Water Intoxication in Dogs Treated with Desmopressin for Diabetes Insipidus

I'm writing about Jazz, a 5-year-old, F/S, Labrador retriever with a working diagnosis of  diabetes insipidus. This dog presented just over a year ago with a history of marked polyuria and polydipsia (PU/PD) but otherwise felt well.  She displayed persistent isosthenuria to hyposthenuria, with urine specific gravities ranging from 1.004 to 1.008 on multiple urine checks (at least 5 at random times during the day, including early morning).

Her initial serum chemistry panel showed no abnormalities. The serum alkaline phosphatase (ALP) was within reference range limits, as were serum electrolytes and calcium concentrations. Serum T4 determination was also normal. An initial urine culture, collected by cystocentesis, grew Klebsiella, so she was treated with an appropriate antibiotic; a subsequent culture 4-weeks later was negative.

An abdominal ultrasound revealed nodule in the right adrenal gland, but subsequent CT showed that both adrenals were of normal size and shape.   Repeat blood work was also normal (including the serum ALP), so I didn't pursue a workup for Cushing’s syndrome.

To rule out diabetes insipidus (DI) as a causes of Jazz's PU/PD, a desmopressin response trial was performed. After 2 days of desmopressin, the low urine specific gravity increased to 1.038. On this basis of this excellent response, a diagnosis of central DI was made. Initially, we administered the desmopressin in the form of eye drops; after a few months, we switched the route of administration to subcutaneous injections (5 μg, given twice daily) when she developed an ocular reaction to the drops. We had been able to keep her urine specific gravity measurements around 1.020-1.025. However, after about 6 months of successful desmopressin treatment, the urine specific gravity has decreased again —down to 1.102-1.015, with recurrence of her PU/PD.

I recently rechecked her routine blood tests, which were all within normal range, except her serum sodium and chloride concentrations, which were both markedly reduced at 123 mEq/L and 95 mEq/L, respectively. I was concerned that she may have developed medullary washout, so I added sodium chloride to her diet and gradually increased the daily desmopressin dose. This has helped her serum electrolytes a bit, with her sodium and chloride rising to 135 mEq/L and 101 mEq/L, respectively. Her urine specific gravity has come up to 1.020, but she remains very PU/PD despite an increased in her subcutaneous desmopressin dose from 5 μg to 30 μg, twice daily.

Jazz also has episodes where she seems to lose awareness, gazes into space, and then paces compulsively. After a few minutes, she appears to return to normal. I haven’t witnessed an episode, but it sounds cerebral-based, petit mal like seizure events.

My queries are the following:

• Do you ever perform urine and plasma osmolalities to help in your diagnostic workup for DI?
• How can you explain the dog's neurologic signs?
• Should I workup this dog for Cushing's disease, bearing in mind normal ALPs over at least the last 12 months, Labrador breed, young age, and no secondary skin changes?
• Do you agree with my presumptive diagnosis?
• Can you add any hints for management, presuming you do agree with my diagnosis?

Thank you very much in advance for your help.

My Response:

There are many potential causes of polyuria and polydipsia (PU/PD). Primary disorders of water balance (i.e. central diabetes insipidus, primary nephrogenic diabetes insipidus and primary polydipsia), although uncommon, should always be considered in the differential diagnoses of polyuria and polydipsia. Clinically, patients with DI have intense thirst and failure to concentrate urine (1-5).

Confirming the diagnosis of DI
In general, animals with DI have only one laboratory abnormality: a low urine specific gravity (SG) or urine osmolality (1-6). To answer your first question, I do not generally use urine and plasma osmolalities for diagnosis of DI — I routinely depend on measurement of urine specific gravity, which is much more practical in clinical practice (7). Measured urine osmolality provides similar information to urine specific gravity, but it can sometimes be easier to interpret changes in osmolality after water deprivation testing or desmopressin (ADH) response testing.

