Acromegaly

From Cat
Acro04.jpg
Acromegaly in a DSH cat. Courtesy Prof Richard Malik
Acromegaly in above cat, different angle. Courtesy Prof Richard Malik
Acromegaly, showing changes to facial bones. Courtesy Prof Richard Malik

Acromegaly, or hypersomatotropism, results from chronic, excessive secretion of growth hormone in the adult cat.

Once thought to be a rare and anomalous tumour in cats, pituitary adenomas and secondary acromegaly are more frequently diagnosed, using MRI and other ancillary diagnostic tools[1].

Cause

Acromegaly in cats is caused by a growth hormone-secreting tumour (often a somatotrophic adenoma or somatotrophic hyperplasia) in the pars distalis of the anterior pituitary in the brain. In cats, these tumours are slow growing and may be present for a long time before clinical signs appear[2]. Double pituitary adenomas have also been reported as causing both hyperadrenocorticism and acromegaly in cats (Niessen et al, 2007).

It is not inconceivable that the underlying triggers for development of pituitary adenomas may be similar to the goitrogenic compounds which cause thyroid adenomas[3]. Feline acromegaly is characterised by a functional somatotropic adenoma in the pars distalis of the anterior pituitary gland, resulting in excessive growth hormone (GH) secretion[4]. At the cellular level, excess GH causes over-expression of the cell cycle gene cyclin B2 (ccnb2)[5]. Systemically, this upregulation of cellular cyclin B2 thence leads to elevated insulin production, increased insensitivity of insulin receptors and impairment of insulin's kinase activity[6].

In a recent survey in the U.K., 59 out of 184 cats with diabetes mellitus had insulin-like growth factor (IGF-1) values strongly suggestive of acromegaly (Niessen et al, 2007), warning that many diabetic cases may be attributed to pituitary adenomas rather than pancreatic amyloid plaque deposition or insulin-resistance due to systemic cellular insulin-receptor deformation.

The expression of GH mRNA in mammary gland tissue can be found in cats, indicating the secretion of GH from mammary gland tissue also could occur in teh cat. Indeed, progestin-induced fibroadenomatous changes in mammary glands of cats also are associated with locally enhanced GH expression. The mammary gene is identical to the pituitary-expressed gene and uses the same promoter for transcription. Nevertheless, feline cases of progestin-induced GH secretion from the mammary glands causing teh clinical syndrome of acromegaly have yet to be described[7][8].

Regardless of underlying triggers, the pituitary adenomas seem to consistently hypersecrete GH, prolactin and/or thyroid stimulating hormone (TSH), in pulses of increased amplitude, frequency and duration[9]. This plurihormonality seems to be a feature in at least some feline cases[10].

Clinical signs

Insulin-like growth factor 1 has extensive anabolic potential, and can be ascribed as the primary instigator of clinical signs.

Feline acromegaly is a disease that appears to occur in middle-aged to older Domestic shorthair cats (8-14 yr) and appears to be more common in males[11]. Clinical signs of uncontrolled diabetes mellitus are often the first symptoms in cats; therefore, polydipsia, polyuria, and polyphagia are the most common presenting signs. Hypertension is as irregular finding[12]. Abdominal organomegaly, respiratory stridor, broad facial features, net weight gain of lean body mass in cats with uncontrolled diabetes mellitus is a key sign of acromegaly (most diabetic cats usually lose weight). Organomegaly including renomegaly, hepatomegaly, and enlargement of endocrine organs is also seen[13].

Some cats show the classic enlargement of extremities, body size, jaw, tongue, and forehead that is characteristic of acromegaly in people. Some of the most striking manifestations 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. Cardiovascular abnormalities such as cardiomegaly (radiographic and echocardiographic), systolic murmurs, and congestive heart failure develop late in the disease course. Atrial enlargement may occur, as well as generalised or focal interventricular septal thickening and/or left ventricular free wall hypertrophy with thinning toward the apex. Diastolic dysfunction, systolic anterior motion of the mitral valve, mitral valve insufficiency and increased left ventricular outflow velocity, poor let atrial wall motion, spontaneous echo contrast, and a restrictive pattern of pulmonary venous flow have all been described (Niessen et al, 2007).

Azotemia also develops late in the course of the disease in ~50% of acromegalic cats, due to diffuse thickening of the glomerular basement membrane, thickening of the Bowman's capsule, periglomerular fibrosis and hydropic change with epithelial degeneration and regeneration of tubules (Niessen et al, 2007).

Neurological signs of acromegaly in humans, such as peripheral neuropathies (paresthesias, carpal tunnel syndrome, sensory and motor defects) and parasellar manifestations (headache and visual field defects), are not generally detected in acromegalic cats.

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 hyperglycaemia, ketosis is rare. Feline acromegaly should be suspected in any diabetic cat that has severe insulin resistance (insulin requirement >20 U/cat/day). Hypercholesterolemia and mild increases in liver enzymes are attributed to the diabetic state. Hyperphosphatemia without azotemia is also a common clinicopathologic finding. Urinalysis is unremarkable except for persistent proteinuria.

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, 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.

Diagnosis

Feline acromegaly develops over months, sometimes years. Although non-diabetic acromegalic cats have been reported, uncontrolled-diabetes mellitus with hyperglycemia is a consistent sign (Feldman & Nelson, 2004). The levels of blood glucose are not consistently different between acromegalic diabetic cats and non-acromegalic diabetic cats, although some acromegalic cats have been reported as requiring up to 150 IU insulin daily for glycemic control (Niessen & Church, 2010).

