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Atypical canine and feline endocrinopathies

 

 

IntroductionKey Points

Certain endocrinopathies in the dog and cat are seldom diagnosed. This may be because they are rare, but it may also be due to under-diagnosis; knowledge regarding a disease clearly has an affect on its frequency of diagnosis. This article reviews some of the more unusual hormone disorders. It is not intended to be an exhaustive assessment, but rather a synopsis of some of the so-called “emerging” endocrinopathies, focusing on feline hyperaldosteronism, feline acromegaly, central diabetes insipidus, hypophyseal dwarfism, and primary hypoparathyroidism. The etiology, clinical presentation, diagnosis, and treatment of each disease will be discussed.




Feline primary hyperaldosteronism

Primary hyperaldosteronism is an emerging feline endocrinopathy. Initially described in clinical case reports, it has recently been the subject of retrospective case studies (1-2). Most cases are due to a unilateral adrenal tumor (adenoma/adenocarcinoma), but cases of bilateral tumors, mixed adrenocortical tumors (secreting aldosterone and progesterone) and bilateral hyperplasia have also been reported (1). The symptoms in cats presenting with primary hyperaldosteronism may be frustrating. The most common presenting signs are weakness, ventroflexion of the head and neck (Figure 1), PU/PD and cardiac or ocular disturbances associated with arterial hypertension (1-2). Two paraclinical signs that may suggest hyperaldosteronism are arterial hypertension in conjunction with hypokalemia associated with normal or high serum sodium concentration. It is also common for renal failure to be diagnosed at the same time (2).

 

The definitive diagnosis of primary Figure 1hyperaldosteronism is achieved by comparing circulating aldosterone levels with basal plasma renin activity, sampled during a hypokalemic episode. The objective is to demonstrate independent secretion of aldosterone by the glomerular zone of the adrenal cortex. Severely reduced plasma renin activity, in conjunction with normal or high serum aldosterone levels, confirms the presence of primary hyperaldosteronism (1). In secondary hyperaldosteronism (e.g. low sodium diet, heart failure, renal failure), the serum aldosterone increase mirrors that of renin activity. Unfortunately, measurement of rennin activity is not widely available, thus hindering diagnosis of the subtle forms of the disease.

 

The origin of the primary hyperaldosteronism can be determined by imaging of the adrenal glands. If a tumor is detected, the search should be widened to check for metastases. Symmetrical adrenal glands with a normal shape tend to indicate bilateral hyperplasia. Adrenalectomy is probably the treatment of choice in most cases of primary hyperaldosteronism (assuming no metastasis is detected). Recorded survival times after surgical resection are, with the exception of perioperative complications, usually good (3,4). If the owners do not consent to surgery, palliative treatment can be considered, with two main objectives: the correction of hypokalemia and the control of arterial hypertension. Correction of hypokalemia involves potassium supplementation (potassium gluconate: 2-6 mmoL/cat bid PO), combined with spironolactone if treatment is prolonged (2.5 to 5 mg/cat sid or bid PO) as it antagonizes aldosterone. Any anti-hypertensive agents (e.g. amlodipine 0.125 to 0.250 mg/kg sid PO) can be considered in cases with marked hypertension.




Feline acromegaly

Feline acromegaly has long been considered to be extremely rare (5) but recent publications have challenged this perception, claiming that the disease incidence is significant amongst diabetic cats (5,6). It is caused by a (usually large) hypophyseal tumor that spontaneously secretes growth hormone (GH) (5,6). At present there is only one published example of an analogous case in the dog. Canine acromegaly is usually of mammary origin, under progesterone regulation (8). There is no apparent breed predisposition but affected animals are usually older male cats (average age ~ 10 years). Typically, acromegaly is associated with major insulin resistance and morphological alterations, such as unexplained weight gain, cardiovascular signs (due to hypertrophic cardiomyopathy), abdominal organomegaly (hepatomegaly, nephromegaly, splenomegaly, etc.), laryngeal stridor secondary to pharyngeallaryngeal extension, inferior prognathism or interdental widening (Figure 2), accelerated growth of claws, spondylosis, arthropathies (5), etc. Finally, neurological or behavioral disturbances may be present due to a hypophyseal macro-adenoma. However, limiting the suspicion of acromegaly to these specific clinical contexts - which are probably late onset - results in underdiagnosis of the disease. Relatively asymptomatic forms, where clinical expression is limited to diabetes mellitus, should also be considered.

