Dr. Peterson Wins Award for Paper: Spontaneous primary hypothyroidism in 7 adult cats

One of Dr. Peterson's recently published papers won an award, presented by Oxford Laboratories, for "excellence in the advancement of knowledge concerning small animal endocrinology."

The paper,  Spontaneous primary hypothyroidism in 7 adult cats, is available in full as a download at this link.

We've cross-posted this paper on Medium here.

Given the paucity of data regarding adult‐onset feline hypothyroidism, we sought to describe the history, clinical features (including presence or absence of goiter), diagnostic testing, treatment, and long‐term outcome of 7 adult cats with spontaneous primary hypothyroidism. For these cats, we used the serum concentrations of T4, free T4 (fT4), and thyroid stimulating hormone (TSH), and results of thyroid scintigraphy to aid in both the diagnosis and long‐term monitoring of thyroid hormone replacement treatment.

Hypothyroidism in Cats—How is it Diagnosed and Treated?

Earlier this year, Dr. Mark Peterson participated in an Endocrinology course organized by the American College of Veterinary Internal Medicine (ACVIM). An overview of his lecture on feline hypothyroidism was summarized by Dr. Jennifer Garcia and published in the July 2015 issue of Veterinary Medicine. To access this article online, click here.

Hypothyroidism in cats—how is it diagnosed and treated? 
More cats may be affected by this disease than you think, and even cats with subclinical or mild forms may benefit from thyroid replacement therapy. In his presentation at the American College of Veterinary Internal Medicine (ACVIM) Small Animal Internal Medicine Endocrinology Course “Feline hypothyroidism: Current aspects on prevalence, diagnosis, and treatment,” Mark E. Peterson, DVM, DACVIM, noted that the number of cats with this disorder may be higher than we think and that many of these cats may benefit from therapy. Peterson explained that most cases of hypothyroidism in cats are iatrogenic in nature—after iodine-131 therapy, antithyroid drug therapy or thyroidectomy. Congenital and adult-onset forms of the disease occur but are considered rare.

As clinicians, we need to be more aware of this disease since even cats with subclinical or mild forms may benefit from thyroid replacement therapy. Peterson pointed out that up to 20% to 50% of cats with hypothyroidism may have azotemia, which will improve with treatment of the hypothyroidism. Diagnosing hypothyroidism in cats could be challenging, as even cats that are ultimately diagnosed with this disorder may initially have a thyroxine (T4) concentration in the low end of the reference range. The same can be true of a free T4 concentration, even if performed by using equilibrium dialysis.

Patient evaluation and monitoring
For patients in which hypothyroidism is suspected, either based on clinical signs or history (e.g. post iodine-131 therapy), Peterson recommends evaluating the T4 concentration in conjunction with a thyroid-stimulating hormone (TSH) concentration. While the only commercially available TSH assay is canine-specific, the assay cross-reacts with feline TSH as well. As in dogs, finding a low or low-normal T4 concentration in conjunction with an elevated TSH concentration is supportive of a diagnosis of hypothyroidism in cats.

Three months after iodine-131 therapy or antithyroid drug therapy is initiated or a thyroidectomy is performed, Peterson recommends monitoring T4 concentrations for up to six months. This should be considered sooner in cats that develop evidence of renal disease. He suggests that a post-treatment T4 concentration should be in the mid-normal range. Cats with values lower than this should have a measurement of their TSH concentration, but Peterson says some cats will experience an increase in their TSH concentration prior to a decrease in their T4 concentration.

Treatment recommendations 
So which cats should be treated with thyroid hormone therapy? Peterson suggests that cats that have supportive clinical signs—lethargy and weight gain—and low T4 or high TSH concentrations should be treated. Cats that have no clinical signs but have supportive laboratory test results and azotemia should also be treated.

For cats that require thyroid hormone supplementation, Peterson recommends a starting dose of levothyroxine 0.075 mg orally twice a day. This is higher than what is commonly used in dogs because cats metabolize the hormone much more quickly and don’t absorb it as well as dogs. Administration on an empty stomach is recommended. To monitor cats that are receiving replacement therapy, Peterson recommends a four-hour post-pill T4 concentration with a therapeutic goal in the mid-normal range.

When To Start Thyroid Hormone Replacement in Cats Treated with Radioiodine (I-131)

I have a question about thyroid hormone supplementation for iatrogenic hypothyroidism, especially in cats treated with radioiodine (I-131). More specifically, how long after radioactive iodine therapy do you wait before recommending supplementing hypothyroid cats with thyroxine?

I work as a small animal internist at a referral hospital where we treat hyperthyroid cats with radioiodine. After treatment, we routinely run serum T4 and free T4 concentrations and full blood work 30 and 90 days after the cat is discharged. I have found that about 20% of these cats are biochemically hypothyroid (low total or free T4 values) at the 30-day recheck, but many of these cats will revert to normal by the 90-day recheck. The other internist at my practice supplements these cats with L-thyroxine at the first recheck if the serum T4 and free T4 values are low. She does this even if they are not azotemic, with the rationale being that the studies show that hypothyroid cats develop worsening azotemia, which can affect their survival (1).

I am not sure if this is the best approach since I have heard that the residual thyroid follicles may take a few months to regain full function after being suppressed by the over-active thyroid tissue for so long. However, I just want to do what's best (don't we all!)

Thank you so much. I enjoy reading your website and attending your lectures at conferences.

My Response:

First of all, I don't find that free T4 determinations are all that helpful in the diagnosis of feline hypothyroidism (2-4). Many cats treated with radioiodine with maintain low-normal values for both total and free T4 but develop high serum TSH concentrations, a situation commonly referred to as subclinical hypothyroidism in human patients. The problem with our cats, however, is that although most of these cats do remain nonclinical for hypothyroidism, many will develop azotemia that will progressively worsen without treatment with thyroid hormone replacement.

So what I do is as follows: at 30-days post-treatment, I monitor serum concentrations of T4, free T4, and TSH, along with a serum chemistry panel to follow kidney values. If T4 or free T4 values fall into the lower third of the reference range (below 1.5-2.0 µg/dl; reference interval ≈1-4 µg/dl) and TSH rises (above 0.5-0.6 ng/dl; reference range, 0.03-0.03 ng/ml), then the cat is mildly hypothyroid. Some of these cats will recover enough thyroid function to end up as euthyroid, but most remain mildly hypothyroid at both 3 and 6 months, at least based on the finding of high TSH concentrations.

In these cats with mild or subclinical hypothyroidism, I don't like to treat with levothyroxine (LT4) at this time unless evidence of chronic kidney disease (CKD) has developed, with serum creatinine values rising from normal to greater than 2.0 mg/dl. However, this definitely indicates the need for LT4 replacement in order to help maintain renal perfusion and stabilize the serum creatinine concentrations (3-5).

If we decide not to treat (which is generally the case unless new azotemia has developed), then we monitor again with the same thyroid and renal profiles at 3- and 6 months. Again, if T4 falls into the low-normal range (less than 1.5-2.0 µg/dl) and TSH is clearly high (above 0.5-0.6 ng/dl), I would definitely supplement if new or worsening azotemia is detected. If no azotemia is present, I generally continue to monitor and don't supplement with LT4 unless azotemia does develop.

Now, if the serum T4 is below normal and the TSH is clearly high at 3 or 6 months (or later), then the cat has overt hypothyroidism (no longer subclinical) and I would definitely supplement with L-T4 (2-4). Many of these cats are still not very symptomatic, but that may simply be a matter of time. If left untreated for 1 to 2 years, most of those cats will develop classical signs of hypothyroidism (eg, lethargy, hair loss, etc).

So in your case, I would add-in serum TSH to your monitoring protocol. If your owners find that too expensive, then I would replace the free T4 measurement with TSH determination, which is more more helpful in monitoring for cats treated with radioiodine.

References:

1. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 
2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4.  
3. Peterson ME. Diagnosis and management of iatrogenic hypothyroidism In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
4. Peterson ME, Guterl JN.Subclinical iatrogenic hypothyroidism in the cat: Clinical, laboratory, and thyroid scintigraphic findings in 35 cases. J Vet Intern Med 2015;29:448-449.
5. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255.

Top Endocrine Publications of 2014: The Feline Thyroid Gland

In my fourth compilation of the canine and feline endocrine publications of 2014, I’m moving on to disorders of the feline thyroid gland. Listed below are 32 papers that deal with a variety of thyroid gland topics of issues of clinical importance in cats.

These range from from a survey of owners' perceptions and experiences after using radioiodine to treat their hyperthyroid cats (1) to the results of an online survey to determine owner experiences and opinions on the management of their cats using oral anti-thyroid medications (14); from case reports of methimazole or carbimazole-induced toxicity in cats with hyperthyroidism (3,5,19) to a number of publications involving various issues of medical treatment with methimazole (2,4,7,14,15,20); from a study of the concurrent diseases detected in hyperthyroid cats undergoing assessment for radioiodine treatment (25) to concurrent diseases and conditions in cats with renal infarcts (including hyperthyroidism (12); and finally, from studies investigating the efficacy of an iodine-restricted diet for management of cats with hyperthyroidism (9,30) to other forms of dietary management for this endocrine disease (19,24).

Finally, 2 investigations add further data concerning chronic renal disease in hyperthyroid cats (31,32), as well as the fact that iatrogenic hypothyroidism contributes to azotemia in these cats (31). A number of 2014 publications deal with the rising prevalence and/or etiopathogenesis of hyperthyroidism in cats (6,16,17,21,22,23,29). Unfortunately, further studies are needed to better define the cause(s) of this perplexing disease (download my review paper for more discussion) (23).

