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Feline Acromegaly
Topics in Compan An Med 27 (2012) 31-35
Topical Review
Feline Acromegaly Deborah S. Greco, DVM, PhD, Dipl. ACVIM
A B S T R A C T Keywords: acromegaly hypersomatotropism growth hormone insulin-like growth factor somatostatin cat feline diabetes mellitus Address reprint requests to: Deborah S. Greco, DVM, PhD, Dipl. ACVIM, Nestle Purina PetCare, New York, NY E-mail: [email protected].
Acromegaly, or hypersomatotropism, results from chronic, excessive secretion of growth hormone in the adult animal. The anabolic effects of growth hormone are exerted through the intermediary hormone, insulin-like growth factor 1, which is produced in the liver under the influence of growth hormone. Feline acromegaly is caused by a pituitary adenoma that secretes excessive amounts of growth hormone. Characteristic effects of excessive growth hormone secretion include the development of diabetes mellitus and growth of the acral segments of the body (jaw, extremities, skull, etc.). Acromegaly occurs in older, predominately male cats and is often associated with diabetes mellitus. Other clinical signs include stridor, enlargement of the jaw and extremities, lean weight gain, and organomegaly (heart, liver, kidney, etc.). Diagnosis is made by documentation of increased levels of growth hormone or insulin-like growth factor (or both) and demonstration of a pituitary mass via magnetic resonance imaging or computed tomography. The most effective treatment to date has been radiation therapy. Prognosis is fair to good with proper treatment. 䉷 2012 Published by Elsevier Inc.
Acromegaly derives its name from the Greek “akros” (meaning “extremity”) and “megale” (meaning “great”) and from the characteristic overgrowth of the acral segments of the body connective tissues, viscera, and bones. The first case of acromegaly was discovered in Greece; the human skull with characteristic changes of acromegaly dates from the 7th century AD.1 In 1886, the French physician Pierre Marie described acromegaly in 2 patients with massive enlargement of the head and extremities.2 Nearly 100 years later, the first case reports of suspected acromegaly were published.3,4 Since the first description of the disease in cats, several series of feline acromegaly cases have been reported.5,6 It is now recognized that acromegaly may be present in as many as 30% of poorly regulated or insulin-resistant diabetic cats.7,8 Pathogenesis As with humans beings with hypersomatotropism, acromegaly in cats is caused by a functional somatotropic adenoma or hyperplasia of the pituitary gland; chronic excessive growth hormone and somatomedin secretion ensues. In human beings, overexpression of the cell cycle gene cyclin B2 (ccnb2) is thought to result in adenomatous changes in the somatotrophs of the pars distalis (anterior pituitary gland).8 In cats, these tumors grow slowly and may be present for a long time before clinical signs appear.9,10 This is in contrast to the disorder in dogs, which is usually observed in older breeding bitches treated with progestational compounds for estrus prevention.11 It has been shown that the canine mammary gland is capable of producing exogenous growth hormone (GH) and insulin-like growth factors (IGF).11,12 Pathophysiology and Manifestations of Growth Hormone Excess Glucose metabolism is affected by growth hormone both directly and through the somatomedins or IGF (IGF-1, 2, and 3). Insulin resistance results from a decrease in insulin receptors, increased insulin receptor binding, and post-receptor antagonism. Although GH antagonizes the peripheral action of insulin, it also has a direct action on pancreatic islets to increase beta cell secretory capacity and can cause beta cell hyperplasia. In feline acromegaly, prolonged hypersomatotropism leads to diabetes mellitus because insulin secretory capacity is exceeded.
Protein metabolism is stimulated by excessive GH secretion resulting in positive balances of nitrogen, phosphorus, potassium, and magnesium needed for new protoplasm. Direct effects of GH in the liver lead to an increase in protein synthesis. Growth hormone is anabolic and its effects are mediated through the somatomedins or IGF. Somatomedins are well recognized for their ability to stimulate the uptake of sulfate by cartilage, collagen, and proteoglycan synthesis and mitogenesis. The anabolic effects of the somatomedins are manifested as an increase in lean body mass in both human beings and cats with acromegaly. Triglyceride lipase is activated in adipocytes and lipolysis is enhanced by the action of growth hormone. After GH administration, increased lipolysis and fatty acid oxidation balance the energy lost through diversion of amino acids from oxidative to anabolic pathways. GH lowers the respiratory quotient and promotes ketogenesis. Like insulin, somatomedins can increase glucose uptake by adipocytes and inhibit lipolysis. The direct anabolic effects of IGF-1 result in some of the more dramatic clinical signs of acromegaly. IGF-1 oversecretion causes growth and enlargement of all the organs in the body, including the kidneys, heart, liver, and endocrine organs. The effect of somatomedins on the myocardium includes moderate to marked interstitial fibrosis, increased collagen content of the cardiac muscle, and hypertrophy of the individual cardiac muscle cells. Acromegalic arthropathy is caused by IGF-1 induction of cartilage hyperplasia and hypertrophy, which leads to disruption of joint geometry and chondrocyte metabolism. Cutaneous changes related to GH excess include increased proliferation of fibroblasts, collagen, and mucopolysaccharide, and hyperplasia of the epidermis and dermal appendages (pilosebaceous structures). Histopathologic changes in the skin consist of dermal and epidermal hyperplasia with an increased amount of collagen and fibroblasts.13 Diffuse mucinous degeneration, myxedema, is often evident and may resemble the changes of hypothyroidism. Lesions Gross necropsy findings in acromegalic cats may include a large expansile pituitary mass (Fig. 1), hypertrophic cardiomyopathy with marked left ventricular and septal hypertrophy (early) or dilated car-
0958-3947/$ – see front matter 䉷 2012 Topics in Companion Animal Medicine. Published by Elsevier Inc. http://dx.doi.org/10.1053/j.tcam.2012.05.004
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Deborah S. Greco / Topics in Companion An Med 27 (2012) 31-35
Fig. 1. Gross necropsy findings of a cat with acromegaly showing a large acidophil tumor.