In dogs with DI, a urinary specific gravity of 1.005 or less and a low urinary osmolality (less than 200 mOsm/kg, but sometimes as low as 50 mOsmol/kg) are the hallmarks of DI (2,4,6).  As long as thirst mechanism is intact and access to water/fluids is not denied, plasma osmolality in dogs with DI is near or above the upper limit of the reference range (greater than 300 mOsm/kg).  In contrast, dogs with psychogenic polydipsia usually have serum osmolality measurements that are in the low- to low-normal range (remember that thirst is not driven by osmolality).

In addition to plasma and urine osmolality measurements, which may not be readily available, a number of other diagnostic approaches can be used to confirm central DI, nephrogenic DI or primary (psychogenic) polydipsia. The water deprivation test is generally considered by most authorities to be the best diagnostic test for differentiating between these disorders (1-4). However, it is labor-intensive, difficult to perform correctly, unpleasant for the animal, relies heavily on repeated emptying of the bladder, and can lead to untoward complications and misdiagnosis in some animals.

My test of choice for diagnosis of DI is to consider a therapeutic trial with the arginine vasopressin analogue desmopressin (5,8), as you have done in this dog. However,DI can be a difficult problem to confirm, especially when a dog doesn't completely respond to low-dose desmopressin treatment or relapses on treatment.

Development of neurologic signs in dogs treated with desmopressin
In this case, I am worried that Jazz is being overdosed with desmopressin, with some degree of water intoxication. The dose of 30 μg, administered subcutaneously twice daily, is very high — in fact, I've never used that high of a dose in any dog. I would consider stopping the drug for a few days to see if the neurological signs improve and serum electrolytes remain normal off the salt supplementation. Remember that the added salt will only make the PU/PD worse.

If the neurologic signs do improve or resolve after stopping the desmopressin, then we know that the clinical signs of mental dullness and pacing are likely due to water intoxication. If the signs continue then further workup for a primary neurological disease or seizure diorder should be undertaken.

Differentials for PU/PD in dogs that develop "resistance" to desmopressin
Given the fact that this dog is no longer responding well to low "phyiologic" doses of desmopressin, I would start looking for another problem leading to PU/PD. DI is rare and we haven't completely ruled out all of the more common causes (see Table 1). Many of these other causes of PU/PD will initially respond, at least to some degree, to desmopressin so it's very likely that Jazz is suffering from another disease process other than DI.

I know that that you have excluded diabetes mellitus, hypercalcemia, and hyperthyroidism. If you haven't done a urine culture in awhile, I would do a complete urinalysis and culture. You might want to consider performing an antibiotic trial to help exclude occult pyelonephritis (5).

Table 1—Differential rule outs for polyuria and polydipsia in dogs, listed from most to least common

Since Cushing's syndrome is the most common cause of PU/PD in dogs, the next step would be to certainly do a Cushing's workup. Not all of these atypical cases look cushingoid, especially if they are a large-breed dog like Jazz. If you see leptospirosis in your area (Table 1), that should also be excluded (5,9,10)

If everything else is ruled out and you are left with a diagnosis of DI, I'd consider doing brain imaging to rule out a pituitary or brain mass, especially if the neurologic signs don't resolve.

Other nonspecific treatments for PU/PD
You could also evaluate the use of an NSAID (COX-2 inhibitors), which may help reduce urine output & improve urine concentrating ability in dogs with nephrogenic diabetes insipidus. These drugs act independent of vasopressin secretion and work by inhibiting renal prostaglandin synthesis (11-13). They can allow circulating vasopressin to work better.