References:

1. Boland LA, Murray JK, Bovens CP, et al. A survey of owners' perceptions and experiences of radioiodine treatment of feline hyperthyroidism in the UK. J Feline Med Surg 2014;16:663-670. 
2. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Transdermal application of methimazole in hyperthyroid cats: a long-term follow-up study. J Feline Med Surg 2014;16:453-459. 
3. Bowlt K, Cattin I, Stewart J. Carbimazole-associated hypersensitivity vasculitis in a cat. J Small Anim Pract 2014;55:643-647. 
4. Bruyette D. Methimazole management of feline hyperthyroidism. Today's Veterinary Practice 2014;July/August:38-41.
5. Castro Lopez J, Lloret A, Ravera I, et al. Pyogranulomatous mural folliculitis in a cat treated with methimazole. J Feline Med Surg 2014;16:527-531. 
6. Chow K, Beatty JA, Barrs VR, et al. PBDEs and feline hyperthyroidism. Vet Rec 2014;175:433-434. 
7. Daminet S, Kooistra HS, Fracassi F, et al. Best practice for the pharmacological management of hyperthyroid cats with antithyroid drugs. J Small Anim Pract 2014;55:4-13. 
8. Daniel GB, Neelis DA. Thyroid scintigraphy in veterinary medicine. Semin Nucl Med 2014;44:24-34. 
9. Fritsch DA, Allen TA, Dodd DE, et al. A restricted iodine food reduces circulating thyroxine concentrations in cats with hyperthyroidism. Intern J Appl Res Vet Med 2014;12:24-32. 
10. Fryers A, Elwood C. Hypokalaemia in a hyperthyroid domestic shorthair cat with adrenal hyperplasia. J Feline Med Surg 2014;16:853-857. 
11. Galgano M, Spalla I, Callegari C, et al. Primary hypothyroidism and thyroid goiter in an adult cat. J Vet Intern Med 2014;28:682-686. 
12. Hickey MC, Jandrey K, Farrell KS, et al. Concurrent diseases and conditions in cats with renal infarcts. J Vet Intern Med 2014;28:319-323. 
13. Higgs P, Costa M, Freke A, et al. Measurement of thyroxine and cortisol in canine and feline blood samples using two immunoassay analysers. J Small Anim Pract 2014;55:153–159. http://onlinelibrary.wiley.com/doi/10.1111/jsap.12181/abstract
14. Higgs P, Murray JK, Hibbert A. Medical management and monitoring of the hyperthyroid cat: a survey of UK general practitioners. J Feline Med Surg 2014;16:788-795. 
15. Hill K, Gieseg M, Bridges J, et al. The pharmacokinetics of methimazole in a novel lipophilic formulation administered transdermally to healthy cats. N Z Vet J 2014;62:208-213. 
16. Hill KE, Shaw IC. Does exposure to thyroxine-mimics cause feline thyroid hyperplasia? Vet Rec 2014;175:228-229. 
17. Kooistra HS. Feline hyperthyroidism: a common disorder with unknown pathogenesis. Vet Rec 2014;175:456-457. 
18. Kujawa A, Olias P, Bottcher A, et al. Thyroid transcription factor-1 is a specific marker of benign but not malignant feline lung tumours. J Comp Pathol 2014;151:19-24. 
19. Laflamme D, Gunn-Moore D. Nutrition of aging cats. Vet Clin North Am Small Anim Pract 2014;44:761-774, vi. 
20. Mardell EJ. Diagnosis and management of feline hyperthyroidism. In Practice 2014;35:162-170.
21. McLean JL, Lobetti RG, Schoeman JP. Worldwide prevalence and risk factors for feline hyperthyroidism: A review. J S Afr Vet Assoc 2014;85:1097. 
22. O'Neill DG, Church DB, McGreevy PD, et al. Prevalence of disorders recorded in cats attending primary-care veterinary practices in England. Vet J 2014;202:286-291. 
23. Peterson ME. Feline hyperthyroidism: an animal model for toxic nodular goiter. J Endocrinol 2014;223:T97-T114. 
24. Peterson ME, Eirmann L. Dietary management of feline endocrine disease. Vet Clin North Am Small Anim Pract2014;44:775-788. 
25. Puig J, Cattin I, Seth M. Concurrent diseases in hyperthyroid cats undergoing assessment prior to radioiodine treatment. J Feline Med Surg 2014. 
26. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats (Letter). Vet Clin Pathol 2014;43:1-3. 
27. Sangster JK, Panciera DL, Abbott JA, et al. Cardiac biomarkers in hyperthyroid cats. J Vet Intern Med 2014;28:465-472. 
28. Schober KE, Kent AM, Aeffner F. Tachycardia-induced cardiomyopathy in a cat. Schweiz Arch Tierheilkd 2014;156:133-139. 
29. Stephens MJ, Neill DG, Church DB, et al. Feline hyperthyroidism reported in primary-care veterinary practices in England: prevalence, associated factors and spatial distribution. Vet Rec 2014;175:458. 
30. van der Kooij M, Becvarova I, Meyer HP, et al. Effects of an iodine-restricted food on client-owned cats with hyperthyroidism. J Feline Med Surg 2014;16:491-498. 
31. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255. 
32. Williams TL, Elliott J, Syme HM. Association between urinary vascular endothelial growth factor excretion and chronic kidney disease in hyperthyroid cats. Res Vet Sci 2014;96:436-441. 

Can Thyroid Function be Monitored in Hypothyroid Dogs Treated with Steroids?

Some of my hypothyroid dogs also intermittently receive corticosteroids at anti-inflammatory doses to treat flare-ups of allergic dermatitis. Does the corticosteroid therapy affect thyroid hormone concentrations and interfere with testing—either for the initial diagnosis or for therapeutic monitoring purposes?

Are thyroxine supplementation dosage adjustments needed during corticosteroid therapy?

My Response:

Glucocorticoids are known to affect serum thyroid hormone concentrations in dogs (1-4). Dogs receiving anti-inflammatory or immunosuppressive doses of prednisone or prednisolone can have altered thyroid function test results, especially if they have been receiving the corticosteroids for more than 2 weeks. In general, I would prefer to see dogs off of all forms of corticosteroids for at least 4-to 6-weeks before trying to evaluate thyroid function.

In dogs receiving thyroid hormone supplementation that subsequently begin to receive corticosteroid therapy, we generally do not perform laboratory tests to evaluate thyroid function until the corticosteroids have been removed. However, one paper in 2011 by O'Neill et al did study the effect of short-term anti-inflammatory doses of prednisone in dogs with naturally occurring hypothyroidism (5).

In that report, 8 dogs with spontaneous hypothyroidism already being treated with levothyroxine (L-T4) were given prednisone (1 mg/kg orally) daily for 7 days and then on alternate days for 14 days (5). Serum total thyroxine (T4), free T4, and thyroid-stimulating hormone (TSH) concentrations were measured on days 7, 21, and 28 and compared with baseline data. Results showed that total T4 concentrations were significantly decreased after 7 days of an anti-inflammatory dose of prednisone, but T4 values were not significantly altered from baseline on days 21 or 28 while on every other day dosing. Free T4 and TSH concentrations were not significantly altered from baseline at any point during the study.

My Bottom Line

Based on the results of the O'Neill study (5) administration of prednisone at a dosage of 1 mg/kg given orally once daily for 7 days decreased total T4 concentrations, while free T4 concentrations were unchanged. This suggests that free T4 concentrations may be less affected by daily prednisone administration. Anti-inflammatory doses of prednisone, when administered every other day, did not interfere with thyroid hormone monitoring.

These results also agree with two previous studies, which showed that anti-inflammatory prednisone did not affect serum total T4 concentrations in thyroid-supplemented, thyroidectomized dogs (3,6).

So, at least with short-term administration of a single daily anti-inflammatory dose of prednisone, thyroid function may be evaluated by looking at free T4 or TSH concentrations. However, these results cannot be generalized to dogs taking prednisone for longer periods or at higher immunosuppressive doses (2-4 mg/kg/day).

References

1. Woltz HH, Thompson FN, Kemppainen RJ, et al. Effect of prednisone on thyroid gland morphology and plasma thyroxine and triiodothyronine concentrations in the dog. Am J Vet Res 1983;44:2000-2003. 
2. Torres SM, McKeever PJ, Johnston SD. Effect of oral administration of prednisolone on thyroid function in dogs. Am J Vet Res 1991;52:416-421. 
3. Moore GE, Ferguson DC, Hoenig M. Effects of oral administration of anti-inflammatory doses of prednisone on thyroid hormone response to thyrotropin-releasing hormone and thyrotropin in clinically normal dogs. Am J Vet Res 1993;54:130-135. 
4. Daminet S, Paradis M, Refsal KR, et al. Short-term influence of prednisone and phenobarbital on thyroid function in euthyroid dogs. Can Vet J 1999;40:411-415. 
5. O'Neill SH, Frank LA, Reynolds LM. Effect of an anti-inflammatory dose of prednisone on thyroid hormone monitoring in hypothyroid dogs. Vet Dermatol 2011;22:202-205.
6. Kaptein EM, Moore GE, Ferguson DC et al. Effects of prednisone on thyroxine and 3,5,3’-triiodothyronine metabolism in normal dogs. Endocrinology 1992;130:1669–1679.

Hypothyroidism Associated with Acromegaly and Insulin-resistant Diabetes Mellitus in a Samoyed

PAPER REVIEW

Hypothyroidism Associated with Acromegaly and Insulin-resistant Diabetes Mellitus in a Samoyed

by T. Johnstone, E. Terzo, and C. Mooney

Australian Veterinary Journal 2014; 92:437-442.

Background

Although both hypothyroidism and diabetes mellitus are common disorders of dogs, it is relatively uncommon for a dog to develop both diseases concurrently. Insulin-resistant diabetes has been reported in a few dogs with underlying hypothyroidism (1-3), but the mechanisms underlying the insulin resistance is not clear. However, hypothyroidism may lead to alteration of other hormones that influence glucose metabolism, and previous studies of hypothyroid dogs have documented excessive production of growth hormone (GH), a known insulin antagonist (4,5). In one study, Beagles with radioiodine-induced hypothyroidism were reported to have a progressive elevation in serum GH concentrations (a known insulin antagonist), but none of those dogs developed overt diabetes (6).

The purpose of this case report by Johnstone et al. (7) is to describe a dog diagnosed with naturally occurring hypothyroidism that also had concurrent signs of acromegaly and diabetes. In this dog, the insulin resistance and associated diabetic state was reversed with appropriate L-thyroxine supplementation.

Case Report
A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics, and glucocorticoid therapy. The dog also exhibited exercise intolerance of 12-months duration. Recently, polydipsia and polyuria were also noted.

Marked interdental spacing

On physical examination, obesity, poor coat condition, widened spaces between the teeth, and mild respiratory stridor were noted (see Figure).

Initial laboratory test results confirmed marked hyperglycemia, consistent with diabetes mellitus. Serum concentrations of total thyroxine (T4), free T4 by equilibrium dialysis, and free triiodothyronine (T3) were below the reference limits, and canine thyroid-stimulating hormone (cTSH) levels was above the reference limits, diagnostic for primary hypothyroidism.