 

Figure 2The measurement of insulin growth factor-1 (IGF- 1) has a central role in the diagnosis of acromegaly. More stable than GH and requiring less strict preanalytical conditions, this test is offered by many laboratories and is considered to be a good reflection of hypophyseal GH secretion over a period of at least 24h. IGF-1 assay is sensitive and acromegaly in a diabetic cat can, within reason, be excluded if the serum IGF-1 is within normal limits. However, the specificity of this assay remains debatable (6,7,9) and diagnosis should be confirmed with other tests, usually brain imaging (CT or MRI). Two treatment approaches can be considered: etiological treatment or palliative control of insulin resistance. The first option comprises radiotherapy or surgery. To date, radiotherapy has undoubtedly proven to be the most effective (10), often enabling a reduction in insulin requirements and restricting tumor growth. Hypophysectomy (via conventional or cryosurgery) is an alternative to radiotherapy (11). Its outcome is highly dependent on the surgeon’s skills. If the owner refuses etiological treatment, the insulin resistance of acromegalic cats with diabetes mellitus can be controlled with twice daily administration of high doses of insulin (6).




Central diabetes insipidus

Central diabetes insipidus (CDI) is caused by a lack of secretion of anti-diuretic hormone (ADH or vasopressin). CDI is most often diagnosed in dogs but a few cases have also been recorded in cats (12). Complete or partial forms are described, depending on whether ADH secretion is absent or present but inappropriate (and thus insufficient). The most common cause of CDI is neoplasia of the hypothalamo-hypophyseal region (13). Other causes include inflammatory, infectious, or traumatic lesions. Iatrogenic cases following hypophysectomy to treat Cushing’s disease have been noted and idiopathic cases have also been described.

 

The principal sign associated with CDI is the presence of PD/PU. Neurological signs may also be present. The PD/PUis associated with hyposthenuric urine (<1.010) and low urinary osmolality (Uosm <290 mOsm/kg). Biochemistry may reveal (usually mild) hypernatremia. However, in the event of water deprivation – or adipsia due to damage to the thirst center – major hypernatremia may be present, resulting in hyperosmolar encephalopathy. The preferred test for confirming CDI is the water deprivation test. In preparation for the test, performed under medical monitoring in a hospital setting, water intake should be reduced progressively over a period of several days (3-7 days for a 50% reduction) to restore the renal corticomedullary gradient. After 12h of fasting, access to water is denied and plasma and urine samples are collected every hour to measure osmolality, volume, and urine density. The animal should also be weighed every hour. The test should be iscontinued if the animal loses more than 3-5% of its bodyweight, if uremia or natremia increase, if neurological signs appear, or if urine specific gravity is >1.030. If urine osmolality (or urine density) remains low despite appropriate osmotic stimulation (signs of dehydration or plasma osmolality >305 mOsm/kg), the result is compatible with diabetes insipidus and ADH should be administrated to differentiate between central and nephrogenic forms. In complete central diabetes insipidus, urine density or osmolality will double after the administration of ADH, whilst only a moderate increase (~ 15%) is seen with the partial form. In nephrogenic diabetes insipidus, the increase will be minimal or even absent. There is, however, one diagnostic pitfall; if the water restriction imposed in the run-up to the test is insufficient to restore the cortico-medullary gradient, thus enabling a response to ADH, the urinary SG may fail to increase irrespective of the cause of the PD/PU. Such an absence may lead to the erroneous diagnosis of nephrogenic diabetes insipidus.

 

A more direct way of diagnosing CDI is to stimulate ADH secretion via perfusion of a hypertonic saline solution. A solution of 20% NaCl is administered at 0.03 mL/kg/min over 2h and ADH and plasma osmolality are measured every 20 min. This test may enable a more precise diagnosis of certain cases of partial CDI but presents more serious risks. Treatment is based on the administration of a vasopressin analogue (desmopressin) into the eyes (1 drop into the conjunctival sac tid) or per os (0.1 to 0.2 mg per animal sid-tid). In the absence of a hypophyseal lesion, the prognosis is favorable, with complete clinical remission if the treatment is correctly administered.




Hypophyseal dwarfism

Any defective organogenesis of the hypophysis can lead to a defect in the secretion of one or more hypophyseal hormones. Dwarfism has been described in the dog, with certain breed predispositions, and occasionally in the cat. Autosomal recessive transmission associated with panhypopituitarism, but sparing corticotropic function, has been demonstrated in German shepherd dogs (14).