diomyopathy (late), hepatomegaly, renomegaly, degenerative joint disease, lumbar vertebral spondylosis, moderate enlargement of the parathyroid glands, adrenocortical hyperplasia, and diffuse enlargement of the pancreas with multifocal nodular hyperplasia. Histopathologic examination of the endocrine glands reveals acidophil adenoma of the pituitary; adenomatous hyperplasia of the thyroid gland; and nodular hyperplasia of the adrenal cortices, parathyroid glands, and pancreas. The pancreas may exhibit ductal fibrosis, interstitial lymphocytic infiltration, and marked hyalinization of the islets of Langerhans. Myocardial lesions are characterized by multifocal severe myocytolysis, interstitial fibrosis, moderate intramural arteriosclerosis, and marked variation of myocyte diameter with hypertrophy. Kidneys of acromegalic cats show moderate to marked expansion of the mesangial matrix, variable periglomerular fibrosis proximal and distal tubular hyaline casts, multifocal fibrosis, and lymphocytic/plasmacytic infiltration of the renal interstitium. Microscopic joint changes include erosion and ulceration of articular cartilage with chondroid hyperplasia and fissure formation. Clinical Findings Feline acromegaly occurs in older (8-14 years) cats and appears to be more common in males.9 Clinical signs of uncontrolled diabetes mellitus are often the first sign of acromegaly in cats; therefore, polydipsia, polyuria, and polyphagia are the most common presenting signs (Table 1).5,7 Diabetic remission may be difficult to induce because of the antagonistic effects of GH on insulin and glucose metabolism. Acromegaly should be considered in cats that do not discontinue insulin injections in the first few months after appropriate
Table 1 Frequency of clinical signs of acromegaly Clinical Signs
Percent of Occurrence
Polydipsia/Polyuria Polyphagia Hepatomegaly Cardiomegaly Insulin resistance Prognathia inferior Heart murmur Weight gain Stridor Weight gain Renal failure Enlarged head and extremities Congestive heart failure Arthropathy Macroglossia Central nervous system signs
100 100 100 86 79 71 64 57 57 50 50 50 43 43 21 14
Fig. 2. Phenotypic appearance of a typical acromegalic cat with overt diabetes mellitus and enlargement of acral segments of the body (head, paw, etc.).
insulin and dietary therapy. However, unregulated diabetic cats may have suppressed levels of IGF-1 before insulin therapy; therefore, screening for acromegaly should not be a first-line diagnostic test. Net weight gain of lean body mass in cats with uncontrolled diabetes mellitus is a key sign of acromegaly. In one study, the average weight of the acromegalic cats was about 6 kg at the time of diagnosis with an average increase of 2 kg over a period of a few months after diagnosis.7 Some cats show the classic enlargement of extremities, body size, jaw, tongue, and forehead that is characteristic of acromegaly in people. Photographs taken before the onset of clinical signs of acromegaly, particularly those taken of the cat as a young adult, may be helpful. Some cats will show the classic enlargement of the extremities, body size, jaw, tongue, and forehead that is characteristic of feline acromegaly, while others may not. Comparison of the cat’s appearance with that in old photographs may reveal the more subtle features of acromegaly. Some of the most striking manifestations of acromegaly occur in the musculoskeletal system and include an increase in muscle mass and growth of the acral segments of the body, including the paws, chin, and skull. Enlargement of the body, abdominal organs, and head may be particularly striking; clubbing of the feet may occur (Fig. 2). Growth of soft tissue in the mouth and pharyngeal region may lead to classic signs of stridor. Osseous signs are related to growth of the flat bones of the skull and mandible; clinically this may be detected by increased interdental spaces (Fig. 3).14 In approximately 50% of the cats reported by Peterson et al, monoarthritis or polyarthritis was observed.5 Furthermore, radiographic evidence of degenerative joint disease also was observed in a significant number of cats even if lameness was not a complaint.5 Affected joints included the shoulder, carpus, elbow, digits, stifle, and spine. Cardiovascular abnormalities such as cardiomegaly (radiographic and echocardiographic), systolic murmurs, and congestive heart failure (CHF) occur late in the course of the disease. Clinical evidence of CHF (i.e., pulmonary edema, pleural effusion) was observed in approximately 40% of the cases of feline acromegaly in one study.5 This is similar to acromegalic human beings, who may exhibit cardiomegaly (80%) and CHF (25%). Hypertension is also observed in a significant portion (25%) of human acromegalics. In acromegalic cats, hypertension is also commonly observed in later studies. In human beings, the secondary effects of increased total peripheral resistance from hypertension also may contribute to cardiomyopathy. Neurologic signs of acromegaly in human beings include peripheral neuropathies paresthesias, carpal tunnel syndrome, sensory and
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human beings do not exhibit renal failure as a component of the acromegalic syndrome. Pathologic findings in one study of 14 cats with acromegaly revealed the primary renal abnormality as proteinuria associated with glomerulosclerosis.5 The cause of acromegalic glomerulopathy in cats is not known; however, the lesions resemble those of a hyperfiltration injury caused by poorly controlled diabetes mellitus or diabetic nephropathy. A recent study documented proteinuria in 70% of diabetic cats.15 Urinalysis is unremarkable except for persistent proteinuria and glycosuria. Urine protein to creatinine ratios are usually mildly elevated, and microalbuminuria may be present because of glomerular hyperfiltration. Urine-specific gravity is usually not affected.5 Radiographs and Ultrasound
Fig. 3. Increased interdental spaces suggestive of acromegaly in a 12-year-old cat with hypersomatotropism.
motor defects and parasellar manifestations such as headache and visual field defects. In a series of 14 acromegalic cats, Peterson et al reported that only 2 of the affected cats developed central nervous system signs including seizures and circling. Both of these cats developed neurologic signs late in the course of the disease, and large pituitary tumors were observed at necropsy.5 The difference in local manifestations of acromegaly is probably related to the anatomical differences in the pituitary and surrounding sella in human beings versus cats. Polyneuropathy is a common sign of acromegaly in human beings and usually results from entrapment of nerves in the hypertrophied bone or ligamentous tissue e.g., carpal tunnel syndrome: polyneuropathies have not been described in acromegalic cats; however, diabetic neuropathy may be observed because of poor diabetic regulation. In acromegalic cats, there is an increased thickness of the epidermis with increased dermal mass resulting in the formation of massive folds, particularly in the head and neck region. This hyperplasia of the epidermis may extend to the mouth and pharyngeal regions where respiratory obstruction may occur. Stridor is a common clinical sign of acromegaly in all species. In cats, the skin changes may help differentiate acromegaly from other diseases that cause insulin resistance such as hyperadrenocorticism, which causes thin, hypotonic, and easily torn skin.
Thoracic radiography of acromegalic cats asymptomatic for cardiovascular disease often reveals cardiomegaly as the only sign. In symptomatic cats, evidence of left-sided or bilateral CHF, such as perihilar pulmonary edema and/or pleural effusion, may be present in addition to cardiomegaly. Echocardiographic changes in acromegalic cats include thickening of the intraventricular septum and left ventricular caudal wall.5 Abdominal radiograph and ultrasound are unremarkable with the exception of marked hepatosplenomegaly and renomegaly. Abdominal detail is not enhanced because most acromegalic cats are not obese. In acromegalic cats with CHF, ascites may be evident. Radiographic skeletal changes associated with degenerative arthropathy in acromegalic cats include periarticular periosteal reactions and osteophytes, soft tissue swelling, and collapse of the joint space (Fig. 4).5 Early radiographic evidence of degenerative arthropathy in human beings includes increased joint space secondary to thickening of the cartilage and periarticular periosteal reaction with osteophyte proliferation. Late in the course of the disease joint space collapse is seen. Some acromegalic cats have boney skull changes including hyperostosis of the nasal bones, trabeculae, and calvarium (Fig. 5). Differential Diagnosis The differential diagnosis of acromegaly includes all the causes of insulin resistance including hyperadrenocorticism, hyperthyroidism, uremia, obesity, infection anti-insulin antibodies, inactive or outdated insulin, glucagonoma, administration of diabetogenic medications (megestrol acetate), problems with insulin administration, and pheochromocytoma. In addition, other causes of hy-
Clinical Pathology Mild erythrocytosis, observed in nonazotemic cats with acromegaly, is probably the result of the anabolic effects of GH on bone marrow. Mild to severe hyperproteinemia (⬎ 8.0 g/dL) also may be observed; however, serum protein electrophoresis is usually normal. Impaired glucose tolerance and insulin resistance resulting in diabetes mellitus are seen in all cats with acromegaly. Measurement of endogenous insulin reveals dramatically increased serum insulin concentrations. Despite severe insulin resistance and hyperglycemia, ketosis is rare. Feline acromegaly should be suspected in any diabetic cat that has insulin resistance (⬎ 2 U/kg/d). Increased serum fructosamine in the face of adequate or excessive insulin therapy (⬎ 1 U/kg) is a sign of acromegaly. Hypercholesterolemia and mild increases in liver enzymes are attributed to the diabetic state. Hyperphosphatemia without azotemia is also a common clinicopathologic finding. Azotemia and chronic renal failure develop late in the course of the disease in approximately 50% of acromegalic cats.5 Renomegaly is observed in both cats and human beings with GH excess; however,
Fig. 4. Radiographs of the carpal joints of an acromegalic cat showing degenerative arthropathy.