Before treatment for diabetes and hypothyroidism was initiated, further tests were performed to investigate a potential link between these two conditions. An upper airway examination revealed mild soft tissue hypertrophy but normal laryngeal function. The pretreatment serum insulin concentration was above the reference limits, suggesting endogenous insulin resistance. A baseline serum IGF-1 concentration was within reference limits. However, basal serum GH concentrations were markedly elevated, and a further paradoxical increase in GH concentration was noted after administration of thyrotropin-releasing hormone (TRH). CT imaging of the pituitary suggested slight enlargement of the gland but no pituitary tumor was evident.

Overall, the high serum GH concentrations, together with the clinical features (e.g., widened interdental spaces, and mild respiratory stridor), was considered diagnostic for acromegaly.

Treatment was initiated using both insulin (Caninsulin, 20 IU every 12 h) and thyroid supplementation (levothyroxine, L-T4, 0.02 mg/kg every 24 h). Over the next few weeks, the exogenous insulin requirements started to decrease, and all exogenous insulin was discontinued 155 days later. The dog remained euglycemic 2 years after diagnosis, with continued daily supplementation of L-T4 alone.

My Bottom Line:

In this dog, diabetes mellitus was thought to be a secondary consequence of insulin resistance, as demonstrated by the high pretreatment serum insulin concentration. Insulin-resistant diabetes mellitus has been previously described in a few dogs with naturally occurring hypothyroidism (1-3), but the pathogenesis for the concurrent development of the two diseases is not totally understood.

It has been reported, however, that primary hypothyroidism can lead to with functional and morphological changes of the pituitary gland (4-6). Most notably, transdifferentiation of pituitary TSH-producing cells to cells producing both TSH and GH has been documented (6), which can result in increased GH production and secretion in these dogs. The high basal GH concentration and the paradoxical increase of GH after stimulation with TRH in this dog (7) confirmed that hypothyroidism-induced acromegaly and secondary diabetes was likely.

Although the true prevalence of hypothyroidism-induced acromegaly in dogs is not known, our clinical experience suggests that hypothyroidism is rarely associated with acromegaly. However, it is likely that acromegaly goes under-diagnosed in some hypothyroid dogs since many of the clinical signs of both disorders are similar. Furthermore, pituitary transdifferentiation of TSH to GH hypersecretion would be expected to take a long time to develop, and therefore, hypothyroidism-induced acromegaly may only become significant when hypothyroidism remains undiagnosed or untreated for several months to years (6).

In this dog, the fact that the diabetic state resolved during treatment with L-T4 suggests that the pituitary GH overproduction resolved as euthyroidism was achieved. Unfortunately, repeat TRH stimulation testing or serum GH measurements were not repeated after resolution of the diabetic state, so we can not say for certain that the acromegalic state truly resolved. Further studies certainly are needed to investigate hypothyroidism-induced GH production, but this interesting case certainly does add some insight to what may be going on in these dogs.

References:

1. Blois SL, Dickie E, Kruth SA, et al. Multiple endocrine diseases in dogs: 35 cases (1996-2009). J Am Vet Med Assoc 2011;238:1616-1621. 
2. Ford SL, Nelson RW, Feldman EC, et al. Insulin resistance in three dogs with hypothyroidism and diabetes mellitus. J Am Vet Med Assoc 1993;202:1478-1480. 
3. Hess RS, Saunders HM, Van Winkle TJ, et al. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998). J Am Vet Med Assoc 2000;217:1166-1173. 
4. Lee WM, Diaz-Espineira M, Mol JA, et al. Primary hypothyroidism in dogs is associated with elevated GH release. J Endocrinol 2001;168:59-66. 
5. Diaz-Espineira MM, Galac S, Mol JA, et al. Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism. Domest Anim Endocrinol 2008;34:176-181. 
6. Diaz-Espineira MM, Mol JA, van den Ingh TS, et al. Functional and morphological changes in the adenohypophysis of dogs with induced primary hypothyroidism: loss of TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation. Domest Anim Endocrinol 2008;35:98-111. 
7. Johnstone T, Terzo E, Mooney CT. Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. Aust Vet J 2014;92:437-442. 

Top Endocrine Publications of 2014: The Canine Thyroid Gland

Large goiter due to thyroid carcinoma

In my third compilation of the canine and feline endocrine publications of 2014, I’m moving on to disorders of the canine thyroid gland. Listed below are 21 research papers written in 2014 that deal with a variety of thyroid gland topics and issues of clinical importance.

A number of these publications deal with clinical, pathologic, diagnostic, or therapeutic aspects of thyroid carcinoma (1-6,10,13,14,17,18).  Of these, two papers (1,14) deal specifically with ectopic thyroid tumors arising in the sublingual location, which may indicate that such ectopic tumors are not as uncommon as once thought.

Other publications include a case report of a hypothyroid dog suffering from insulin-resistant diabetes mellitus and acromegaly (8); interestingly, after treatment with L-thyroxine, the insulin resistance and diabetes resolved.

Other papers report on various studies on hypothyroidism in dogs including the effect of age of lipid metabolism (9) to the association between gall bladder mucoceles and hyperlipidemia (12);  and from exercise-induced hypercoagulability, von Willebrand factor, and thyroid hormone concentrations in sled dogs (11) to evaluation of serum thyroid hormones in dogs with systemic inflammation or sepsis (16).

Finally, other papers include a case report of a hypothyroid dog with polyneuropathy that resolved following thyroid supplementation (20), to a study of the pharmacokinetics of total T4 after repeated oral administration of L-T4 solution in hypothyroid dogs (21). 

References:

1. Broome MR, Peterson ME, Walker JR. Clinical features and treatment outcomes of 41 dogs with sublingual ectopic thyroid neoplasia. J Vet Intern Med 2014;28:1560-1568. 
2. Campos M, Ducatelle R, Kooistra HS, et al. Immunohistochemical expression of potential therapeutic targets in canine thyroid carcinoma. J Vet Intern Med 2014;28:564-570. 
3. Campos M, Ducatelle R, Rutteman G, et al. Clinical, pathologic, and immunohistochemical prognostic factors in dogs with thyroid carcinoma. J Vet Intern Med 2014;28:1805-1813. 
4. Campos M, Kool MM, Daminet S, et al. Upregulation of the PI3K/Akt pathway in the tumorigenesis of canine thyroid carcinoma. J Vet Intern Med 2014;28:1814-1823. 
5. Ciaputa R, Nowak M, Kandefer-Gola M, et al. Morphological and immunohistological characteristics of follicular-compact thyroid carcinoma in dog. Folia Histochem Cytobiol 2014;52:157-161. 
6. Deitz K, Gilmour L, Wilke V, et al. Computed tomographic appearance of canine thyroid tumours. J Small Anim Pract 2014;55:323-329. 
7. Higgs P, Costa M, Freke A, et al. Measurement of thyroxine and cortisol in canine and feline blood samples using two immunoassay analysers. J Small Anim Pract 2014;55:153–159. 
8. Johnstone T, Terzo E, Mooney CT. Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. Aust Vet J 2014;92:437-442. 
9. Kawasumi K, Kashiwado N, Okada Y, et al. Age effects on plasma cholesterol and triglyceride profiles and metabolite concentrations in dogs. BMC Vet Res 2014;10:57. 
10. Kobayashi R, Yamada N, Kitamori T, et al. Follicular thyroid carcinoma characterized by abundant stromal components with chondroid and osseous metaplasia in a dog. J Vet Med Sci 2014;76:1161-1164. 
11. Krogh AK, Legind P, Kjelgaard-Hansen M, et al. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs. Acta Vet Scand 2014;56:11. 
12. Kutsunai M, Kanemoto H, Fukushima K, et al. The association between gall bladder mucoceles and hyperlipidaemia in dogs: A retrospective case control study. Vet J 2014;199:76-79. 
13. Metivier KS, Deitz K, Xu WW, et al. Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs. Vet Comp Oncol 2014;12:181-197. 
14. Milovancev M, Wilson DM, Monnet E, et al. Partial resection of the hyoid apparatus during surgical treatment of ectopic thyroid carcinomas in dogs: 5 cases (2011-2013). J Am Vet Med Assoc 2014;244:1319-1324. 
15. Muller TR, Assis MM, Doiche DP, et al. Do thyroid ultrasonographic features change according to age in euthyroid dogs? Anat Histol Embryol 2014;43:468-473. 
16. Pashmakova MB, Bishop MA, Steiner JM, et al. Evaluation of serum thyroid hormones in dogs with systemic inflammatory response syndrome or sepsis. J Vet Emerg Crit Care (San Antonio) 2014;24:264-271. 
17. Pessina P, Castillo V, Sartore I, et al. Semiquantitative immunohistochemical marker staining and localization in canine thyroid carcinoma and normal thyroid gland. Vet Comp Oncol 2014. 
18. Pineyro P, Vieson MD, Ramos-Vara JA, et al. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog. J Vet Sci 2014;15:449-453. 
19. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats. Vet Clin Pathol 2014;43:1-3. 
20. Utsugi S, Saito M, Shelton GD. Resolution of polyneuropathy in a hypothyroid dog following thyroid supplementation. J Am Anim Hosp Assoc 2014;50:345-349. 
21. van Dijl IC, Le Traon G, van de Meulengraaf BD, et al. Pharmacokinetics of total thyroxine after repeated oral administration of levothyroxine solution and its clinical efficacy in hypothyroid dogs. J Vet Intern Med 2014;28:1229-1234. 

Top Endocrine Publications of 2013: The Feline Thyroid Gland

In my eighth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline thyroid gland.

Listed below are 26 papers published in 2013 that deal with a variety of thyroid gland topics of issues of clinical importance in cats.

These range from from studies of the duration of serum T4 suppression in cats treated with methimazole (1) to the results of a long-term follow-up study of cats treated with transdermal methimazole (2); and from case reports of methimazole or carbimazole-induced toxicity in cats (3,6,19) to the results of an online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications (5).

Other studies report the variability in iodine concentrations found in commercial cats foods in the USA (7) to investigation of the radioactivity in the excreta of hyperthyroid cats treated with radioiodine (8); from a comparison of computed tomography and scintigraphy for thyroid imaging in hyperthyroid cats (9) to a review of the clinical usefulness of an assay for measurement of circulating B-type natriuretic peptide (BNP) concentration in hyperthyroid cats (11); and from an overview of the diagnostic tests useful for confirming feline hyperthyroidism (4,12,13,15,17) and hypothyroidism (14) to a study of the effects of an iodine-restricted diet for management of cats with hyperthyroidism (22); from investigations of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats (24) to studies of the renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without hypertension (25).

