor cells that are producing and secreting GH.  It has been reported that radiation therapy is able to control tumor growth in GH-secreting adenomas in approximately 90% of human patients.  Limited feline data is available, however reports have indicated that radiotherapy does appear to induce some degree of clinical improvement in cats.  As for any radiation therapy regime, however, there are potential negative consequences to nontumor tissues and organs. (7)  The use of stereotactic radiation therapy for the treatment of pituitary tumors is currently being investigated at Colorado State University.  Stereotactic radiation therapy is a method of radiotherapy that allows for very precise radiation doses to the target tissue, thereby sparing adjacent normal tissue.  Along with this, because adjacent tissue is spared, higher radiation doses can be utilized to more effectively eradicate the tumor.

Other methods of tumor eradication that have previously been utilized include transsphenoidal hypophysectomy (surgical removal of the pituitary through the sphenoid bone of the skull) and cryohypophysectomy (freezing of the pituitary tissue).  Limited data regarding outcomes of such pituitary removal methods in cats is available, and further studies are needed to evaluate the efficacy of either of these methods for the treatment of acromegaly in cats. (1)

Medical therapy has proven to be less successful than radiation therapy for the management of acromegaly in cats.  A variety of drugs are currently available to the human population, and include somatostatin analogs and dopamine agonists, which aim to decreases pituitary GH secretion, and GH antagonists, which aim to block the peripheral effects of GH, and thus, decrease IGF-1 production.  Therapy with these drugs in cats has been described, but limited success rates have been reported.  This may, in part, be due to a limited number of trial therapies.  Further research will need to be done to determine if medical therapy will be a viable option for treatment of cats with acromegaly in the future. (1)

Prognosis for Patients with Acromegaly

The prognosis and quality of life for patients with acromegaly is actually quite variable.  Some reports indicate that patients can live up to nearly four years following diagnosis with acromegaly, while some report a much smaller window of time. (8)  Some cats may enjoy a relatively comfortable quality of life after diagnosis, while others may suffer a poorer quality of life.  Quality of life will depend on a multitude of factors including tolerance of treatment modalities, degree of uncontrolled diabetes, and development of secondary diseases.

Some cats may tolerate treatment therapy much better than others, and owners should consider initiating quality of life discussion regarding treatment therapy if the veterinarian has not already done so.  An additional factor that may contribute to quality of life is the degree of management of diabetes.  Uncontrolled diabetes and secondary diseases such as renal disease, heart disease, and neurological disease are ultimately the cause of death for more cats with acromegaly.  As the disease progresses it is important that owners be responsive to the changes occurring with their cat, and aim to make their last days as comfortable as possible.  Hopefully with the recently recognized increased prevalence of the disease and ongoing research, we will be able to make great strides in the medical management of cats with acromegaly, thereby helping owners provide a higher quality of life during their last years.

Bibliography

1. Niessen S. Feline Acromegaly: An essential differential diagnosis for the difficult diabetic. Journal of Feline Medicine and Surgery 2010; 12: 15-23.

2. Feldman EC and Nelson RW: Disorders of Growth Hormone, p. 45-82. In Canine and Feline Endocrinology and Reproduction, 3rd ed. St. Louis, MO, 2004. Saunders.

3. Barken AL, Stred SE, Reno K, et al. Increased growth hormone pulse frequency in acromegaly. J Bibliographe ynol Metab 1989; 69: 1225-1233.

4. Dominici FP, Argentno DP, Muñoz MC, et al. Influence of the crosstalk between growth hormone and insulin signaling on the modulation of insulin sensititvity. Growth Horm IGF Res 2005; 15: 324-326.

5. Niessen SJ, Petrie G, Gaudiano F, et al. Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med 2007; 21: 899-905.

6. Cornell Feline Health Center website.

7. Mayer MN, Greco DS, LaRue SM. Outcomes of pituitary tumor irradiation in cats. J Vet Intern Med 2006; 20: 1151-1154

8. Peterson ME, Taylor RS, Greco DS, et al. Acromegaly in 14 cats. J Vet Intern Med 1990; 4: 192-201


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