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Fig. 5. Skull radiographs of an acromegalic cat at a young age and after the development of acromegaly. Note the enlargement of the skull and jaw bones.
pertrophic cardiomyopathy such as hypertension, hyperthyroidism, and idiopathic hypertrophic cardiomyopathy should be considered in cats with cardiovascular manifestations of the disease. Finally if central nervous system signs are also apparent or are primary manifestations, non-GH–secreting pituitary tumors or focal/multifocal lesions toxoplasmosis, neoplasia, feline infectious peritonitis may be included in the differential list. Establishing a Diagnosis Given the large percentage (30%) of cats identified with acromegaly in one series of cats with poorly regulated diabetes mellitus, acromegaly should be on the differential list for causes of secondary or insulin-resistant diabetes.7 In some studies, 70% of diabetes cats will go into remission (no longer needing insulin) when fed an ultra low carbohydrate diet.16,17 Other causes of insulin resistance such as urinary tract infections, insulin administration problems, dietary noncompliance, concurrent hyperthyroidism, etc., should be ruled out by routine laboratory assessment. In both human beings and cats, acromegaly is an underdiagnosed entity18; therefore, any cat that fails to go into remission after appropriate carbohydrate restriction and insulin therapy should be screened for acromegaly with a GH and/or an IGF-1 assay.8,19
assays are impractical because of sample handling requirements (plasma, ice), wide interassay and intra-assay variation, and lack of sensitivity or specificity.23 In human beings, a serum GH concentration of ⬎ 10 ng/mL is highly suggestive of acromegaly; however, submission of a single GH sample has proven unreliable in documenting the disease on a regular basis.7 Recently, a validated feline GH radioimmunoassay has been developed and has proved useful in distinguishing normal from acromegalic cats24; furthermore, unlike the case for IGF-1, there is no overlap between the 2 groups studied. However, a separate study that used 10 ng/mL as a cutoff showed that 2 out of 34 non-acromegalic cats were classified as having acromegaly. Nevertheless, the sensitivity and specificity of the feline-specific GH assay were 84% and 95%, respectively.24 Insulin resistance may be caused by a variety of factors including management-associated errors (incorrect insulin, injection problems, etc.), infections (urinary, dental), inflammatory conditions (pancreatitis, inflammatory bowel disease), neoplasia, obesity, and endocrinopathies (hyperthyroidism, hypersomatotropism, progesterone excess, and hyperadrenocorticism). Therefore, a diagnosis of acromegaly may require additional tests such as urine culture, imaging, TT4 or FT4 concentrations, or dexamethasone suppression testing to rule out other causes of insulin resistance.
IGF
Imaging of the Pituitary
Serum IGF-1 concentrations are often dramatically increased in acromegalic cats and human beings.7,20,21 Documentation of elevated IGF-1 concentrations does not provide a definitive diagnosis, however, because increased IGF-1 has been reported in apparently nonacromegalic diabetic cats.22 Furthermore, untreated diabetic cats with acromegaly may have suppressed IGF-1 concentrations because of impaired portal insulin secretion as insulin is required for GH-dependent hepatic synthesis and secretion of IGF-1.20 Treatment of the diabetes with exogenous insulin therapy for several weeks may allow normal expression of IGF-1 from the liver.20 IGF-1 or somatomedin C is particularly cost-effective as a screening tool because it is readily available from most commercial laboratories, is inexpensive, and requires no special handling.
Computed tomography or magnetic resonance imaging reveals the presence of a large pituitary mass in most cats with acromegaly.25 However, with recent advances in the diagnosis of the disease and earlier detection, about 10% of cases of acromegaly will show no signs of pituitary tumors.8 Results of computed tomography, coupled with the exclusion of other disorders that cause insulin resistance (hyperthyroidism, hyperadrenocorticism) and clinical signs and laboratory abnormalities, support a diagnosis of acromegaly.