References:

1. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Duration of T4 suppression in hyperthyroid cats treated once and twice daily with transdermal methimazole. J Vet Intern Med 2013;27:377-381. 
2. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Transdermal application of methimazole in hyperthyroid cats: a long-term follow-up study. J Feline Med Surg 2013;16:453-459. 
3. Bowlt K, Cattin I, Stewart J. Carbimazole-associated hypersensitivity vasculitis in a cat. J Small Anim Pract 2013; doi: 10.1111/jsap.12154. 
4. Bruyette D. Feline hyperthyroidism: Diagnosis and therapeutic modalities. Today's Veterinary Practice 2013;3:25-30.
5. Caney SM. An online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications. J Feline Med Surg 2013;15:494-502. 
6. Castro Lopez J, Lloret A, Ravera I, et al. Pyogranulomatous mural folliculitis in a cat treated with methimazole. J Feline Med Surg 2013;16:527-531. 
7. Edinboro CH, Pearce EN, Pino S, et al. Iodine concentration in commercial cat foods from three regions of the USA, 2008-2009. J Feline Med Surg 2013;15:717-724. 
8. Lamb V, Gray J, Parkin T, et al. Measurement of the radioactivity in the excreta of cats treated with iodine-131 for hyperthyroidism. Vet Rec 2013;172:45. 
9. Lautenschlaeger IE, Hartmann A, Sicken J, et al. Comparison between computed tomography and Tc-Pertechnetate scintigraphy characteristics of the thyroid gland in cats with hyperthyroidism. Vet Radiol Ultrasound 2013;54:666-673. 
10. North DL. Uptake of 131-I in households of thyroid cancer patients. Health Phys 2013;104:434-436. 
11. Oyama MA, Boswood A, Connolly DJ, et al. Clinical usefulness of an assay for measurement of circulating N-terminal pro-B-type natriuretic peptide concentration in dogs and cats with heart disease. J Am Vet Med Assoc 2013;243:71-82. 
12. Paepe D, Verjans G, Duchateau L, et al. Routine health screening: findings in apparently healthy middle-aged and old cats. J Feline Med Surg 2013;15:8-19. 
13. Peterson ME. More than just T4: Diagnostic testing for hyperthyroidism in cats. J Feline Med Surg 2013;15:765-777. 
14. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4. 
15. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet 2013;35:E3. 
16. Ramoo S, Bradbury L, Anderson G, et al. Sedation of hyperthyroid cats with subcutaneous administration of a combination of alfaxalone and butorphanol. Aust Vet J 2013;91:131-136. 
17. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats (Letter). Vet Clin Pathol 2014;43:1-3. 
18. Sabatino BR, Rohrbach BW, Armstrong PJ, et al. Amino acid, iodine, selenium, and coat color status among hyperthyroid, Siamese, and age-matched control cats. J Vet Intern Med 2013;27:1049-1055. 
19. Snead E, Kerr M, Macdonald V. Cutaneous lymphoid hyperplasia mimicking cutaneous lymphoma in a hyperthyroid cat. Can Vet J 2013;54:974-978. 
20. Sparkes A. Health screening of cats: some timely justification. J Feline Med Surg 2013;15:5. 
21. Taylor BE, Leibman NF, Luong R, et al. Detection of carcinoma micrometastases in bone marrow of dogs and cats using conventional and cell block cytology. Vet Clin Pathol 2013;42:85-91.
22. van der Kooij M, Becvarova I, Meyer HP, et al. Effects of an iodine-restricted food on client-owned cats with hyperthyroidism. J Feline Med Surg 2013;14:491-498. 
23. Whitehouse-Tedd KM, Cave NJ, Ugarte CE, et al. Isoflavone metabolism in domestic cats (Felis catus): Comparison of plasma metabolites detected after ingestion of two different dietary forms of genistein and daidzein. J Anim Sci 2013;91:1295-1306. 
24. Williams TL, Elliott J, Berry J, et al. Investigation of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats. J Small Anim Pract 2013;54:367-373. 
25. Williams TL, Elliott J, Syme HM. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J Vet Intern Med 2013;27:522-529. 
26. Wongbandue G, Jewgenow K, Chatdarong K. Effects of thyroxin (T4) and activin A on in vitro growth of preantral follicles in domestic cats. Theriogenology 2013;79:824-832. 

Dog on Long-Term Thyroid Hormone Supplementation: Hypothyroid, Hyperthyroid, or Cushing's Syndrome?

My patient is an 11-year old, spayed female Spaniel-Mix, named Molly. She weighs 31 pounds (14.1 kg) and is slightly overweight, with a body condition score of 7/9. About 5 years ago, she was initially diagnosed as having hypothyroidism based upon clinical signs of hair loss, together with low serum concentrations of total thyroxine (T4) and free T4. Molly responded well to thyroid hormone replacement with brand-name levothyroxine (L-T4) at the dose of 0.2 mg, twice daily.

Over the following 3 years, the dog did well (complete hair regrowth), but the daily L-T4 dose was increased (to 0.3 mg, twice daily) based on post-pill serum T4 testing, done about 5 hours after administration of the morning dose.

About 2 years ago, Molly was seen for new hair loss, increased appetite, and polyuria and polydipsia (PU/PD). Results of a CBC and serum chemistry panel were considered to be normal, and a post-pill serum T4 concentration was low-normal at 1.5 µg/dl (40 nmol/L). A complete urinalysis was unremarkable, other than a urine specific gravity of 1.013. Based on Molly's relapse of her hair loss and low-normal post-pill T4, the L-T4 dose was increased to 0.4 mg, BID.

Follow-up thyroid testing 6 months later revealed a post-pill serum T4 value in the high-normal range (3.9 µg/dL; 50 nmol/L) so the L-T4 was maintained at 0.4 mg BID. At that time, the PU/PD had lessened, and the increased appetite had normalized so no further workup was recommended.

On followup 1 year later (now 5 months ago), Molly again presented with increased appetite and more severe PU/PD. Her post-pill total T4 concentration was quite high at was 10.1 µg/dl (130 nmol/L), so the dosage of LT4 was decreased to 0.2 mg, BID. Repeat testing 2 months later revealed that the serum T4 value remained high (5.5 µg/dL; 70 nmol/L) so administration of L-T4 was discontinued. Other than truncal hair thinning, Molly's physical examination at that time was normal, with a normal heart rate (85 bpm); no thyroid masses could be palpated.

Now 3 months later, the owner reports progressive truncal hair loss, PU/PD, increased appetite, panting, and weight gain. Molly's physical exam was again unremarkable. Results of routine testing revealed a normal CBC (no stress leukogram), with severe hypercholesterolemia (660 mg/dL; 17.0 mmol/L). The serum alkaline phosphatase activity was also moderately high at 311 U/L (reference interval less than 100 U/L).

We next ran a complete thyroid profile, with the following results:

• Total T4: 16 nmol/L (reference interval, 11-60 nmol)
• Total T3: 0.4 nmol/L (reference interval, 0.8-2.1 nmol)
• Free T4 by dialylsis: 12 pmol/L (reference interval, 10-50 pmol/L)
• TSH: 1.0 ng/ml (reference interval, 0-0.6 ng/ml)
• Thyroglobulin autoantibodies: 10% (reference interval, 0-35%)

I'm at a loss. I thought that the dog's signs might indicate hyperthyroidism but these results appear to be most consistent with hypothyroidism. Should L-T4 be restarted? We have only used a single brand-name L-T4 preparation in this dog — should we switch to another product?

Should I be testing Molly's pituitary-adrenal axis to rule out Cushing's syndrome?

My Response:

This dog is indeed a rather complicated case. Looking back at the history, Molly has displayed clinical signs of hair loss, PU/PD, and increased appetite for the past 2 years. All of these signs have waxed and waned in severity over this time, which explains her long duration of illness.

During that entire time, she was being treated with adequate replacement doses of thyroid hormone and never had post-pill T4 values that were low. In fact, many of her serum T4 concentrations checked during monitoring were too high— clearly in the hyperthyroid range (1). Overall, this strongly suggests that hypothyroidism alone cannot explain all the dog's problems, a conclusion that also is consistent with the fact that neither PU/PD nor increased appetite are signs of thyroid hormone deficiency (2,3).

Hypothyroid or hyperthyroid?
Given the fact that 2 of the post-pill serum T4 values were high, could this dog have iatrogenic hyperthyroidism secondary to an overdosage of L-T4? That certainly is possible, and thyrotoxicosis could account for the increased appetite and PU/PD (4-6). In fact, almost all hyperthyroid dogs will develop moderate to marked PU/PD, which is a much more prominent sign in dogs than in most cats with hyperthyroidism (7).

However, these signs persisted for 3 months after we stopped all thyroid hormone supplementation. In addition, the last thyroid hormone panel showed low to low-normal serum concentrations of total T4, T3, and free T4, in conjunction with high serum concentration of TSH; this combination of results is most consistent with primary hypothyroidism (the original diagnosis) (2,3). Overall, these findings completely rule out either natural hyperthyroidism associated with a hyperfunctional thyroid tumor or iatrogenic thyrotoxicosis from overdosage of L-T4 (5-7).

Hypothyroid or Cushing's syndrome?
Since Molly's clinical signs are also classical for hyperadrenocorticism, we should consider testing for that common canine disorder. While the high cholesterol concentration could be due to hypothyroidism or Cushing's syndrome, the finding of a high serum alkaline phosphatase activity certainly is consistent with chronic cortisol excess (8,9).

Before embarking on a workup for spontaneous Cushing's syndrome, remember to first make sure that Molly is not on any exogenous steroids, including a topical preparation for her eyes, ears, or skin, which can result in iatrogenic hyperadrenocorticism. You determine that not only by reviewing the record to see what your hospital has dispensed, but also by asking the owner what they're using to treat their dog, as they may have bags of steroid medications at home that weren't dispensed by you.

If Molly is suffering from Cushing's syndrome, it is possible that chronic cortisol excess is contributing to the low serum thyroid hormone concentrations.  Canine Cushing's syndrome can actually produce a secondary form of hypothyroidism, one that is reversible upon correction of the hyperadrenocorticism (10,11). However, it is very unlikely that Molly has had undiagnosed Cushing's disease for the past 5 years, given that she appears to be doing so well clinically. In addition, chronic cortisol excess suppresses serum TSH values (9,11), so Molly's high TSH value goes along more with primary hypothyroidism than a secondary form of hypothyroidism resulting from Cushing's syndrome.