 

Affected animals usually present at 2-5 months of age for proportionate delayed growth (Figure 3), mental retardation, persistent puppy coat, alopecia of the trunk, cutaneous hyperpigmentation, flaking, etc. Disproportionate dwarfism (head and torso normal but short limbs) is more suggestive of hypothyroidism. Cryptorchidism is often present in the male, whilst females present with persistent anestrus. In general, the animals remain well until 2-3 years of age, when systemic signs may start to appear, sometimes related to renal failure. The diagnosis can be supported by low IGF-1 or GH levels, but the definitive diagnosis requires a stimulation test. GHRH (Growth hormone releasing hormone 1 μg/kg) or alpha-agonists (clonidine 10 μg/kg or xylazine 100 μg/kg) can be used to stimulate GH secretion. Measurements of GH immediately before, 20, and 30 minutes after the intravenous injection are required. If GH levels fail to increase this confirms the diagnosis. The other hypophyseal functions (thyrotropin, gonadotropin, corticotropin, and prolactin) may be assessed using a combined pituitary stimulation test (15). Medical imaging of the hypophysis often reveals the presence of cysts in Rathke’s pouch.

 

Canine GH is not available for the treatment of dwarfism, but porcine GH has been used (0.1-0.3 IU/kg SC 3 times per week with monitoring of blood glucose and GH). The use of recombinant human GH has not yet been reported. The benefits of the treatment on growth depend on the stage of the growth cartilages at the start of treatment. However, cutaneous signs improve after 6-8 weeks. A therapeutic alternative is the use of progestogens to stimulate the secretion of growth hormone from mammary tissue (16,17). Medroxyprogesterone acetate (2.5-5 mg/kg every 3 weeks, then every 6 weeks SC) as well as proligestone (10 mg/kg subcutaneously every 3 weeks) have been shown to induce clinical improvement. In females, ovariohysterectomy should be recommended before starting treatment to limit the risk of pyometra. Finally, appropriate substitution with levothyroxine should be prescribed in parallel in cases with concurrent hypothyroidism. Appropriate treatment improves the quality of life of affected animals, provided that treatment is instigated early.


Figure 3 and 4


Primary hypoparathyroidism

Primary hypoparathyroidism is caused by the destruction (or atrophy) of the parathyroid glands. The spontaneous form is more common in dogs than in cats; the etiology is probably immunemediated in most cases (18). Rarely, it can be secondary to the destruction of the parathyroid glands by a tumor of the cervical region. Iatrogenic hypoparathyroidism can be caused by surgical damage to the parathyroids (e.g. during thyroidectomy). Deficient parathyroid hormone (PTH) causes hypocalcemia and moderate hyperphosphatemia. Affected dogs are usually 6 months - 13 years of age; the most commonly affected breeds are poodles, golden retrievers, schnauzers, German shepherds, and terriers (18).

 

Neurological symptoms, including tetany, seizures, fasciculation, and tremors, are predominant. Weakness and ataxia have been described less commonly. Earlier signs of hypocalcemia are sometimes noted, such as anxiety and occasionally aggression, probably due to muscle pain. Intense rubbing of the face against the ground or with the paws has also been described; this is thought to be due to contraction of the masseter and temporal muscles. In a few cases, a cataract typical of chronic hypocalcemia may be observed: immature, cortical, diffuse, and punctate, it is characteristic of hypoparathyroidism if associated with hypocalcemia (Figure 4) (18,19).

 

 

Concurrent assay of phosphorous levels can provide additional diagnostic proof. Indeed, the combination of hypocalcemia and hyperphosphatemia, other than in cases of renal failure, is highly suggestive of hypoparathyroidism. To confirm the diagnosis, demonstration of a low or undetectable plasma PTH concentration in an animal with hypocalcemia is sufficient (18,20). In all other causes of hypocalcemia, the calcium regulatory feedback loop is preserved and the plasma concentration of PTH increases.

 

Immediate and urgent treatment with intravenous calcium is required if the patient is presented in tetany or with seizures (18,20). Once the attack has been resolved, treatment should be continued with oral calcium and vitamin D. Initially, both must be given, as intestinal absorption of calcium is dependent on vitamin D and is therefore not very effective at the start of treatment. Calcium administered in large quantities will enable passive absorption, and can then be progressively reduced before being stopped altogether. Long-term treatment involves the administration of vitamin D. Several different preparations are available; a hydroxylated 1αform of vitamin D should be used, since hydroxylation requires PTH. The best forms are calcitriol and alfacalcidol; both are rapidly eliminated and their dose rate can therefore be quickly altered. The objective is not to maintain normal blo

 

od calcium concentration, as this is more likely to induce erratic calcium precipitates where there is concurrent hyperphosphatemia; a mild hypocalcemia is preferable. Regular monitoring is essential during the course of treatment to guard against hypercalcemia or hyperphosphatemia. At the time of writing, there is no published data concerning the use of human recombinant PTH in the dog. The prognosis is favorable if treatment is well balanced. There is currently no treatment that enables complete compensation of the actions of PTH, so treatment with vitamin D cannot substitute for the protective renal effects of PTH against hypercalciuria or its effects on bone.