Growth Hormone Assays Species-specific growth hormone assays (feline, canine) are not commercially available in the United States and often even human GH
Treatment Medical therapy in people includes the use of dopamine agonists, such as bromocriptine, and somatostatin analogues (octreotide). Treatment with octreotide has been mildly to moderately unsuccessful in acromegalic cats.5,26 The lack of efficacy of the long-acting somatostatin analogues may result from species-specific tissue binding. Long-acting somatostatin analogues that require only a monthly injection have greatly improved patient compliance in human medi-
Deborah S. Greco / Topics in Companion An Med 27 (2012) 31-35
cine, with about 50% responding to monotherapy. A GH receptor antagonist, pegvisomant, may be helpful in treating human patients who do not respond to somatostatin; however, this drug has not been evaluated in cats with acromegaly. Radiation therapy probably offers the greatest chance for success with low rates of morbidity and mortality.27,28 The disadvantages include the slow rate of tumor shrinkage (⬎ 3 years), the occurrence of hypopituitarism, cranial and optic nerve damage, and radiation injury to the hypothalamus. In some cases, resolution of clinical signs was achieved with radiation therapy, particularly with linear acceleratorbased modified radiosurgery.29,30 Surgical treatment of acromegaly is used routinely in human beings with acromegaly; in fact, endonasal endoscopic transsphenoidal pituitary surgery can be performed with excellent results.31 In the cat, transsphenoidal hypophysectomy is only available in selected locations in Europe and the United States. In a series of 7 cats, removal of the pituitary tumor was successful; however, 2 of the 7 cats died within 4 weeks of surgery from unrelated causes.32,33 Cryohypophysectomy has been described as a treatment for feline acromegaly; however, it may be too early to determine the efficacy of this therapy.34 Nevertheless, hypophysectomy is the gold standard for therapy in humans because it provides rapid and complete reductions in serum GH and IGF-1 concentrations that lead to resolution of insulin resistance. As with all therapies, there are risks involved including regrowth of the tumor in about 30% to 40% of cases.35 Prognosis The short-term prognosis in cats with untreated acromegaly is fair to good. Insulin resistance is generally controlled satisfactorily by judicious insulin and dietary therapy. All cats with acromegaly should be fed a balanced diet that is low in carbohydrates and high in protein. Insulin therapy using glargine or protamine zinc insulin augmented with shorter-acting insulin at meal times is the most effective way to address insulin resistance. The long-term prognosis is relatively poor, however, with most cats dying of CHF, chronic renal failure, or signs of an expanding pituitary mass. The long-term prognosis may improve with early diagnosis and appropriate treatment (surgery, radiation therapy). References 1. Charlier P, Tsigonaki C: A case of acromegaly (Greece, 7th century AD). Eur J Endocrinol 165:819 – 821, 2011. 2. Mammis A, Eloy JA, Liu JK: Early descriptions of acromegaly and gigantism and their historical evolution as clinical entities. Neurosurg Focus 29:E1, 2010. 3. Lichtensteiger CA, Wortman JA, Eigenmann JE: Functional pituitary acidophil adenoma in a cat with diabetes mellitus and acromegalic features. Vet Pathol 23:518 – 521, 1986. 4. Morrison SA, Randolph J, Lothrop CD: Hypersomatotropism and insulin-resistant diabetes mellitus in a cat. J Am Vet Med Assoc 194:91–94, 1989. 5. Peterson ME, Taylor RS, Greco DS, et al: Acromegaly in 14 cats. J Vet Intern Med 4:192–201, 1990. 6. Norman EJ, Mooney CT: Diagnosis and management of diabetes mellitus in five cats with somatotrophic abnormalities. J Feline Med Surg 2:183–190, 2000. 7. Niessen SJ, Petrie G, Gaudiano F, et al: Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med 21:899 –905, 2007. 8. Niessen SJ: Feline acromegaly: an essential differential diagnosis for the difficult diabetic. J Feline Med Surg 12:15–23, 2010.
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9. Gunn-Moore D: Feline endocrinopathies. Vet Clin North Am Small Anim Pract 35: 171–210, 2005, vii. 10. Bruyette DS: Feline endocrinology update. Vet Clin North Am Small Anim Pract 31: 1063–1081, 2001, ix. 11. Rijnberk A, Mol JA: Progestin-induced hypersecretion of growth hormone: an introductory review. J Reprod Fertil Suppl 51:335–338, 1997. 12. Mol JA, Lantinga-van Leeuwen I, van Garderen E, Rijnberk A: Progestin-induced mammary growth hormone (GH) production. Adv Exp Med Biol 480:71–76, 2000. 13. Merchant SR, Taboada J: Systemic diseases with cutaneous manifestations. Vet Clin North Am Small Anim Pract 25:945–959, 1995. 14. Siegel ET: Effect of hormones on bone. Cornell Vet 58(suppl):95–103, 1968. 15. Al-Ghazlat SA, Langston CE, Greco DS, Reine NJ, May SN, Shofer FS: The prevalence of microalbuminuria and proteinuria in cats with diabetes mellitus. Top Companion Anim Med 26:154 –157, 2011. 16. Mazzaferro EM, Greco DS, Turner AS, Fettman MJ: Treatment of feline diabetes mellitus using an alpha-glucosidase inhibitor and a low-carbohydrate diet. J Feline Med Surg 5:183–189, 2003. 17. Bennett N, Greco DS, Peterson ME, Kirk C, Mathes M, Fettman MJ: Comparison of a low carbohydrate-low fiber diet and a moderate carbohydrate-high fiber diet in the management of feline diabetes mellitus. J Feline Med Surg 8:73– 84, 2006. 18. Rosario PW: Frequency of acromegaly in adults with diabetes or glucose intolerance and estimated prevalence in the general population. Pituitary 14:217–221, 2011. 19. Peterson ME: Acromegaly in cats: are we only diagnosing the tip of the iceberg? J Vet Intern Med 21:889 – 891, 2007. 20. Berg RI, Nelson RW, Feldman EC, Kass PH, Pollard R, Refsal KR: Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly. J Vet Intern Med 21:892– 898, 2007. 21. Frystyk J, Freda P, Clemmons DR: The current status of IGF-I assays—a 2009 update. Growth Horm IGF Res 20:8 –18, 2010. 22. Reusch CE, Kley S, Casella M, Nelson RW, Mol J, Zapf J: Measurements of growth hormone and insulin-like growth factor 1 in cats with diabetes mellitus. Vet Rec 158:195–200, 2006. 23. Bidlingmaier M, Freda PU: Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res 20:19 –25, 2010. 24. Niessen SJ, Khalid M, Petrie G, Church DB: Validation and application of a radioimmunoassay for ovine growth hormone in the diagnosis of acromegaly in cats. Vet Rec 160:902–907, 2007. 25. Posch B, Dobson J, Herrtage M: Magnetic resonance imaging findings in 15 acromegalic cats. Vet Radiol Ultrasound 52:422– 427, 2011. 26. Slingerland LI, Voorhout G, Rijnberk A, Kooistra HS: Growth hormone excess and the effect of octreotide in cats with diabetes mellitus. Domest Anim Endocrinol 35:352–361, 2008. 27. Littler RM, Polton GA, Brearley MJ: Resolution of diabetes mellitus but not acromegaly in a cat with a pituitary macroadenoma treated with hypofractionated radiation. J Small Anim Pract 47:392–395, 2006. 28. Brearley MJ, Polton GA, Littler RM, Niessen SJ: Coarse fractionated radiation therapy for pituitary tumours in cats: a retrospective study of 12 cases. Vet Comp Oncol 4:209 –217, 2006. 29. Sellon RK, Fidel J, Houston R, Gavin PR: Linear-accelerator-based modified radiosurgical treatment of pituitary tumors in cats: 11 cases (1997-2008). J Vet Intern Med 23:1038 –1044, 2009. 30. Mayer MN, Greco DS, LaRue SM: Outcomes of pituitary tumor irradiation in cats. J Vet Intern Med 20:1151–1154, 2006. 31. Sand MS, Gendeh BS, Husain S: Endonasal endoscopic transsphenoidal pituitary surgery for pituitary adenoma: a retrospective analysis of surgical outcome. Med J Malaysia 66:443– 446, 2011. 32. Meij BP, Voorhout G, Van Den Ingh TS, Rijnberk A: Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats. Vet Surg 30:72– 86, 2001. 33. Meij BP, Auriemma E, Grinwis G, Buijtels JJ, Kooistra HS: Successful treatment of acromegaly in a diabetic cat with transsphenoidal hypophysectomy. J Feline Med Surg 12:406 – 410, 2010. 34. Blois SL, Holmberg DL: Cryohypophysectomy used in the treatment of a case of feline acromegaly. J Small Anim Pract 49:596 – 600, 2008. 35. Wagenmakers MA, Netea-Maier RT, van Lindert EJ, Pieters GF, Grotenhuis AJ, Hermus AR: Results of endoscopic transsphenoidal pituitary surgery in 40 patients with a growth hormone-secreting macroadenoma. Acta Neurochir (Wien) 153: 1391–1399, 2011.