References:

1. Barsanti JA, DiBartola SP, Finco DR. Diagnostic approach to polyuria and polydipsia. In: Kirk’s Current Veterinary Therapy XIII. Small Animal Practice, WB Saunders, Philadelphia. 2000; 831–835.
2. Feldman EC, Nelson RW. Water metabolism and diabetes insipidus. In: Canine and Feline Endocrinology and Reproduction, 3rd edition, WB Saunders, Philadelphia. 2004; 2–44. 
3. Harb MF, Nelson RW, Feldman EC, et al. Central diabetes insipidus in dogs: 20 cases (1986– 1995). J Am Vet Med Assoc 1996;209:1884-1888.
4. Shiel RE. Disorders of vasopressin production In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;15-27.
5. Nichols R, Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth edition. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;215-220.
6. Waldrop JE. Urinary electrolytes, solutes, and osmolality. Vet Clin North Am Small Anim Pract 2008;38:503-512. 
7. Watson ADJ. Urine specific gravity in practice. Australian Vet J 1998; 76: 392-398. 
8. Nichols R. Clinical use of the vasopressin analogue DDAVP for the diagnosis and treatment of diabetes insipidus. In: Kirk’s Current Veterinary Therapy XIII. Small Animal Practice, WB Saunders, Philadelphia. 2000; 325–326. 
9. Greene CE, Sykes JE, Brown CA et al. Leptospirosis. In: Infectious Diseases of the Dog and Cat, 3rd edn. Elsevier, Philadelphia. 2006;402–417. 
10. Van De Maele I, Claus A, Haesebrouck F, et al. Leptospirosis in dogs: a review with emphasis on clinical aspects. Vet Rec 2008;163:409–413.
11. Vanherweghem JL, Ducobu J, D'Hollander A. Effects of indomethacin on renal hemodynamics and on water and sodium excretion by the isolated dog kidney. Pflugers Arch 1975;357:243-252. 
12. Kim GH, Choi NW, Jung JY, et al. Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2. Am J Physiol Renal Physiol 2008;294:F702-709. 
13. Anderson RJ, Berl T, McDonald KD, et al. Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney. J Clin Invest 1975;56:420-426. 

Canine Acromegaly and GH-Secreting Mammary Gland Tumors

GH-Producing Mammary Tumors in Two Dogs with Acromegaly

Atsuko Murai, Naohito Nishii, Takehito Morita, and Masashi Yuki

The Journal of Veterinary Medical Science 2012;74:771-774.

Acromegaly is the clinical syndrome caused by growth hormone (GH) excess, and is characterized by overgrowth of the soft tissue, bone, and viscera (1). In humans and cats, acromegaly is commonly caused by pituitary adenomas producing GH (1-4), whereas the pathogenesis of the GH excess in dogs is completely different.

In female dogs, acromegaly is most often caused by endogenous or exogenous progestagens that induce GH overproduction (4-6). Old, intact, female dogs may spontaneously develop acromegaly because of the high progesterone concentrations characteristic of diestrus. Attempts to suppress estrus by administration of a long-acting progestagen (e,g,, medroxyprogesterone acetate) may also lead to acromegaly in dogs. This progestin-induced GH excess originates from foci of hyperplastic ductular epithelium in the mammary glands (7-9). Mammary GH is biochemically identical to GH produced and secreted by the pituitary gland (7).

Canine acromegaly is usually associated with GH oversecretion by hyperplastic mammary glands (7-10), but GH can also be produced by mammary tumors in dogs (11). However, to date, there has been no report of dogs that suffered from acromegaly associated with GH-producing mammary tumors.

In this report by Murai et al (12), the authors describe the clinical course of two well-documented dogs with acromegaly caused by GH-producing mammary tumors.

Case studies —Two intact female dogs (10 -year-old Miniature Dachsund and 13-year-old Papillon) were examined because of growing mammary tumors. Based upon history and clinical examination findings, both dogs had clinical features of acromegaly including weight gain, enlargement of the head, excessive skin folds, and inspiratory stridor. Serum concentrations of growth hormone (GH), insulin-like growth factor-I (IGF-1), and insulin were elevated in both dogs (Table 1). From these findings, both dogs were diagnosed with acromegaly.