As you continue to work up this dog, I would restart your thyroid hormone supplementation at a low dose (0.2-0.3 mg per day, divided). The dog certainly appears to be hypothyroid, based on the last serum thyroid profile, as well as worsened hair loss.

Causes of marked variation in L-T4 absorption
The marked variation in serum post-pill T4 concentrations are both interesting, as well as somewhat perplexing.

I'd start by questioning the owners about the timing of L-T4 administration, since the absorption of the medication is known to be increased when given on an empty stomach, as compared to when administered with meals (12,13). Could some of the marked variation in her past serum post-pill T4 levels have been due to administration of the drug with meals on some occasions and on an empty stomach on others? 

Other drugs and medications can also have an effect on L-T4 absorption (14). In this dog, we must carefully record all dietary changes as well as any administered drugs or supplements, all of which could potentially alter the absorption of the L-T4 preparation. 

References:

1. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
2. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
3. Mooney CT. Canine hypothyroidism: a review of aetiology and diagnosis. N Z Vet J 2011;59:105-114. 
4. Bosje T, den Hertog E, Dijksta M. Does the T4 measurement belong in the standard blood analysis in polyuria/polydipsia? Tijdschr Diergeneeskd 2013;138:230-231. 
5. Peterson ME. Hyperthyroidism and thyroid tumors in dogs In: Melian C, Perez Alenza MD, Peterson ME, et al., eds. Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Barcelona, Spain: Multimedica, 2008;113-125.
6. Mooney CT. Canine hyperthyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;86-91.
7. Nichols, R., Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Gloucester: British Small Animal Veterinary Association, 2012;215-220.
8. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;167-189.
9. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
10. Peterson ME, Ferguson DC, Kintzer PP, et al. Effects of spontaneous hyperadrenocorticism on serum thyroid hormone concentrations in the dog. Am J Vet Res 1984;45:2034-2038. 
11. Ferguson DC, Peterson ME. Serum free and total iodothyronine concentrations in dogs with hyperadrenocorticism. Am J Vet Res 1992;53:1636-1640. 
12. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876.
13. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101.
14. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.

Treatment and Monitoring of Hypothyroid Dogs with Thyroid Hormone Autoantibodies

I'm a veterinarian from Finland, and I'd like your opinion and advice on a 2-year old, male neutered Doberman Pincher (body weight, 42 kg). This dog had been diagnosed with hypothyroidism together with serum T3 antibodies by another veterinarian.

Clinically, the dog has shown a partial response to treatment with L-thyroxine (L-T4), but serum T4 concentrations remain very low and serum TSH remains high on post-pill testing. These are results of my thyroid testing (always at 4 hours post-pill), together with the L-T4 dose and physical examination:

Initial exam:

• Dose: Levothyroxine 400 µg BID
• Exam findings: Clinically quite normal but slightly overweight
• Total T4:  <9.0 nmol/L (reference interval =  13 - 52 nmol/L)
• Free T4 (CLIA): >77 pmol/L (reference interval =  8 - 48 pmol/L )
• TSH: 3.24 ng/ml (reference interval = less than 0.5 ng/ml)

4-week recheck:

• Dose: Levothyroxine 500 µg BID
• Exam findings: Clinically normal; but still overweight
• Total T4: < 9.0 nmol/L  
• TSH: 3.59 ng/ml  

8-week recheck:

• Dose: Levothyroxine 600 µg BID
• Exam findings: Mild weight loss, heart rate 82/bpm, very active and perky
• Total T4: <9.0 nmol/L  
• Free T4 (CLIA): 62 pmol/L
• TSH: 2.2 ng/ml  

I reviewed the L-T4 supplementation with the owner and made sure the dog is ingesting the pills and made certain that they administered the thyroid medication the morning of each recheck—  no problem there. I next recommended repeat testing, again looking at the autoantibody levels and free T4 measured by equilibrium dialysis (ED).

11-week recheck:

• Dose: Levothyroxine 800 µg BID
• Exam findings: Normal
• Total T4: < 9.0 nmol/L 
• Free T4 (ED): 8 pmol/L (reference interval = 6-40 pmol/L) 
• TSH: 1.5 ng/ml  
• T4 antibodies: 13% (1-20%)
• T3 antibodies: 43% (1-10%)
• Thyroglobulin autoantibodies: positive

Overall, I'm confused about this dog's thyroid status. Biochemically, this dog appears to have persistent hypothyroidism (low T4, high TSH) but may also have iatrogenic hyperthyroidism (high free T4 values). How do I know?

I also need advice about how to determine the correct L-T4 replacement dose for this dog. Do I just keep on increasing the medication until the serum T4 concentration normalizes?

My Response:

Obviously, your testing confirms that this dog has thyroiditis, with positive thyroglobulin autoantibodies and high levels of T3 autoantibodies (1-4). Based on the low serum concentrations of free T4 by dialysis and high TSH levels, the dog certainly is hypothyroid (5), but it does not appear that the dog is responding well to the L-T4 supplementation.

Method for T4 assay
What method is being used to measure total T4 concentrations? These days, most commercial veterinary labs don't use radioimmunoassay (RIA) to measure serum T4, even though that method is still considered the gold standard (5,6). Most laboratories use either a chemiluminescent immunoassay method (CLIA; Immulite) or an automated enzyme immunoassay (EIA) method (7,8).

For some reason not well understood, the EIA method will fail to accurately detect circulating post-pill T4 values, at least in some T4-treated dogs. In other words, the serum T4 values remain falsely low, even when the actual T4 values are within the mid- to high-normal range and the dogs are clinically improved. This issue needs more research and has not been published, but there is no doubt that the problem exists. If suspected, one can verify the problem very easily, simply by repeating the post-pill serum T4 concentration by either RIA or chemiluminescence.

Method for Free T4 assay
In this dog, the finding of a high free T4, measured by CLIA (Immulite) can not be easily explained. The fact that the serum TSH is persistently high in your dog suggests persistent hypothyroidism, not hyperthyroidism (5,9).  The low-normal value for the free T4 concentration, when remeasured by equilibrium dialysis (ED), also points to hypothyroidism. Thyroid autoantibodies can not interfere with the free T4 value when determined by the dialysis method, since all protein molecules (including the thyroid autoantibodies) are removed (dialyzed) prior to assay.

Given that we know your dog has thyroid hormone autoantibodies, it's tempting to postulate that the high free T4 value measured by CLIA are falsely high due to the autoantibodies. The bottom line is that we just don't know. However, what is clear is that these free T4 values are not helping us to determine the best treatment for this dog — only confusing the situation.

Brand of L-thyroxine
What brand of LT4 is being administered? In any dog that is not responding well to thyroid hormone supplementation, a brand name product is always recommended.  In addition, sometimes it can help to switch to another size or brand, suggesting that the absorption rate may vary slightly between products. In some studies, use of a liquid L-T4 solution has been found to be be better absorbed, at least in select patients (10,11).

Timing of L-T4 and meals
Are the owners giving the LT4 with meals or on an empty stomach?  The standard of care for human patients requiring L-T4 is to administer the drug on an empty stomach, generally an hour before meals.

Simultaneous administration of L-T4 with food can markedly delay and inhibit the absorption of the drug in both humans and dogs (11-13). In one study of dogs, giving the L-T4 with food decreased its absorption by about 45% (11).

Follow-up Information:

The serum T4 is being measured by EIA. We are giving a brand-name L-T4 product (14). The owner is consistently giving the L-T4 at 12-hour intervals at the time of meals. No other medication is being given.

My Response:

Again, with the EIA method, the total T4 result may not be accurate when measuring a post-pill T4 concentration. We need to do the post-pill T4 by either chemiluminescence (CLIA; Immulite) or RIA on the next followup.

However, the fact that the free T4 concentration is low-normal and the TSH is still high means that the absorbed dose of L-T4 is not high enough. None of your problems appear to have anything to do with T4 or T3 autoantibodies.

I'd first change the timing between the L-T4 dose and feeding to ensure "empty stomach dosing." If that fails to adequately increase the total T4 concentration (RIA or CLIA) and normalize the high serum TSH concentrations, I'd next consider switching to a liquid L-T4 preparation to see if that helps. Finally, if all else fails, you may have to continue to increase the L-T4 dose, but at 0.8 mg twice daily, your dog is already on a more-than-adequate dose for most dogs (5).

References:

1. Refsal KR, Nachreiner RF. Thyroid hormone autoantibodies in the dog: their association with serum concentrations of iodothyronines and thyrotropin and distribution by age, sex, and breed of dog. Canine Practice 1997;22:16-17.
2. Young DW. Antibodies to thyroid hormone and thyroglobulin in canine autoimmune lymphocytic thyroiditis. Canine Practice 1997;22:14-15. 
3. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc 2002;220:466-471. 
4. Patzl M, Mostl E. Determination of autoantibodies to thyroglobulin, thyroxine and triiodothyronine in canine serum. J Vet Med A Physiol Pathol Clin Med 2003;50:72-78. 
5. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
6. Kemppainen RJ, Birchfield JR. Measurement of total thyroxine concentration in serum from dogs and cats by use of various methods. Am J Vet Res 2006;67:259-265.
7. Singh AK, Jiang Y, White T, et al. Validation of nonradioactive chemiluminescent immunoassay methods for the analysis of thyroxine and cortisol in blood samples obtained from dogs, cats, and horses. J Vet Diagn Invest 1997;9:261-268. 
8. Horney BS, MacKenzie AL, Burton SA, et al. Evaluation of an automated, homogeneous enzyme immunoassay for serum thyroxine measurement in dog and cat serum. Vet Clin Pathol 1999;28:20-28. 
9. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
10. Pirola I, Formenti AM, Gandossi E, et al. Oral liquid L-thyroxine (L-T4) may be better absorbed compared to L-T4 tablets following bariatric surgery. Obes Surg 2013;23:1493-1496. 
11. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101. 
12. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.
13. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876. 
14. Forthyron LT4 product insert: http://www.forthyron.com/data/acms/docs/treatment/1_forthyron_pi_200_400_en.pdf

Top Endocrine Publications of 2013: The Canine Thyroid Gland

In my fifth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the canine thyroid gland. Listed below are 22 research papers written in 2013 that deal with a variety of thyroid gland topics and issues of clinical importance.