Topical Review
Feline Acromegaly Deborah S. Greco, DVM, PhD, Dipl. ACVIM
A B S T R A C T Keywords: acromegaly hypersomatotropism growth hormone insulin-like growth factor somatostatin cat feline diabetes mellitus Address reprint requests to: Deborah S. Greco, DVM, PhD, Dipl. ACVIM, Nestle Purina PetCare, New York, NY E-mail: [email protected].
Acromegaly, or hypersomatotropism, results from chronic, excessive secretion of growth hormone in the adult animal. The anabolic effects of growth hormone are exerted through the intermediary hormone, insulin-like growth factor 1, which is produced in the liver under the influence of growth hormone. Feline acromegaly is caused by a pituitary adenoma that secretes excessive amounts of growth hormone. Characteristic effects of excessive growth hormone secretion include the development of diabetes mellitus and growth of the acral segments of the body (jaw, extremities, skull, etc.). Acromegaly occurs in older, predominately male cats and is often associated with diabetes mellitus. Other clinical signs include stridor, enlargement of the jaw and extremities, lean weight gain, and organomegaly (heart, liver, kidney, etc.). Diagnosis is made by documentation of increased levels of growth hormone or insulin-like growth factor (or both) and demonstration of a pituitary mass via magnetic resonance imaging or computed tomography. The most effective treatment to date has been radiation therapy. Prognosis is fair to good with proper treatment. 䉷 2012 Published by Elsevier Inc.
Acromegaly derives its name from the Greek “akros” (meaning “extremity”) and “megale” (meaning “great”) and from the characteristic overgrowth of the acral segments of the body connective tissues, viscera, and bones. The first case of acromegaly was discovered in Greece; the human skull with characteristic changes of acromegaly dates from the 7th century AD.1 In 1886, the French physician Pierre Marie described acromegaly in 2 patients with massive enlargement of the head and extremities.2 Nearly 100 years later, the first case reports of suspected acromegaly were published.3,4 Since the first description of the disease in cats, several series of feline acromegaly cases have been reported.5,6 It is now recognized that acromegaly may be present in as many as 30% of poorly regulated or insulin-resistant diabetic cats.7,8 Pathogenesis As with humans beings with hypersomatotropism, acromegaly in cats is caused by a functional somatotropic adenoma or hyperplasia of the pituitary gland; chronic excessive growth hormone and somatomedin secretion ensues. In human beings, overexpression of the cell cycle gene cyclin B2 (ccnb2) is thought to result in adenomatous changes in the somatotrophs of the pars distalis (anterior pituitary gland).8 In cats, these tumors grow slowly and may be present for a long time before clinical signs appear.9,10 This is in contrast to the disorder in dogs, which is usually observed in older breeding bitches treated with progestational compounds for estrus prevention.11 It has been shown that the canine mammary gland is capable of producing exogenous growth hormone (GH) and insulin-like growth factors (IGF).11,12 Pathophysiology and Manifestations of Growth Hormone Excess Glucose metabolism is affected by growth hormone both directly and through the somatomedins or IGF (IGF-1, 2, and 3). Insulin resistance results from a decrease in insulin receptors, increased insulin receptor binding, and post-receptor antagonism. Although GH antagonizes the peripheral action of insulin, it also has a direct action on pancreatic islets to increase beta cell secretory capacity and can cause beta cell hyperplasia. In feline acromegaly, prolonged hypersomatotropism leads to diabetes mellitus because insulin secretory capacity is exceeded.
Protein metabolism is stimulated by excessive GH secretion resulting in positive balances of nitrogen, phosphorus, potassium, and magnesium needed for new protoplasm. Direct effects of GH in the liver lead to an increase in protein synthesis. Growth hormone is anabolic and its effects are mediated through the somatomedins or IGF. Somatomedins are well recognized for their ability to stimulate the uptake of sulfate by cartilage, collagen, and proteoglycan synthesis and mitogenesis. The anabolic effects of the somatomedins are manifested as an increase in lean body mass in both human beings and cats with acromegaly. Triglyceride lipase is activated in adipocytes and lipolysis is enhanced by the action of growth hormone. After GH administration, increased lipolysis and fatty acid oxidation balance the energy lost through diversion of amino acids from oxidative to anabolic pathways. GH lowers the respiratory quotient and promotes ketogenesis. Like insulin, somatomedins can increase glucose uptake by adipocytes and inhibit lipolysis. The direct anabolic effects of IGF-1 result in some of the more dramatic clinical signs of acromegaly. IGF-1 oversecretion causes growth and enlargement of all the organs in the body, including the kidneys, heart, liver, and endocrine organs. The effect of somatomedins on the myocardium includes moderate to marked interstitial fibrosis, increased collagen content of the cardiac muscle, and hypertrophy of the individual cardiac muscle cells. Acromegalic arthropathy is caused by IGF-1 induction of cartilage hyperplasia and hypertrophy, which leads to disruption of joint geometry and chondrocyte metabolism. Cutaneous changes related to GH excess include increased proliferation of fibroblasts, collagen, and mucopolysaccharide, and hyperplasia of the epidermis and dermal appendages (pilosebaceous structures). Histopathologic changes in the skin consist of dermal and epidermal hyperplasia with an increased amount of collagen and fibroblasts.13 Diffuse mucinous degeneration, myxedema, is often evident and may resemble the changes of hypothyroidism. Lesions Gross necropsy findings in acromegalic cats may include a large expansile pituitary mass (Fig. 1), hypertrophic cardiomyopathy with marked left ventricular and septal hypertrophy (early) or dilated car-
0958-3947/$ – see front matter 䉷 2012 Topics in Companion Animal Medicine. Published by Elsevier Inc. http://dx.doi.org/10.1053/j.tcam.2012.05.004
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Fig. 1. Gross necropsy findings of a cat with acromegaly showing a large acidophil tumor.