Table 1

In the Miniature Dachsund, the GH, IGF-1, and insulin levels normalized within a few days after removal of focal benign mammary tumors and ovariohysterectomy (Table 1).

In the Papillon, metastasis of the mammary tumor was suspected from thoracic radiographs. Despite this finding, one of the mammary tumors was so large that the owner opted for the mammary tumor excision to improve the quality of life. Therefore, the mammary tumors were removed focally with regional lymph node. Histological examination of the large tumor revealed mammary complex carcinoma and metastasis to the regional lymph node. The serum concentrations of GH, IGF-1, and insulin fell dramatically within a few days of surgery, despite the fact that metastasis was present (Table 1)

In both dogs, immunohistochemical staining for GH was positive in the mammary tumor cells but not in the normal mammary glands.

Conclusions and Clinical Relevance— In dogs, high GH secretion and clinical features of acromegaly may be caused by mammary tumors that hypersecrete GH.

My Bottom Line:

Overall, the two dogs reported in this study by Murai et al (12) clearly demonstrate that the acromegalic features and higher serum concentrations of GH and IGF-1 were caused by excessive GH production from the mammary tumors. In both dogs, removing the mammary gland tumor lead to remission of the acromegalic state, as well as a marked decrease in serum GH and IGF-1 values. To the best of my knowledge, this is the first report providing concrete evidence of a causal relationship between GH-producing mammary tumors and naturally occurring canine acromegaly.

Canine acromegaly typically occurs in middle-aged to elderly female dogs in the luteal phase or after administration of exogenous progestins (4-6). Endogenous progesterone or exogenous progestins stimulate GH production in hyperplastic mammary glands in dogs (7-10), This GH can act via the autocrine system to promote the growth of mammary glands or elevate systemic IGF-1 secretion (1). Excessive GH also induces glucose intolerance, which can lead to hyperinsulinemia and/or hyperglycemia (1,6).

A previous report demonstrated that complete removal of normal mammary glands can reduce GH and IGF-I levels in dogs (2). In the two dogs of this report, normal mammary tissue was left intact, and removal of only the mammary tumors decreased the serum concentrations of both GH and IGF-1. In addition, the positive immunostaining for GH were found only in the mammary tumor cells but not in the normal mammary glands, suggesting that GH produced by mammary tumors caused the acromegaly. This is supported by a previous report that most mammary tumors produce GH in dogs (12).

In contrast to the dogs of this report, a previous study has shown that canine malignant mammary tumors contain high GH levels without causing acromegalic symptoms (13).The differences that determine whether mammary tumors do or do not develop high serum GH concentrations or clinical features of acromegaly is not clear.

In any case, now that we know that canine acromegaly can develop as a result of GH-secreting mammary gland tumors, we should be looking for this syndrome in dogs that present with mammary gland tumors. To that end, determination of serum concentrations of insulin, IGF-1, and GH (if available) should be monitored in dogs with mammary gland tumors, especially in those in which complete resection is not possible.

References:

1. Niessen S, Peterson ME, Church DB. Acromegaly In: Mooney CT,Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;35-42.
2. Peterson ME, Taylor RS, Greco DS, et al. Acromegaly in 14 cats. J Vet Intern Med 1990;4:192-201.
3. Fischetti AJ, Gisselman K, Peterson ME. CT and MRI evaluation of skull bones and soft tissues in six cats with presumed acromegaly versus 12 unaffected cats. Vet Radiol Ultrasound 2012;53:535-539. 
4. Concannon P, Altszuler N, Hampshire J, et al. Growth hormone, prolactin, and cortisol in dogs developing mammary nodules and an acromegaly-like appearance during treatment with medroxyprogesterone acetate. Endocrinology 1980;106:1173-1177. 
5. Eigenmann JE, Venker-van Haagen AJ. Progestagen-induced and spontaneous canine acromegaly due to reversible growth hormone overproduction: Clinical picture and pathogenesis. J Am Anim Hosp Assoc 1981;17:813-822 
6. Eigenmann JE, Eigenmann RY, Rijnberk A, et al. Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly. Acta Endocrinol (Copenh) 1983;104:167-176. 
7. Selman PJ, Mol JA, Rutteman GR, et al. Progestin-induced growth hormone excess in the dog originates in the mammary gland. Endocrinology 1994;134:287-292. 
8. Mol JA, van Garderen E, Selman PJ, et al. Growth hormone mRNA in mammary gland tumors of dogs and cats. J Clin Invest 1995;95:2028-2034. 
9. Mol JA, Lantinga-van Leeuwen I, van Garderen E, et al. Progestin-induced mammary growth hormone (GH) production. Adv Exp Med Biol 2000;480:71-76. 
10. Rijnberk A, Mol JA. Progestin-induced hypersecretion of growth hormone: an introductory review. J Reprod Fertil Suppl 1997;51:335-338. 
11. van Garderen E, de Wit M, Voorhout WF, et al. Expression of growth hormone in canine mammary tissue and mammary tumors. Evidence for a potential autocrine/paracrine stimulatory loop. Am J Pathol 1997;150:1037-1047. 
12. Murai A, Nishii N, Morita T, et al. GH-producing mammary tumors in two dogs with acromegaly. J Vet Med Sci 2012;74:771-774. 
13. Queiroga FL, Perez-Alenza MD, Silvan G, et al. Crosstalk between GH/IGF-I axis and steroid hormones (progesterone, 17-beta-estradiol) in canine mammary tumours. J Steroid Biochem Mol Biol 2008;110:76-82. 

Top Endocrine Publications of 2012: The Canine and Feline Pituitary Gland

As I've done for the last three years, I’ve now finished compiling a fairly extensive list of references concerning canine and feline endocrinology that were written last year (in 2012). I’ll be sharing these with you over the next few weeks, as well as reviewing a few of the best papers from my lists of clinical endocrine publications.

In this post, I am going to start off with papers that deal with the theme of diagnosis and treatment of pituitary problems in dogs and cats.

Listed below are 16 clinical and research papers written in 2012 that deal with a variety of pituitary gland issues of clinical importance in dogs and cats.

These range from a case report of a cat with pituitary apoplexy (1) to studies of plasma ACTH precursors in cats with pituitary-dependent hyperadrenocorticism (2); from an excellent review of feline acromegaly (8) to a study of a CT and MRI evaluation of skull bones and soft tissues in cats with this disease (4); and to the use of insulin-like growth factor (IGF-1) validation and measurements for diagnosis of acromegaly in diabetic cats (14,15) to a report of two dogs with acromegaly resulting from GH-secreting mammary gland tumors (12).

Other publications include a dog with congenital adenohypophyseal hypoplasia associated with secondary hypothyroidism (5) to a review of the disorders associated with deficient pituitary hormone secretion (7); and from a report of diabetes insipidus (DI) in a dog with lymphocytic hypophysitis (11) to a case report of a dog suffering from the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (9).

References:

1. Beltran E, Dennis R, Foote A, et al. Imaging diagnosis: pituitary apoplexy in a cat. Vet Radiol Ultrasound 2012;53:417-419. 
2. Benchekroun G, de Fornel-Thibaud P, Dubord M, et al. Plasma ACTH precursors in cats with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2012;26:575-581. 
3. Corbee RJ, Tryfonidou MA, Meij BP, et al. Vitamin D status before and after hypophysectomy in dogs with pituitary-dependent hypercortisolism. Domest Anim Endocrinol 2012;42:43-49. 
4. Fischetti AJ, Gisselman K, Peterson ME. CT and MRI evaluation of skull bones and soft tissues in six cats with presumed acromegaly versus 12 unaffected cats. Vet Radiol Ultrasound 2012;53:535-539. 
5. Gal A, Raetzman LT, Singh K. Congenital adenohypophyseal hypoplasia associated with secondary hypothyroidism in a 2-week-old Portuguese water dog. Can Vet J 2012;53:659-664. 
6. Gestier S, Cook RW, Agnew W, et al. Silent pituitary corticotroph carcinoma in a young dog. J Comp Pathol 2012;146:327-331. 
7. Greco DS. Pituitary deficiencies. Top Companion Anim Med 2012;27:2-7. 
8. Greco DS. Feline acromegaly. Top Companion Anim Med 2012;27:31-35. 
9. Kang MH, Park HM. Syndrome of inappropriate antidiuretic hormone secretion concurrent with liver disease in a dog. J Vet Med Sci 2012;74:645-649. 
10. Lowrie M, De Risio L, Dennis R, et al. Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage. Vet Radiol Ultrasound 2012;53:381-388. 
11. Meij BP, Voorhout G, Gerritsen RJ, et al. Lymphocytic hypophysitis in a dog with diabetes insipidus. J Comp Pathol 2012;147:503-507. 
12. Murai A, Nishii N, Morita T, et al. GH-producing mammary tumors in two dogs with acromegaly. J Vet Med Sci 2012;74:771-774. 
13. Tsai KL, Noorai RE, Starr-Moss AN, et al. Genome-wide association studies for multiple diseases of the German Shepherd Dog. Mamm Genome 2012;23:203-211. 
14. Tschuor F, Zini E, Schellenberg S, et al. Evaluation of four methods used to measure plasma insulin-like growth factor 1 concentrations in healthy cats and cats with diabetes mellitus or other diseases. Am J Vet Res 2012;73:1925-1931. 
15. Tvarijonaviciute A, German AJ, Martinez-Subiela S, et al. Analytical performance of commercially-available assays for feline insulin-like growth factor 1 (IGF-1), adiponectin and ghrelin measurements. J Feline Med Surg 2012;14:138-146. 
16. van Rijn SJ, Gremeaux L, Riemers FM, et al. Identification and characterisation of side population cells in the canine pituitary gland. Vet J 2012;192:476-482. 

Diagnosing Cats with Borderline or Occult Hyperthyroidism

My patient is a 12-year-old, female, DSH that presented for hematuria. Routine blood work was normal but her serum T4 value was slightly high at 4.6 μg/dl (reference range, 1-4 μg/dl). Results of abdominal radiographs showed a bladder urolith which has resolved after 1 month of feeding a diet of Royal Canin Urinary SO.

The cat has been asymptomatic for hyperthyroidism and the serum T4 determination was only performed because of her age (we routinely screen all cats that are older than 10 years). She may be drinking more water but that is most likely due to the urinary SO diet).

On reexamination now, her weight is stable (5.3 kg), her body condition score is perfect, and she has a normal heart rate (200 bpm).  I did not palpate a thyroid nodule on this cat on either of my examinations. I repeated a serum T4 on this cat but now the value (3.1 μg/dl) is within the lab's reference range.

Do you think that this cat is hyperthyroid, or do we need a free T4 in this cat? Should I do any other testing?

My Response:

First of all, I agree with your protocol of starting to screen all senior cats for hyperthyroidism after the age of 10 years. Hyperthyroidism is a common disease, affecting about 10% of senior or geriatric cats (1). In the early stages of the disease, the owners (or their veterinarian) might not notice any clinical signs. Many of these cats are overweight, so loss of some body weight is commonly viewed as a "good" sign, rather than a problem. Screening allows us to pick up cats with mild or early hyperthyroidism before the disorder is allowed to progress to severe disease.

That said, we can never base a diagnosis of hyperthyroidism solely upon a single high T4 value. Lab error is not uncommon, and it's possible to see false-positive results. This is especially true today, when more and more commercial laboratories have stopped using the "gold standard" methods for T4 analysis (such as RIA or chemiluminence) and are switching to automated assays (homogenous enzyme immunoassays) that are run on the auto-analyzer together with the chemistry panel.