These range from a review of the neurologic manifestations of canine hypothyroidism (1) to a review of laryngeal paralysis (and related hypothyroidism) (8) to a dog with hypothyroid-related polyneuropathy (20); and from a case study of two dogs with thyroid carcinoma and hyperthyroidism that presented primarily for polyuria, polydipsia (2) to a case report of a dog suffering from thyroid carcino-sarcoma (6).

Other publications which deal with canine thyroid carcinoma include a CT study of eight dogs with sublingual ectopic thyroid tumors (13), a comparison between clinical, ultrasound, CT, MRI, and pathology findings in dogs presented for thyroid carcinoma (18), and use of conventional and cell block cytology for detection of thyroid carcinoma micrometastases to bone marrow (19). Reports of exogenous hyperthyroidism in dogs included two dogs with food-induced thyrotoxicosis (22) and one dog that developed hyperthyroidism secondary to ingestion of feces of another dog being treated with levothyroxine (16).

Three basic research studies involved dogs and the thyroid gland: one was designed to identify the critical amino acids along the transport channel cavity involved in thyroid hormone transport across the blood-brain barrier into neurons (3), whereas the goal of the second study was to develop a systems pharmacology model to describe the impact of thyroperoxidase inhibition on thyroid hormone homeostasis and drug-induced changes in thyroid hormone concentrations (4). The third study looked at thyroid peroxidase enzyme expression in the dog and determined that the structure of the canine gene has diverged with evolution and differs from both human and mouse (5).

Other papers report on various studies concerning diagnostic testing for hypothyroidism in dogs (12,15) to the issue of nonthyroidal illness (leishmaniosis) affecting thyroid function in dogs (14); from a study of the effect of the type of diet fed on thyroid hormone absorption in dogs (7) to the bioavailability of two preparations of L-T4 in dogs (17).

Finally, in this review, I have also included two papers that deal with species other than dogs. The first is a study of thyrotropin (TSH) stimulation testing in ferrets (9), and the other is a comparison of serum thyroid hormone concentrations in horses and donkeys, which were found to differ significantly (11).

References:

1. Bertalan A, Kent MS, Glass E. Neurologic manifestations of hypothyroidism in dogs. Compend Contin Educ Vet 2013;35:E2. 
2. Bosje T, den Hertog E, Dijksta M. Does the T4 measurement belong in the standard blood analysis in polyuria/polydipsia? Tijdschr Diergeneeskd 2013;138:230-231. 
3. Braun D, Lelios I, Krause G, et al. Histidines in potential substrate recognition sites affect thyroid hormone transport by monocarboxylate transporter 8 (MCT8). Endocrinology 2013;154:2553-2561. 
4. Ekerot P, Ferguson D, Glamsta EL, et al. Systems pharmacology modeling of drug-induced modulation of thyroid hormones in dogs and translation to human. Pharm Res 2013;30:1513-1524. 
5. Fyfe JC, Lynch M, Olsen J, et al. A thyroid peroxidase (TPO) mutation in dogs reveals a canid-specific gene structure. Mammalian genome 2013;24:127-133. 
6. Giuliano A, Grant J, Benoit J. Thyroid carcino-sarcoma in a dog. J S Afr Vet Assoc 2013;84:E1-5. 
7. Iemura R, Toyota M, Micallef MJ. Effects of type of diet on pharmacokinetics of levothyroxine sodium oral solution. Res Vet Sci 2013;94:695-697. 
8. Kitshoff AM, Van Goethem B, Stegen L, et al. Laryngeal paralysis in dogs: an update on recent knowledge. J S Afr Vet Assoc 2013;84:E1-9.
9. Mayer J, Wagner R, Mitchell MA, et al. Use of recombinant human thyroid-stimulating hormone for thyrotropin stimulation testing in euthyroid ferrets. J Am Vet Med Assoc 2013;243:1432-1435. 
10. McGonigle KM, Randolph JF, Center SA, et al. Mineralocorticoid before glucocorticoid deficiency in a dog with primary hypoadrenocorticism and hypothyroidism. J Am Anim Hosp Assoc 2013;49:54-57. 
11. Mendoza FJ, Perez-Ecija RA, Toribio RE, et al. Thyroid hormone concentrations differ between donkeys and horses. Equine Vet J 2013;45:214-218. 
12. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats (Letter). Vet Clin Pathol 2014;43:1-3. 
13. Rossi F, Caleri E, Bacci B, et al. Computed tomographic features of basihyoid ectopic thyroid carcinoma in dogs. Vet Radiol Ultrasound 2013;54:575-581. 
14. Saridomichelakis MN, Xenoulis PG, Chatzis MK, et al. Thyroid function in 36 dogs with leishmaniosis due to Leishmania infantum before and during treatment with allopurinol with or without meglumine antimonate. Vet Parasitol 2013;197:22-28. 
15. Schaefer S, Hassa PO, Sieber-Ruckstuhl NS, et al. Characterization of recombinant human and bovine thyroid-stimulating hormone preparations by mass spectrometry and determination of their endotoxin content. BMC Vet Res 2013;9:141. 
16. Shadwick SR, Ridgway MD, Kubier A. Thyrotoxicosis in a dog induced by the consumption of feces from a levothyroxine-supplemented housemate. Can Vet J 2013;54:987-989. 
17. Simpson C, Devi JL, Whittem T. Bioavailability of two L-thyroxine formulations after oral administration to healthy dogs. Aust Vet J 2013;91:83-88. 
18. Taeymans O, Penninck DG, Peters RM. Comparison between clinical, ultrasound, CT, MRI, and pathology findings in dogs presented for suspected thyroid carcinoma. Vet Radiol Ultrasound 2013;54:61-70. 
19. Taylor BE, Leibman NF, Luong R, et al. Detection of carcinoma micrometastases in bone marrow of dogs and cats using conventional and cell block cytology. Vet Clin Pathol 2013;42:85-91. 
20. Tsuboi M, Uchida K, Ide T, et al. Pathological features of polyneuropathy in three dogs. J Vet Med Sci 2013;75:327-335. 
21. Tvarijonaviciute A, Jaillardon L, Ceron JJ, et al. Effects of thyroxin therapy on different analytes related to obesity and inflammation in dogs with hypothyroidism. Vet J 2013;196:71-75. 
22. Zeugswetter FK, Vogelsinger K, Handl S. Hyperthyroidism in dogs caused by consumption of thyroid-containing head meat. Schweiz Arch Tierheilkd 2013;155:149-152. 

Top Endocrine Publications of 2012: The Feline Thyroid Gland

In my sixth compilation of the canine and feline endocrine publications of 2012, I’m moving on to disorders of the feline thyroid gland.

Listed below are 18 papers published in 2012 that deal with a variety of thyroid gland topics of issues of clinical importance in cats.

These range from an investigation of the antioxidant status of cats with hyperthyroidism (1) to studies of adrenal size and function in hyperthyroidism (4,14); from the role of cadmium in the development of feline hypertension (5) to studies of the role of environmental contaminants (such as the brominated flame retardants) in the development of feline hyperthyroidism (6,9,11-13); and, from the influence of L-carnitine on metabolic function in cats (3) to a study of leptin levels before and after treatment of hyperthyroidism (7).

Other studies included a review of the use of recombinant human TSH in diagnosis and treatment of thyroid disease (2) to an in-depth investigation of calcium and phosphate homeostasis in hyperthyroid cats (17); and from the development of more accurate methods to calculate the thyroid tumor volume in hyperthyroid cats (16) to the role of dietary iodine in thyroid function in normal and hyperthyroid cats (18).

References:

1. Branter E, Drescher N, Padilla M, et al. Antioxidant status in hyperthyroid cats before and after radioiodine treatment. J Vet Intern Med 2012;26:582-588. 
2. Campos M, van Hoek I, Peremans K, et al. Recombinant human thyrotropin in veterinary medicine: current use and future perspectives. J Vet Intern Med 2012;26:853-862. 
3. Center SA, Warner KL, Randolph JF, et al. Influence of dietary supplementation with l-carnitine on metabolic rate, fatty acid oxidation, body condition, and weight loss in overweight cats. Am J Vet Res 2012;73:1002-1015. 
4. Combes A, Vandermeulen E, Duchateau L, et al. Ultrasonographic measurements of adrenal glands in cats with hyperthyroidism. Vet Radiol Ultrasound 2012;53:210-216. 
5. Finch NC, Syme HM, Elliott J. Association of urinary cadmium excretion with feline hypertension. Vet Rec 2012;170:125. 
6. Guo W, Park JS, Wang Y, et al. High polybrominated diphenyl ether levels in California house cats: house dust a primary source? Environ Toxicol Chem 2012;31:301-306.  
7. Jaillardon L, Burger M, Siliart B. Leptin levels in hyperthyroid cats before and after treatment. Vet Rec 2012;170:155. 
8. Menaut P, Connolly DJ, Volk A, et al. Circulating natriuretic peptide concentrations in hyperthyroid cats. J Small Anim Pract 2012;53;673-378. 
9. Mensching DA, Slater M, Scott JW, et al. The feline thyroid gland: a model for endocrine disruption by polybrominated diphenyl ethers (PBDEs)? J Toxicol Environ Health A 2012;75:201-212. 
10. Nelson LL, Coelho JC, Mietelka K, et al. Pharyngeal pouch and cleft remnants in the dog and cat: a case series and review. J Am Anim Hosp Assoc 2012;48:105-112. 
11. Norrgran J, Athanassiadis I, Jones B, et al. Are serum levels of brominated flame retardants and thyroid status correlated in cats? Organohalogen Compd 2012.
12. Norrgran J, Jones B, Lindquist NG, et al. Decabromobiphenyl, polybrominated diphenyl ethers, and brominated phenolic compounds in serum of cats diagnosed with the endocrine disease feline hyperthyroidism. Arch Environ Contam Toxicol 2012;63:161-168. 
13. 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. 
14. Ramspott S, Hartmann K, Sauter-Louis C, et al. Adrenal function in cats with hyperthyroidism. J Feline Med Surg 2012;14:262-266. 
15. Scott-Moncrieff JC. Thyroid disorders in the geriatric veterinary patient. Vet Clin North Am Small Anim Pract 2012;42:707-725.
16. Volckaert V, Vandermeulen E, Saunders JH, et al. Scintigraphic thyroid volume calculation in hyperthyroid cats. J Feline Med Surg 2012;14:889-894. 
17. Williams TL, Elliott J, Syme HM. Calcium and phosphate homeostasis in hyperthyroid cats - associations with development of azotaemia and survival time. J Small Anim Pract 2012;53:561-571. 
18. Zicker S, Schoenherr B. Focus on nutrition: the role of iodine in nutrition and metabolism. Compendium 2012;October:E1-E4.