diomyopathy (late), hepatomegaly, renomegaly, degenerative joint disease, lumbar vertebral spondylosis, moderate enlargement of the parathyroid glands, adrenocortical hyperplasia, and diffuse enlargement of the pancreas with multifocal nodular hyperplasia. Histopathologic examination of the endocrine glands reveals acidophil adenoma of the pituitary; adenomatous hyperplasia of the thyroid gland; and nodular hyperplasia of the adrenal cortices, parathyroid glands, and pancreas. The pancreas may exhibit ductal fibrosis, interstitial lymphocytic infiltration, and marked hyalinization of the islets of Langerhans. Myocardial lesions are characterized by multifocal severe myocytolysis, interstitial fibrosis, moderate intramural arteriosclerosis, and marked variation of myocyte diameter with hypertrophy. Kidneys of acromegalic cats show moderate to marked expansion of the mesangial matrix, variable periglomerular fibrosis proximal and distal tubular hyaline casts, multifocal fibrosis, and lymphocytic/plasmacytic infiltration of the renal interstitium. Microscopic joint changes include erosion and ulceration of articular cartilage with chondroid hyperplasia and fissure formation. Clinical Findings Feline acromegaly occurs in older (8-14 years) cats and appears to be more common in males.9 Clinical signs of uncontrolled diabetes mellitus are often the first sign of acromegaly in cats; therefore, polydipsia, polyuria, and polyphagia are the most common presenting signs (Table 1).5,7 Diabetic remission may be difficult to induce because of the antagonistic effects of GH on insulin and glucose metabolism. Acromegaly should be considered in cats that do not discontinue insulin injections in the first few months after appropriate
Table 1 Frequency of clinical signs of acromegaly Clinical Signs
Percent of Occurrence
Polydipsia/Polyuria Polyphagia Hepatomegaly Cardiomegaly Insulin resistance Prognathia inferior Heart murmur Weight gain Stridor Weight gain Renal failure Enlarged head and extremities Congestive heart failure Arthropathy Macroglossia Central nervous system signs
100 100 100 86 79 71 64 57 57 50 50 50 43 43 21 14
Fig. 2. Phenotypic appearance of a typical acromegalic cat with overt diabetes mellitus and enlargement of acral segments of the body (head, paw, etc.).
insulin and dietary therapy. However, unregulated diabetic cats may have suppressed levels of IGF-1 before insulin therapy; therefore, screening for acromegaly should not be a first-line diagnostic test. Net weight gain of lean body mass in cats with uncontrolled diabetes mellitus is a key sign of acromegaly. In one study, the average weight of the acromegalic cats was about 6 kg at the time of diagnosis with an average increase of 2 kg over a period of a few months after diagnosis.7 Some cats show the classic enlargement of extremities, body size, jaw, tongue, and forehead that is characteristic of acromegaly in people. Photographs taken before the onset of clinical signs of acromegaly, particularly those taken of the cat as a young adult, may be helpful. Some cats will show the classic enlargement of the extremities, body size, jaw, tongue, and forehead that is characteristic of feline acromegaly, while others may not. Comparison of the cat’s appearance with that in old photographs may reveal the more subtle features of acromegaly. Some of the most striking manifestations of acromegaly occur in the musculoskeletal system and include an increase in muscle mass and growth of the acral segments of the body, including the paws, chin, and skull. Enlargement of the body, abdominal organs, and head may be particularly striking; clubbing of the feet may occur (Fig. 2). Growth of soft tissue in the mouth and pharyngeal region may lead to classic signs of stridor. Osseous signs are related to growth of the flat bones of the skull and mandible; clinically this may be detected by increased interdental spaces (Fig. 3).14 In approximately 50% of the cats reported by Peterson et al, monoarthritis or polyarthritis was observed.5 Furthermore, radiographic evidence of degenerative joint disease also was observed in a significant number of cats even if lameness was not a complaint.5 Affected joints included the shoulder, carpus, elbow, digits, stifle, and spine. Cardiovascular abnormalities such as cardiomegaly (radiographic and echocardiographic), systolic murmurs, and congestive heart failure (CHF) occur late in the course of the disease. Clinical evidence of CHF (i.e., pulmonary edema, pleural effusion) was observed in approximately 40% of the cases of feline acromegaly in one study.5 This is similar to acromegalic human beings, who may exhibit cardiomegaly (80%) and CHF (25%). Hypertension is also observed in a significant portion (25%) of human acromegalics. In acromegalic cats, hypertension is also commonly observed in later studies. In human beings, the secondary effects of increased total peripheral resistance from hypertension also may contribute to cardiomyopathy. Neurologic signs of acromegaly in human beings include peripheral neuropathies paresthesias, carpal tunnel syndrome, sensory and
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human beings do not exhibit renal failure as a component of the acromegalic syndrome. Pathologic findings in one study of 14 cats with acromegaly revealed the primary renal abnormality as proteinuria associated with glomerulosclerosis.5 The cause of acromegalic glomerulopathy in cats is not known; however, the lesions resemble those of a hyperfiltration injury caused by poorly controlled diabetes mellitus or diabetic nephropathy. A recent study documented proteinuria in 70% of diabetic cats.15 Urinalysis is unremarkable except for persistent proteinuria and glycosuria. Urine protein to creatinine ratios are usually mildly elevated, and microalbuminuria may be present because of glomerular hyperfiltration. Urine-specific gravity is usually not affected.5 Radiographs and Ultrasound
Fig. 3. Increased interdental spaces suggestive of acromegaly in a 12-year-old cat with hypersomatotropism.
motor defects and parasellar manifestations such as headache and visual field defects. In a series of 14 acromegalic cats, Peterson et al reported that only 2 of the affected cats developed central nervous system signs including seizures and circling. Both of these cats developed neurologic signs late in the course of the disease, and large pituitary tumors were observed at necropsy.5 The difference in local manifestations of acromegaly is probably related to the anatomical differences in the pituitary and surrounding sella in human beings versus cats. Polyneuropathy is a common sign of acromegaly in human beings and usually results from entrapment of nerves in the hypertrophied bone or ligamentous tissue e.g., carpal tunnel syndrome: polyneuropathies have not been described in acromegalic cats; however, diabetic neuropathy may be observed because of poor diabetic regulation. In acromegalic cats, there is an increased thickness of the epidermis with increased dermal mass resulting in the formation of massive folds, particularly in the head and neck region. This hyperplasia of the epidermis may extend to the mouth and pharyngeal regions where respiratory obstruction may occur. Stridor is a common clinical sign of acromegaly in all species. In cats, the skin changes may help differentiate acromegaly from other diseases that cause insulin resistance such as hyperadrenocorticism, which causes thin, hypotonic, and easily torn skin.
Thoracic radiography of acromegalic cats asymptomatic for cardiovascular disease often reveals cardiomegaly as the only sign. In symptomatic cats, evidence of left-sided or bilateral CHF, such as perihilar pulmonary edema and/or pleural effusion, may be present in addition to cardiomegaly. Echocardiographic changes in acromegalic cats include thickening of the intraventricular septum and left ventricular caudal wall.5 Abdominal radiograph and ultrasound are unremarkable with the exception of marked hepatosplenomegaly and renomegaly. Abdominal detail is not enhanced because most acromegalic cats are not obese. In acromegalic cats with CHF, ascites may be evident. Radiographic skeletal changes associated with degenerative arthropathy in acromegalic cats include periarticular periosteal reactions and osteophytes, soft tissue swelling, and collapse of the joint space (Fig. 4).5 Early radiographic evidence of degenerative arthropathy in human beings includes increased joint space secondary to thickening of the cartilage and periarticular periosteal reaction with osteophyte proliferation. Late in the course of the disease joint space collapse is seen. Some acromegalic cats have boney skull changes including hyperostosis of the nasal bones, trabeculae, and calvarium (Fig. 5). Differential Diagnosis The differential diagnosis of acromegaly includes all the causes of insulin resistance including hyperadrenocorticism, hyperthyroidism, uremia, obesity, infection anti-insulin antibodies, inactive or outdated insulin, glucagonoma, administration of diabetogenic medications (megestrol acetate), problems with insulin administration, and pheochromocytoma. In addition, other causes of hy-
Clinical Pathology Mild erythrocytosis, observed in nonazotemic cats with acromegaly, is probably the result of the anabolic effects of GH on bone marrow. Mild to severe hyperproteinemia (⬎ 8.0 g/dL) also may be observed; however, serum protein electrophoresis is usually normal. Impaired glucose tolerance and insulin resistance resulting in diabetes mellitus are seen in all cats with acromegaly. Measurement of endogenous insulin reveals dramatically increased serum insulin concentrations. Despite severe insulin resistance and hyperglycemia, ketosis is rare. Feline acromegaly should be suspected in any diabetic cat that has insulin resistance (⬎ 2 U/kg/d). Increased serum fructosamine in the face of adequate or excessive insulin therapy (⬎ 1 U/kg) is a sign of acromegaly. Hypercholesterolemia and mild increases in liver enzymes are attributed to the diabetic state. Hyperphosphatemia without azotemia is also a common clinicopathologic finding. Azotemia and chronic renal failure develop late in the course of the disease in approximately 50% of acromegalic cats.5 Renomegaly is observed in both cats and human beings with GH excess; however,
Fig. 4. Radiographs of the carpal joints of an acromegalic cat showing degenerative arthropathy.