In this cat, a total T4 value of 3.1 μg/dl is in the upper third of the lab's reference range so it is still possible that the cat is suffering from mild hyperthyroidism. Fluctuations in circulating T4 and T3 in and out of the reference range is common in cats with mild hyperthyroidism, which can make diagnosis more difficult (2-6). The fact that a thyroid nodule cannot be palpated goes against the diagnosis of hyperthyroidism; however, tiny thyroid nodules can be very difficult to palpate.

So how do we handle cats like this?
We have a number of options, ranging from use of T3 suppression testing (7) to thyroid scintigraphy (8).  What I like to do as a first step in cats like this is to run a complete thyroid panel, which includes the following tests:

• serum T4 by RIA or chemiluminescence (Immulite)
• free T4 by equilibrium dialysis
• serum TSH (measured using the widely available canine TSH assay).

Cats with mild or occult hyperthyroidism will almost always have a low TSH value, at or below the limit of detection of the assay (<0.03 ng/ml) (4-6,9). The reason for this is based on endocrine physiology and the principle of pituitary negative feedback. In early hyperthyroidism, even very mild elevations in circulating T4 "feed-back" to the pituitary gland to shut off TSH secretion. However, the finding of undetectable TSH levels alone are NOT diagnostic for hyperthyroidism because 10-20% of normal cats will also have undetectable levels of TSH (9,10). That's why we have to look at the TSH level together with the total and free T4 values.

If the T4 is high-normal but the free T4 is high and TSH is undetectable, then hyperthyroidism is likely. However, if the total and free T4 are normal to borderline, and the serum TSH value is not suppressed, then hyperthyroidism is much less likely (4-6, 9).

You do have one other option, however, which is just to wait and recheck the cat in 1 to 3 months. In some cats, simply repeating the serum T4 concentration may be diagnostic if the T4 is fluctuating in and out of the reference range. In other cats with preclinical disease, it may take a number of weeks or even months for the serum total T4 concentrations to increase into the “high” range diagnostic for hyperthyroidism.

With time, however, all cats with mild hyperthyroidism will develop more severe disease as the thyroid tumor goes and secretes more T4, making it easier to diagnose (1). Mild or occult hyperthyroidism in a 12-year old cat is never an emergency. Sometimes close monitoring of body weight, heart rate, and thyroid size every few weeks to months is the best way to handle cats like this.

References:

1. Peterson M. Hyperthyroidism in cats: What's causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 2012;14:804-818. 
2. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clin Tech Small Anim Pract 2006;21:2-9.
3. Peterson ME, Melian C, Nichols R. Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease. J Am Vet Med Assoc 2001;218:529-536.
4. Mooney CT, Peterson ME. Feline hyperthyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association. 2012;92-110.
5. Baral RM, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;571-592.
6. Peterson ME. Hyperthyroidism in cats In: Rand JS, Behrend E, Gunn-Moore D, et al., eds. Clinical Endocrinology of Companion Animals. Ames, Iowa Wiley-Blackwell, 2013;295-310.
7. Peterson ME, Graves TK, Gamble DA: Triiodothyronine (T3) suppression test: An aid in the diagnosis of mild hyperthyroidism in cats. J Vet Intern Med 1990;4:233-238.
8. Broome MR. Thyroid scintigraphy in hyperthyroidism. Clin Tech Small Anim Pract 2006;21:10-16.
9. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Can Vet J 2010;51:33-34.
10. Wakeling J, Moore K, Elliott J, et al. Diagnosis of hyperthyroidism in cats with mild chronic kidney disease. J Small Anim Pract 2008;49:287-294.

NYSVMS Veterinary News Interviews Dr. Peterson About His Endocrine Textbook