Top 10 Clinical Endocrinology ACVIM Abstracts, Part 3

Today’s post completes our look at some of the interesting research that was presented at the annual American College of Veterinary Internal Medicine Forum last month in Seattle, Washington.

I'm ending with 4 abstracts on thyroid disease, two of which I'm a coauthor. I apologize in advance for including my own work in this top list, but I'm biased! As always, if you disagree with any of my picks or my reviews, I welcome your comments.

Finally, if you can count, you will realize that I've reviewed 11 abstracts in my last 3 posts, rather than the "Top 10" as my title indicated.  To be honest, I couldn't decide which abstract to exclude from my list and the "Top 10" title sounded better!

Broome MR, Peterson ME. Use of L-thyroxine supplementation after radioiodine therapy helps blunt the worsening of azotemia in hyperthyroid cats with pre-existing kidney disease. J Vet Intern Med 2013;27:685-686.

Hyperthyroidism develops in cats secondary to 1 or more autonomously functional thyroid adenomas. The progressive thyrotoxicosis that ensues causes the chronic suppression of endogenous TSH release and ultimately the atrophy of normal thyroid tissue in these cats. This thyroid atrophy can lead to a period of transient hypothyroidism following curative radioiodine therapy. Once T4 values fall, circulating TSH levels increase, leading to reactivation of the previously suppressed and atrophied thyroid tissue in the large majority of these cats. Between 30-40% of cats with hyperthyroidism have preexisting chronic kidney disease (CKD). Iatrogenic hypothyroidism has been shown to contribute to worsening of azotemia and shortened life expectancy in cats with preexisting CKD (Williams et al, J Vet Intern Med. 2010;24:1086). In hyperthyroid cats with concurrent azotemia, the transient hypothyroidism that follows radioiodine therapy may contribute to additional renal function decline and worsening of the cats’ CKD stage. The purpose of this study was to evaluate if prevention of this transient hypothyroidism would blunt the progression of azotemia commonly seen following the resolution of thyrotoxicosis in these cats with preexisting CKD. In this study, 195 hyperthyroid cats with concurrent CKD (IRIS stage 2 to 3) were treated with radioiodine (range, 1-10 mCi, median, 3 mCi). Of the 195 CKD cats, 85 cats were discharged on L-T4 (0.1 mg, PO q24 h), whereas the remaining 110 cats served as controls (no L-T4 supplementation). In both groups, total T4, BUN, and creatinine levels were recorded before treatment and then again at 1, 3 and 12 months following radioiodine therapy. Following successful radioiodine therapy, both groups of cats with preexisting CKD demonstrated increases in serum BUN and creatinine levels that gradually progressed over the 12-month period (Table 1). However, the percent rise in median creatinine concentrations in the 85 cats treated with L-T4 was significantly less than the rise in the 110 cats not supplemented with L-T4 (12.5% vs 33.3%; P < 0.05). These results suggest that L-T4 supplementation of radioiodine-treated cats with CKD may help limit progression of azotemia, presumably by avoiding the transient hypothyroidism that commonly develops after radioiodine therapy. 

Comments—Untreated hyperthyroidism can lead to the development of chronic kidney disease (CKD) by many mechanisms (1-3). Between 30-40% of cats with hyperthyroidism have pre-existing CKD at time of diagnosis of the thyroid condition (3,4).

Treatment of the hyperthyroid state can worsen azotemia, but this worsening may be related to degree of lowering in circulating T4 and T3 concentrations. Iatrogenic hypothyroidism has been shown to contribute to worsening of azotemia and shorten the life expectancy in cats with pre-existing CKD (5). In hyperthyroid cats with concurrent azotemia, the transient hypothyroidism that follows radioiodine therapy may contribute to additional renal function decline and worsening of the cats’ CKD stage (6).

The Bottom Line— The results of this study suggest that L-T4 supplementation of radioiodine-treated cats with concurrent CKD may help limit progression of azotemia by avoiding the transient hypothyroidism that commonly develops after radioiodine therapy.  In agreement with our feline studies, recent reports also show that thyroid hormone replacement can help attenuates the decline of renal function in CKD patients with subclinical or overt hypothyroidism (7-9).

Further research is in progress, but short-term L-T4 supplementation has become an integral part of the protocol for treating hyperthyroid cats with renal disease at our practice.

References:

1. Basu G, Mohapatra A. Interactions between thyroid disorders and kidney disease. Indian J Endocrinol Metab 2012;16:204-213. 
2. Mariani LH, Berns JS. The renal manifestations of thyroid disease. J Am Soc Nephrol 2012;23:22-26. 
3. Williams TL. Is hyperthyroidism damaging to the feline kidney? PhD thesis, Department of Veterinary Clinical Sciences: Royal Veterinary College,  University of London, 2013.
4. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743.
5. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092. 
6. Peterson ME, Broome MR. Radioiodine for feline hyperthyroidism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013;in press.
7. Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2012;97:2732-2740. 
8. Hataya Y, Igarashi S, Yamashita T, et al. Thyroid hormone replacement therapy for primary hypothyroidism leads to significant improvement of renal function in chronic kidney disease patients. Clin Exp Nephrol 2012. 
9. Shin DH, Lee MJ, Lee HS, et al. Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism. Thyroid  2013;23:654-661. 

Chciuk K, Behrend EN, Martin L, et al. Evaluation of thyroid-stimulating hormone, total thyroxine,and free thyroxine concentrations in 65 hyperthyroid cats receiving methimazole therapy. J Vet Intern Med 2013;27:691-692.

Iatrogenic hypothyroidism following treatment of feline hyperthyroidism can have deleterious effects on renal function. Serum total thyroxine concentration (T4) is commonly used to evaluate therapy, but no study has examined the use of both serum free thyroxine by equilibrium dialysis (FT4ed) and thyroid-stimulating hormone (TSH) concentrations. The purpose of this study was to compare the ability of T4, FT4ed, and TSH concentrations to diagnose treatment-induced hypothyroidism in hyperthyroid cats receiving methimazole. We hypothesized that FT4ed would identify more cats with iatrogenic hypothyroidism as compared to T4. A total of 65 samples from previously-diagnosed hyperthyroid cats receiving methimazole therapy and with T4 concentrations <48 nmol/L were included. Samples had been submitted to the diagnostic laboratories at Auburn University (n = 22) and Michigan State University (n = 43). T4, FT4ed and TSH concentrations were measured via assays previously validated for use in cats. Correlation was tested via a Spearman Rank Order test. Significance was set at the p < 0.05 level. The median (range) T4, FT4ed, and TSH concentrations were 20 (3-48) nmol/L, 20 (3-57) pmol/L, and 0.1 (.08-9.1) ng/ml, respectively. Overall, 23 cats (35%) had an elevated TSH concentration (>0.30 ng/ml). For cats with elevated TSH concentrations, median T4 and FT4ed concentrations were 11 (3-40) nmol/L and 12 (3-35) pmol/L, respectively. Cats with normal TSH concentrations (<0.30 ng/ml) had median T4 and FT4ed concentrations of 23.5 (5-48) nmol/L and 27.0 (6-57) pmol/L, respectively. The percentage of cats with an elevated TSH concentration in combination with a low T4 (<10 nmol/L), FT4ed (<10 pmol/L), or both T4 and FT4ed concentration were 17%, 12% and 11%, respectively. Eleven cats (17%) had an elevated TSH despite normal T4 and FT4ed concentrations. One cat (1.5%) had a normal TSH despite low T4 and FT4ed concentrations. Of 24 cats with T4 concentrations between 10-25 nmol/L (low end of the reference range 10 nmol/L), 7 (29%) had an elevated TSH. Of 26 cats with FT4ed concentrations between 10-25 pmol/L (low end of the reference range 10 pmol/L), 11 (42%) had an elevated TSH. A significant positive correlation was found between T4 and FT4ed concentrations (p < 0.001). A significant negative correlation was found between both T4 and TSH concentrations (p < 0.001) and between FT4ed and TSH concentrations (p < 0.0001). The data suggest that FT4ed does not identify more cats with iatrogenic hypothyroidism as compared to T4. As some cats had an elevated TSH concentration despite having a normal T4 or FT4ed, further investigation may be warranted.

Comments—Iatrogenic hypothyroidism can develop during therapy with antithyroid drugs (1-3), after thyroidectomy (1,3,4), or following radioiodine therapy (1,5-8). Although early reports suggested that clinical signs associated with severe iatrogenic hypothyroidism in cats were uncommon and that most cats did not require treatment, it is now realized that milder degrees of iatrogenic hypothyroidism are relatively common and that these cats may benefit from thyroid replacement therapy (especially if concurrent CKD is present) (3).

Many cats with iatrogenic hypothyroidism will develop high serum TSH concentration as measured by the cTSH assay (1,3,9). In a cat suspected of hypothyroidism, the finding of a high serum TSH value in combination with low serum concentrations of total or free T4 can generally be considered diagnostic for hypothyroidism.

As reported in this study, high serum TSH values are common (over a third) in hyperthyroid cats treated with methimazole. However, 17% of these cats had a high TSH value despite completely normal T4 and free T4 concentrations.

The Bottom Line— As reported in this study, it is not uncommon for high serum TSH to develop in cats treated for hyperthyroidism despite maintenance of completely normal concentrations of T4, free T4, or both (9). This brings up a number of questions that still remain unanswered.

Do these cats really have mild degrees of hypothyroidism? Is this a form of subclincal hypothyroidism, as reported in man (10-11)? Should the methimazole dosage be reduced or should they be treated with levothyroxine despite their normal circulating thyroid hormone values? Or are these serum TSH values falsely high, simply representing a TSH laboratory artifact? At this time, the answers to these questions remain unknown.