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Fig. 5. Skull radiographs of an acromegalic cat at a young age and after the development of acromegaly. Note the enlargement of the skull and jaw bones.
pertrophic cardiomyopathy such as hypertension, hyperthyroidism, and idiopathic hypertrophic cardiomyopathy should be considered in cats with cardiovascular manifestations of the disease. Finally if central nervous system signs are also apparent or are primary manifestations, non-GH–secreting pituitary tumors or focal/multifocal lesions toxoplasmosis, neoplasia, feline infectious peritonitis may be included in the differential list. Establishing a Diagnosis Given the large percentage (30%) of cats identified with acromegaly in one series of cats with poorly regulated diabetes mellitus, acromegaly should be on the differential list for causes of secondary or insulin-resistant diabetes.7 In some studies, 70% of diabetes cats will go into remission (no longer needing insulin) when fed an ultra low carbohydrate diet.16,17 Other causes of insulin resistance such as urinary tract infections, insulin administration problems, dietary noncompliance, concurrent hyperthyroidism, etc., should be ruled out by routine laboratory assessment. In both human beings and cats, acromegaly is an underdiagnosed entity18; therefore, any cat that fails to go into remission after appropriate carbohydrate restriction and insulin therapy should be screened for acromegaly with a GH and/or an IGF-1 assay.8,19
assays are impractical because of sample handling requirements (plasma, ice), wide interassay and intra-assay variation, and lack of sensitivity or specificity.23 In human beings, a serum GH concentration of ⬎ 10 ng/mL is highly suggestive of acromegaly; however, submission of a single GH sample has proven unreliable in documenting the disease on a regular basis.7 Recently, a validated feline GH radioimmunoassay has been developed and has proved useful in distinguishing normal from acromegalic cats24; furthermore, unlike the case for IGF-1, there is no overlap between the 2 groups studied. However, a separate study that used 10 ng/mL as a cutoff showed that 2 out of 34 non-acromegalic cats were classified as having acromegaly. Nevertheless, the sensitivity and specificity of the feline-specific GH assay were 84% and 95%, respectively.24 Insulin resistance may be caused by a variety of factors including management-associated errors (incorrect insulin, injection problems, etc.), infections (urinary, dental), inflammatory conditions (pancreatitis, inflammatory bowel disease), neoplasia, obesity, and endocrinopathies (hyperthyroidism, hypersomatotropism, progesterone excess, and hyperadrenocorticism). Therefore, a diagnosis of acromegaly may require additional tests such as urine culture, imaging, TT4 or FT4 concentrations, or dexamethasone suppression testing to rule out other causes of insulin resistance.
IGF
Imaging of the Pituitary
Serum IGF-1 concentrations are often dramatically increased in acromegalic cats and human beings.7,20,21 Documentation of elevated IGF-1 concentrations does not provide a definitive diagnosis, however, because increased IGF-1 has been reported in apparently nonacromegalic diabetic cats.22 Furthermore, untreated diabetic cats with acromegaly may have suppressed IGF-1 concentrations because of impaired portal insulin secretion as insulin is required for GH-dependent hepatic synthesis and secretion of IGF-1.20 Treatment of the diabetes with exogenous insulin therapy for several weeks may allow normal expression of IGF-1 from the liver.20 IGF-1 or somatomedin C is particularly cost-effective as a screening tool because it is readily available from most commercial laboratories, is inexpensive, and requires no special handling.
Computed tomography or magnetic resonance imaging reveals the presence of a large pituitary mass in most cats with acromegaly.25 However, with recent advances in the diagnosis of the disease and earlier detection, about 10% of cases of acromegaly will show no signs of pituitary tumors.8 Results of computed tomography, coupled with the exclusion of other disorders that cause insulin resistance (hyperthyroidism, hyperadrenocorticism) and clinical signs and laboratory abnormalities, support a diagnosis of acromegaly.
Growth Hormone Assays Species-specific growth hormone assays (feline, canine) are not commercially available in the United States and often even human GH
Treatment Medical therapy in people includes the use of dopamine agonists, such as bromocriptine, and somatostatin analogues (octreotide). Treatment with octreotide has been mildly to moderately unsuccessful in acromegalic cats.5,26 The lack of efficacy of the long-acting somatostatin analogues may result from species-specific tissue binding. Long-acting somatostatin analogues that require only a monthly injection have greatly improved patient compliance in human medi-
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cine, with about 50% responding to monotherapy. A GH receptor antagonist, pegvisomant, may be helpful in treating human patients who do not respond to somatostatin; however, this drug has not been evaluated in cats with acromegaly. Radiation therapy probably offers the greatest chance for success with low rates of morbidity and mortality.27,28 The disadvantages include the slow rate of tumor shrinkage (⬎ 3 years), the occurrence of hypopituitarism, cranial and optic nerve damage, and radiation injury to the hypothalamus. In some cases, resolution of clinical signs was achieved with radiation therapy, particularly with linear acceleratorbased modified radiosurgery.29,30 Surgical treatment of acromegaly is used routinely in human beings with acromegaly; in fact, endonasal endoscopic transsphenoidal pituitary surgery can be performed with excellent results.31 In the cat, transsphenoidal hypophysectomy is only available in selected locations in Europe and the United States. In a series of 7 cats, removal of the pituitary tumor was successful; however, 2 of the 7 cats died within 4 weeks of surgery from unrelated causes.32,33 Cryohypophysectomy has been described as a treatment for feline acromegaly; however, it may be too early to determine the efficacy of this therapy.34 Nevertheless, hypophysectomy is the gold standard for therapy in humans because it provides rapid and complete reductions in serum GH and IGF-1 concentrations that lead to resolution of insulin resistance. As with all therapies, there are risks involved including regrowth of the tumor in about 30% to 40% of cases.35 Prognosis The short-term prognosis in cats with untreated acromegaly is fair to good. Insulin resistance is generally controlled satisfactorily by judicious insulin and dietary therapy. All cats with acromegaly should be fed a balanced diet that is low in carbohydrates and high in protein. Insulin therapy using glargine or protamine zinc insulin augmented with shorter-acting insulin at meal times is the most effective way to address insulin resistance. The long-term prognosis is relatively poor, however, with most cats dying of CHF, chronic renal failure, or signs of an expanding pituitary mass. The long-term prognosis may improve with early diagnosis and appropriate treatment (surgery, radiation therapy). References 1. Charlier P, Tsigonaki C: A case of acromegaly (Greece, 7th century AD). Eur J Endocrinol 165:819 – 821, 2011. 2. Mammis A, Eloy JA, Liu JK: Early descriptions of acromegaly and gigantism and their historical evolution as clinical entities. Neurosurg Focus 29:E1, 2010. 3. Lichtensteiger CA, Wortman JA, Eigenmann JE: Functional pituitary acidophil adenoma in a cat with diabetes mellitus and acromegalic features. Vet Pathol 23:518 – 521, 1986. 4. Morrison SA, Randolph J, Lothrop CD: Hypersomatotropism and insulin-resistant diabetes mellitus in a cat. J Am Vet Med Assoc 194:91–94, 1989. 5. Peterson ME, Taylor RS, Greco DS, et al: Acromegaly in 14 cats. J Vet Intern Med 4:192–201, 1990. 6. Norman EJ, Mooney CT: Diagnosis and management of diabetes mellitus in five cats with somatotrophic abnormalities. J Feline Med Surg 2:183–190, 2000. 7. Niessen SJ, Petrie G, Gaudiano F, et al: Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med 21:899 –905, 2007. 8. Niessen SJ: Feline acromegaly: an essential differential diagnosis for the difficult diabetic. J Feline Med Surg 12:15–23, 2010.