Conclusion

Certain endocrinopathies may be rare, but this does not mean they do not occur. An awareness of the typical presenting signs and a systematic approach will ensure that the veterinarian does not miss these interesting and challenging cases. 

 

 

This article was kindly provided by Royal Canin, makers of a range of veterinary diets for dogs and cats. For the full range please visit www.RoyalCanin.co.uk or speak to your Veterinary Business Manager:

 

 

 

 

REFERENCES

1. Ash RA, Harvey AM, Tasker S. Primary hyperaldosteronism in the cat: a series of 13 cases. J Feline Med Surg 2005; 7(3): 173-182.

2. Javadi S, Djajadiningrat-Laanen SC, Kooistra HS, et al. Primary hyperaldosteronism, a mediator of progressive renal disease in cats. Domest Anim Endocrinol 2005; 28(1): 85-104.

3. MacKay AD, Holt PE, Sparkes AH. Successful surgical treatment of a cat with primary aldosteronism. J Feline Med Surg 1999; 1(2): 117-122.

4. Rose SA, Kyles AE, Labelle P, et al. Adrenalectomy and caval thrombectomy in a cat with primary hyperaldosteronism. J Am Anim Hosp Assoc 2007; 43(4): 209-214.

5. Elliott DA, Feldman EC, Koblik PD, et al. Prevalence of pituitary tumors among diabetic cats with insulin resistance. J Am Vet Med Assoc 2000; 216(11): 1765-1768.

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

7. Berg RI, Nelson RW, Feldman EC, et al. Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly. J Vet Intern Med 2007; 21(5): 892-898.

8. Fracassi F, Gandini G, Diana A, et al. Acromegaly due to a somatroph adenoma in a dog. Domest Anim Endocrinol 2007; 32(1): 43-54.

9. Starkey SR, Tan K, Church DB. Investigation of serum IGF-I levels amongst diabetic and non-diabetic cats. J Feline Med Surg 2004; 6(3): 149-155.

10. Dunning MD, Lowrie CS, Bexfield NH, et al. Exogenous insulin treatment after hypofractionated radiotherapy in cats with diabetes mellitus and acromegaly. J Vet Intern Med 2009; 23(2): 243-249.

11. Meij BP, Auriemma E, Grinwis G, et al. Successful treatment of acromegaly in a diabetic cat with transsphenoidal hypophysectomy. J Feline Med Surg 2010; 12(5): 406-410.

12. Aroch I, Mazaki-Tovi M, Shemesh O, et al. Central diabetes insipidus in five cats: clinical presentation, diagnosis and oral desmopressin therapy. J Feline Med Surg 2005; 7(6): 333-339.

13. Harb MF, Nelson RW, Feldman EC, et al. Central diabetes insipidus in dogs: 20 cases (1986-1995). J Am Vet Med Assoc 1996; 209(11): 1884-1888.

14. Andresen E, Willeberg P. Pituitary dwarfism in German shepherd dogs: additional evidence of simple, autosomal recessive inheritance. Nord Vet Med 1976; 28(10): 481-486.

15. Kooistra HS, Voorhout G, Mol JA, et al. Combined pituitary hormone deficiency in German shepherd dogs with dwarfism. Domest Anim Endocrinol 2000; 19(3): 177-190.

16. Kooistra HS, Voorhout G, Selman PJ, et al. Progestin-induced growth hormone (GH) production in the treatment of dogs with congenital GH deficiency. Domest Anim Endocrinol 1998; 15(2): 93-102.

17. Knottenbelt CM, Herrtage ME. Use of proligestone in the management of three German shepherd dogs with pituitary dwarfism. J Small Anim Pract 2002; 43(4): 164-170.

18. Feldman EC, Nelson RW. Hypocalcemia and primary hypoparathyroidism. In: Feldman EC, editor. Canine and Feline Endocrinology and Reproduction. Philadelphia: WB Saunders, 2004: 497-515.

19. Russell N, Bond K, Robertson I, et al. Primary hypoparathyroidism in dogs: a retrospective study of 17 cases. Aust Vet J 2006; 84(8): 285-290.

20. Henderson AK, Mahony O. Hypoparathyroidism. Comp Cont Educ Pract 2005; 27(4): 270-287.


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