References:

1. Graham P. Measurement of feline thyrotropin using a commercial canine-specific immunoradiometric assay. J Vet Intern Med 2000;14:342.
2. Fischetti AJ, Drost WT, DiBartola SP, et al. Effects of methimazole on thyroid gland uptake of 99mTC-pertechnetate in 19 hyperthyroid cats. Vet Radiol Ultrasound 2005;46:267-272.
3. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092.
4. Welches CD, Scavelli TD, Matthieson DT, et al. Occurrence of problems after three techniques of bilateral thyroidectomy in cats. Vet Surg 1989;18:392-396.
5. Meric SM, Rubin SI. Serum thyroxine concentrations following fixed-dose radioactive iodine treatment in hyperthyroid cats: 62 cases (1986-1989). J Am Vet Med Assoc 1990;197:621-623.
6. Jones BR, Cayzer J, Dillon EA, et al. Radio-iodine treatment of hyperthyroid cats. N Z Vet J 1991;39:71-74.
7. Peterson ME, Becker DV. Radioiodine treatment of 524 cats with hyperthyroidism. J Am Vet Med Assoc 1995;207:1422-1430.
8. Nykamp SG, Dykes NL, Zarfoss MK, et al. Association of the risk of development of hypothyroidism after iodine 131 treatment with the pretreatment pattern of sodium pertechnetate Tc-99m uptake in the thyroid gland in cats with hyperthyroidism: 165 cases (1990-2002). J Am Vet Med Assoc 2005;226:1671-1675.
9. Peterson ME. Diagnostic testing for feline thyroid disease: hypothyroidism. Compend 2013; 35: E1-E6.
10. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76-131.
11. Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat and how. Drugs 2012;72:17-33. 

Gallagher B, Mooney CT. Prevalence and risk factors for hyperthyroidism in Irish cats from the greater Dublin area. J Vet Intern Med 2013;27:689.

Hyperthyroidism is a common feline endocrinopathy. However, prevalence varies widely with geographical location. Anecdotal reports suggest this disorder is rare within the Irish feline population. The aim of this study was to document the prevalence of hyperthyroidism in geriatric cats in the greater Dublin area of Ireland and to assess risk factors for development of the disease. Practitioners within the study area were requested to select cats presenting to their clinic aged 10 years or older, in which blood sampling was being performed for geriatric health screening or clinical investigation purposes, independent of suspected thyroid status. Serum samples were submitted to University College Dublin Diagnostic Endocrine Laboratory for total thyroxine (T4) measurement by a chemiluminescent method (Canine Total T4, Immulite 1000, Siemens). Cats were classified as hyperthyroid, equivocal or euthyroid based on a total T4 concentration of > 60 nmol/L, 30–60 nmol/L or <30 nmol/L, respectively. Repeat measurement of total T4 after 4-6 weeks, or free T4 by equilibrium dialysis was recommended in all equivocal cases. Animals receiving treatment for hyperthyroidism were excluded. In order to fulfill the study criteria a questionnaire completed by the client and veterinarian detailing historical and physical information was requested with each submission. Associations between different categorical variables were analysed by Chi- square or Fisher’s exact test. Total T4 concentrations in hyperthyroid animals reported to have palpable or non-palpable goitre were compared using the Mann-Whitney U test. A P-value of < 0.05 was considered statistically significant. A response rate of 77% from 45 targeted practices was achieved. Samples were submitted from 508 cats; 181 male, 238 female and 89 unreported. Thyroid hormone analysis identified 107 (21%) hyperthyroid, 53 (10%) equivocal and 348 (69%) euthyroid cases. Weight loss (P < 0.0001), polyphagia (P < 0.0006) and dyspnoea (P = 0.0370) were significantly associated with a diagnosis of hyperthyroidism. Vomiting or diarrhoea was not (P = 0.684 and P = 0.2758 respectively). Cats with goitre were more likely to be diagnosed as hyperthyroid (odds ratio (OR) = 2.958, 95% CI = 1.778 – 4.920) compared to those without. Tachycardia (P = 0.0018), but not the presence of a cardiac murmur (P = 0.1892) had a significant association with hyperthyroidism. Increasing age was the only significant risk factor (P = 0.0015). A relationship between sex, breed, vaccination status, parasite control, environment or preferred food flavour was not established. There was no significant difference between the total T4 concentration of hyperthyroid cats with or without reportedly palpable goitre (P = 0.3316). Hyperthyroidism is not uncommon in Irish cats. Historical and physical examination findings including weight loss, polyphagia, dyspnoea, goitre and tachycardia are significantly associated with hyperthyroidism. Surprisingly age was the only recognised risk factor for the development of the disease. The identified but unexplained inability of the study practitioners to palpate goitre in hyperthyroid animals over a range of total T4 concentrations may explain the previously perceived low prevalence of this condition in Ireland.

Comments—In this study, a large population of Irish geriatric cats were screened for hyperthyroidism. Although it has been thought that feline hyperthyroidism was a rare condition in Ireland (1), this study found that that 107 (21%) of the 508 screened cats were definitely hyperthyroid and another 52 cats (10%) were borderline hyperthyroid.

The Bottom Line— Hyperthyroidism is an extremely common condition in older cats, occurring in about 10% of cats older than 9 years of age (1-3).  Even in a country, such as Ireland, where hyperthyroidism has traditionally been considered to be a rare condition, this study proves that this is not the case.

Since all hyperthyroid cats develop a thyroid tumor as part of their disease, thyroid palpation should be incorporated into the routine physical examination for all cats, especially for geriatric cats (2,4). Even if a thyroid nodule cannot be palpated, annual thyroid screening is recommended for all cats older than 10-years of age to help in earlier detection of this condition.

References:

1. Caney S. Advances in our understanding of feline hyperthyroidism. Vet Ireland J 2012;2:450-454.
2. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
3. 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. 
4. Peterson ME. Diagnostic testing for hyperthyroidism in cats: more than just T4. J Fel Med Surg 2013: in press. 

Broome MR, Peterson ME. Ectopic sublingual thyroid neoplasia in the dog: 25 cases (1995-2012). J Vet Intern Med 2013;27:685-686. 

Thyroid embryology defines the normal migration of thyroid tissue from its origin as an epithelial proliferation in the floor of the pharynx at the base of the tongue (ie, the foramen caecum) along the path of the thyroglossal tract. The embryologic path of the thyroid gland includes the tongue and hyoid apparatus. Failure to associate fully with the embryologic aortic sac leads to the incomplete descent of the thyroid and the presence of sublingual ectopic thyroid tissue. Ectopic thyroid tissue in this location can occasionally become neoplastic. Two previous reports describe a total of 9 cases of sublingual thyroid carcinoma in dogs (JAVMA 1989;195:1606; ASVS Veterinary Symposium 2011;217). No reports of benign thyroid neoplasia developing in this location have been identified. Medical records reviewed between 1995-2012 revealed 519 dogs with thyroid carcinoma, confirmed by thyroid scintigraphy. During that period, 25 dogs with ectopic sublingual thyroid neoplasia were identified (5% of all thyroid carcinoma cases). The dogs ranged in age from 4-15 years (median, 9 yrs), with 13 neutered males and 12 spayed females. Breeds included mix (6 dogs), Golden Retriever (4), American Staffordshire Terrier (2), and Labrador Retrievers (2). Eight dogs (32%) had high serum T4 levels, consistent with hyperthyroidism. Twelve dogs had normal total T4 levels, 4 dogs had low values, and 1 dog’s T4 value was not available. Four dogs had pulmonary metastases confirmed by scintigraphy and 4 had concurrent cervical disease, and 1 dog had both concurrent cervical disease and pulmonary metastasis. Seventeen dogs had histopathologic confirmation and 7 dogs had cytologic confirmation of thyroid malignancy. Fourteen dogs were treated with surgery; of these, 9 had excision of the basihyoid bone. All tolerated surgical intervention, including hyoid bone resection. Gross surgical excision of thyroid disease was confirmed scintigraphically in 7 dogs, 5 of which required hyoid bone resection. Thirteen dogs were treated with high-dose radioiodine (dose range, 40-130 mCi; mean, 95 mCi). No lasting complications following radioiodine were identified. Radioiodine therapy resulted in a marked response, as measured by percent decreased radionuclide uptake (range 42-100%, mean, 80%) in 8 dogs with gross disease. Radioiodine was also successful in ablating normal thyroid tissue in 3 dogs without persistent gross disease. Nine dogs were treated with both surgery and radioiodine. Surgery was performed prior to radioiodine therapy in all 9 dogs. One dog with a thyroid tumor deemed initially surgically unresectable had a successful surgical excision following radioiodine therapy. Conclusions: In dogs, ectopic sublingual thyroid carcinoma is not uncommon. Surgical excision of the basihyoid bone is often indicated for gross resection of laryngeal thyroid carcinoma and is well tolerated. Adjunctive high dose radioiodine therapy is indicated for cases of incomplete surgical excision of local disease or when metastatic disease is confirmed scintigraphically.

 Comments—Numerous cases of ectopic cranial mediastinal and heart base thyroid carcinomas in the dog have been reported (1-3). Ectopic thyroid tissue higher up in the sublingual area is also not rare, and this tissue may also become neoplastic. Until this report, however, only 9 cases of sublingual thyroid carcinoma have been reported in the dog (4,5).

The Bottom Line— In dogs, ectopic sublingual thyroid carcinoma is not uncommon, diagnosed at a rate of 5% of all thyroid carcinomas in our practice. These results reveal that partial surgical excision of the hyoid apparatus is generally indicated for gross resection of sublingual thyroid carcinoma, which is well tolerated.

High dose radioiodine therapy may be helpful in treating those dogs with overt hyperthyroidism (about 30% of the dogs of this report were hyperthyroid.cases).  Adjunctive high dose radioiodine or chemotherapy therapy may also be useful with incomplete surgical excision and/or with metastatic or multicentric disease.

References:

1. Birchard SJ, Roesel OF. Neoplasia of the thyroid gland in the dog—a retrospective study of 16 cases. J Am Anim Hosp Assoc 1981;17:369–372. 
2. Liptak JM, Kamstock DA, Dernell WS, et al. Cranial mediastinal carcinomas in nine dogs. Vet Comp Oncol 2008;6:19-30.  
3. Stassen QE, Voorhout G, Teske E, et al. Hyperthyroidism due to an intrathoracic tumour in a dog with test results suggesting hyperadrenocorticism. J Small Anim Pract 2007;48:283-287. 
4. Donner G.S. Common head/neck tumors in uncommon locations —hyoid apparatus, nasal septum. In: Conference Proceedings American College of Veterinary Surgeons. Chicago, Ill, 2011;217-220.
5. Lantz GC, Salisbury SK. Surgical excision of ectopic thyroid carcinoma involving the base of the tongue in dogs: three cases (1980-1987). J Am Vet Med Assoc 1989;195:1606-1608.