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9. Gunn-Moore D: Feline endocrinopathies. Vet Clin North Am Small Anim Pract 35: 171–210, 2005, vii. 10. Bruyette DS: Feline endocrinology update. Vet Clin North Am Small Anim Pract 31: 1063–1081, 2001, ix. 11. Rijnberk A, Mol JA: Progestin-induced hypersecretion of growth hormone: an introductory review. J Reprod Fertil Suppl 51:335–338, 1997. 12. Mol JA, Lantinga-van Leeuwen I, van Garderen E, Rijnberk A: Progestin-induced mammary growth hormone (GH) production. Adv Exp Med Biol 480:71–76, 2000. 13. Merchant SR, Taboada J: Systemic diseases with cutaneous manifestations. Vet Clin North Am Small Anim Pract 25:945–959, 1995. 14. Siegel ET: Effect of hormones on bone. Cornell Vet 58(suppl):95–103, 1968. 15. Al-Ghazlat SA, Langston CE, Greco DS, Reine NJ, May SN, Shofer FS: The prevalence of microalbuminuria and proteinuria in cats with diabetes mellitus. Top Companion Anim Med 26:154 –157, 2011. 16. Mazzaferro EM, Greco DS, Turner AS, Fettman MJ: Treatment of feline diabetes mellitus using an alpha-glucosidase inhibitor and a low-carbohydrate diet. J Feline Med Surg 5:183–189, 2003. 17. Bennett N, Greco DS, Peterson ME, Kirk C, Mathes M, Fettman MJ: Comparison of a low carbohydrate-low fiber diet and a moderate carbohydrate-high fiber diet in the management of feline diabetes mellitus. J Feline Med Surg 8:73– 84, 2006. 18. Rosario PW: Frequency of acromegaly in adults with diabetes or glucose intolerance and estimated prevalence in the general population. Pituitary 14:217–221, 2011. 19. Peterson ME: Acromegaly in cats: are we only diagnosing the tip of the iceberg? J Vet Intern Med 21:889 – 891, 2007. 20. Berg RI, Nelson RW, Feldman EC, Kass PH, Pollard R, Refsal KR: Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly. J Vet Intern Med 21:892– 898, 2007. 21. Frystyk J, Freda P, Clemmons DR: The current status of IGF-I assays—a 2009 update. Growth Horm IGF Res 20:8 –18, 2010. 22. Reusch CE, Kley S, Casella M, Nelson RW, Mol J, Zapf J: Measurements of growth hormone and insulin-like growth factor 1 in cats with diabetes mellitus. Vet Rec 158:195–200, 2006. 23. Bidlingmaier M, Freda PU: Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res 20:19 –25, 2010. 24. Niessen SJ, Khalid M, Petrie G, Church DB: Validation and application of a radioimmunoassay for ovine growth hormone in the diagnosis of acromegaly in cats. Vet Rec 160:902–907, 2007. 25. Posch B, Dobson J, Herrtage M: Magnetic resonance imaging findings in 15 acromegalic cats. Vet Radiol Ultrasound 52:422– 427, 2011. 26. Slingerland LI, Voorhout G, Rijnberk A, Kooistra HS: Growth hormone excess and the effect of octreotide in cats with diabetes mellitus. Domest Anim Endocrinol 35:352–361, 2008. 27. Littler RM, Polton GA, Brearley MJ: Resolution of diabetes mellitus but not acromegaly in a cat with a pituitary macroadenoma treated with hypofractionated radiation. J Small Anim Pract 47:392–395, 2006. 28. Brearley MJ, Polton GA, Littler RM, Niessen SJ: Coarse fractionated radiation therapy for pituitary tumours in cats: a retrospective study of 12 cases. Vet Comp Oncol 4:209 –217, 2006. 29. Sellon RK, Fidel J, Houston R, Gavin PR: Linear-accelerator-based modified radiosurgical treatment of pituitary tumors in cats: 11 cases (1997-2008). J Vet Intern Med 23:1038 –1044, 2009. 30. Mayer MN, Greco DS, LaRue SM: Outcomes of pituitary tumor irradiation in cats. J Vet Intern Med 20:1151–1154, 2006. 31. Sand MS, Gendeh BS, Husain S: Endonasal endoscopic transsphenoidal pituitary surgery for pituitary adenoma: a retrospective analysis of surgical outcome. Med J Malaysia 66:443– 446, 2011. 32. Meij BP, Voorhout G, Van Den Ingh TS, Rijnberk A: Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats. Vet Surg 30:72– 86, 2001. 33. Meij BP, Auriemma E, Grinwis G, Buijtels JJ, Kooistra HS: Successful treatment of acromegaly in a diabetic cat with transsphenoidal hypophysectomy. J Feline Med Surg 12:406 – 410, 2010. 34. Blois SL, Holmberg DL: Cryohypophysectomy used in the treatment of a case of feline acromegaly. J Small Anim Pract 49:596 – 600, 2008. 35. Wagenmakers MA, Netea-Maier RT, van Lindert EJ, Pieters GF, Grotenhuis AJ, Hermus AR: Results of endoscopic transsphenoidal pituitary surgery in 40 patients with a growth hormone-secreting macroadenoma. Acta Neurochir (Wien) 153: 1391–1399, 2011.