Diagnosis is based on suspicious clinical signs of polyuria, polydipsia, polyphagia, weight gain, upper respiratory stridor, broad facial features, prognathia, organomegaly, clubbed paws and neurological signs, in conjunction with hyperglycemia, hyperproteinemia, and elevated fructosamine, growth hormone (usually >10 ng/mL in acromegalic cats) and insulin-like growth factor (IGF-1) concentration.

Intracranial imaging is indicated in most cases and therefore limits definitive diagnosis to exclusively referral clinics. Contrast-enhanced CT and MRI have proven useful but false negatives have been documented and differentiation of differing types of pituitary abnormalities is not possible without surgical or post-mortem examination[14].

Treatment

Medical therapy in people includes the use of dopamine agonists, such as the dopamine agonist bromocriptine, and the somatostatin analogue octreotide. Treatment with octreotide has been unsuccessful in acromegalic cats. The lack of efficacy of the long-acting somatostatin analogs may result from species-specific tissue binding[15].

Radiation therapy probably offers the greatest chance for success with low rates of morbidity and mortality. Recommended protocols include a total radiation dosage ranging from 45-54 Gray (Gy) administered in 5 daily doses of 2.7 or 3.0 Gy fractions per week for 4 weeks[16]. The disadvantages include the slow rate of tumour shrinkage (>3 yr) and the occurrence of hypopituitarism, cranial and optic nerve damage, and radiation injury to the hypothalamus. Resolution or improvement of diabetes mellitus and neurological signs has been seen in cats undergoing a variety of radiotherapy protocols with survival rates of 1-2 years post-radiation reported[17].

Transsphenoidal hypophysectomy has been reported in one cat with acromegaly and diabetes mellitus[18] and in seven cats with Cushing's syndrome[19][20]. With the cat that had concurrent diabetes, insulin requirement was reduced by 95% in the first week after hypophysectomy. Surgical expertise is required, but this procedure offers the only antemortem method of definitive diagnosis of this disease.

Cryotherapy has been used experimentally on a number of cats with moderate success. More cases need to be assessed in order to provide reliable recommendations for this procedure[21].

The short-term prognosis in cats with untreated acromegaly is fair to good. Insulin resistance is generally controlled satisfactorily by using large doses of insulin divided into several daily doses, e.g. with use of glargine. Mild cardiac disease can be managed with diuretics and angiotensin-converting enzyme (ACE) inhibitors (e.g. benazepril (fortekor)).

The long-term prognosis is relatively poor, however, and most cats die of congestive heart failure, chronic renal failure, or signs of an expanding pituitary mass. The long-term prognosis may improve with early diagnosis and treatment.

References

  1. Niessen, S (2010) Feline acromegaly: An essential differential diagnosis for the difficult diabetic. JFMS 12:15-23
  2. Niessen, SJM & Church, DB (2010) In August, JR (Ed): Consultations in feline internal medicine. Vol 6. Elsevier Saunders, Philadelphia. pp:304
  3. Euclid, J (2010) Pers comm
  4. Niessen, SJ et al (2007) Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Int Med 21:899-905
  5. De Martino, I et al (2009) Fusco A proteins upregulate CCNB2 gene in mouse and human pituitary adenomas. Cancer Res 69:1844-1850
  6. Dominici, FP et al (2005) Influence of the crosstalk between growth hormone and insulin signalling on the modulation of insulin sensitivity. Growth Horm IGF Res 15:324-336
  7. Mol, JA et al (1995) Growth hormone mRNA in mammary gland tumours in dogs and cats. J Clin Invest 95:2028
  8. Mol JA et al (2000) Progestin-induced mammary growth hormone (GH) production. Adv Exp Med Biol 480:71
  9. Barkan, AL et al (1989) Increased growth hormone pulse frequency in acromegaly. J Clin Endocrinol Metab 69:1225-1233
  10. Meij, BP et al' (2004) Somatotroph and corticotroph pituitary adenoma (double adenoma) in a cat with diabetes mellitus and hyperadrenocorticism. J Comp Pathol 130:209-215
  11. Gunn-Moore, D (2005) Feline endocrinopathies. Vet Clin North Am Small Anim Pract 35:171
  12. Feldman, EC & Nelson, RW (2004) Disorders of growth hormone. In Feldman,, EC & Belson RW (Eds). Canine and feline endocrinology and reproduction. 3rd edn. WB Saunders, Missouri. pp:69
  13. Hurty, CA & Flatland, B (2005) Feline acromegaly: a review of the syndrome. J Am Anim Hosp Assoc 41:292-297
  14. Peterson, ME et al (1990) Acromegaly in 14 cats. J Vet Intern Med 4:192-201
  15. Feldman, EC & Nelson, RW (2004) Disorders of growth growth hormone. In Feldman, EC & Nelson, RW (Eds): Canine and feline endocrinology and reproduction. 3rd Edn. Saunders, St Louis. pp:69
  16. Mayer, MN et al (2006) Outcomes of pituitary tumour irradiation in cats. J Vet Intern Med 20:1151
  17. Brearley, MJ et al (2006) Coarse fractionated radiation therapy for pituitary tumours in cats: a retrospective study of 12 cases. Vet Comp Oncol 4:209-217
  18. Meij, M et al (2010) Successful treatment of acromegaly in a diabetic cat with transsphenoidal hypophysectomy. JFMS 12:406-410
  19. Meij, BP et al (2004) Somatotroph and corticotroph pituitary adenoma (double adenoma) in a cat with diabetes mellitus and hyperadrenocorticism. J Comp Pathol 130:209
  20. Meij, BP et al (2001) Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats. Vet Surg 30:72
  21. Blois, SL & Holmberg, DL (2008) Cryohypophysectomy used n the treatment of a case of feline acromegaly. J Small Anim Pract 49:596