Methimazole Treatment of Canine Hyperthyroidism

My patient is a 13-year old spayed female Golden retriever that presented with history of progressive polydispia, polyuria, panting, and weight loss despite a good appetite. On my physical examination, I palpated a freely-movable right cervical mass (2-3 inch in diameter) in the area of the thyroid gland. I aspirated the mass, and the results of thyroid cytology were consistent with carcinoma of thyroid origin.

Chest radiographs were clear, with no metastasis detected. Routine blood testing (CBC and serum chemistry panel) was normal except for a slightly high serum alkaline phosphatase (281 U/L; reference interval, 20-120 IU/L).

Results of a serum thyroid panel showed a high total T4 concentration (6.5 µg/dl; normal, 1-4 µg/dl), a high free T4 by dialysis (75 pmol/L; normal, 10-50 pmol/L), and suppressed cTSH value (less than 0.03 ng/ml).

I advised a thyroid biopsy and thyroidectomy, but owner is reluctant to do because of the expense and dog’s older age. If this dog is hyperthyroid, what is the treatment of choice? Do I have any medical options to control the signs? Can I use methimazole to lower the high serum T4 and free T4 values?

My Response:

I agree that this dog likely has a hyperfunctioning thyroid tumor, based on the clinical features, high T4 and free T4, suppressed TSH concentration, and results of the thyroid cytology (1-4). As in cats (5), high serum alkaline phosphatase activity is also seen in some dogs with hyperthyroidism, so that finding too goes along with the diagnosis.

Most dogs with hyperfunctioning thyroid tumors have thyroid carcinoma. In general, these thyroid carcinomas are quite malignant in dogs and pulmonary metastasis in not uncommon (1-4).

Methimazole can be used to control the hyperthyroidism but this will not stop tumor growth, local invasion, or metastasis. Radioiodine, surgery followed by chemotherapy, or local external radiation are all options (1-4). In this dog, radioiodine might be ideal because the tumor would likely concentrate the injected radioiodine very nicely; it may result in cure, even if we have undetected metastasis (6).

If methimazole is used, I'd start with 5 mg twice daily, in a dog of this size. You should adjust the dose as needed, monitoring serum T4 concentrations as you would in a hyperthyroid cat. Again, without definitive treatment, this dog’s thyroid tumor will likely metastasize and eventually lead to the dog's death.

References:

1. Rijnberk A. Hyperthyroidism in the dog and its treatment with radioactive iodide. Tijdschr Diergeneeskd 1966;91:789-794.
2. Rijnberk A, der Kinderen PJ. Toxic thyroid carcinoma in the dog. Acta Endocrinological 1969;Supplement 138:177.
3. Peterson ME, Kintzer PP, Hurley JR, et al. Radioactive iodine treatment of a functional thyroid carcinoma producing hyperthyroidism in a dog. J Vet Intern Med 1989;3:20-25. 
4. 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.
5. Berent AC, Drobatz KJ, Ziemer L, et al. Liver function incats with hyperthyroidism before and after 131I therapy. J Vet Intern Med 2007;21:1217-1223. 
6. Turrel JM, McEntee MC, Burke BP, et al. Sodium iodide I 131 treatment of dogs with nonresectable thyroid tumors: 39cases (1990-2003). J Am Vet Med Assoc 2006;229:542-548. 

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 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. 

How to Best Manage Non-functional Thyroid Tumors in Cats

I have a 3½ year old castrated male DLH that was found to have a 1-cm mass in the region of the left thyroid gland on a wellness exam 10 months ago. The owner declined cytology at that time, and on followup last week the mass has now grown to ~2-cm (22mm) in size. This is an incidental finding on physical exam, and the cat is maintaining his weight and otherwise seems normal at home. The body condition score, muscle condition score, and heart rate are all normal in this cat.

Routine lab work, including a CBC, serum chemistry profile, and urinalysis were all normal. Results of a serum concentrations of total T4 (2.5 µg/dl; normal, 0.8-4.0 µg/dl) and free T4 (26 pmol/L; normal, 10-50 pmol/L) were also well within reference range limits. The results of my aspiration cytology of the mass is as follows:

• The slides are of moderate to high cellularity containing scattered clusters of epithelial cells in a background of peripheral blood and scattered bare round nuclei. The epithelial cells display round to oval nuclei with a moderate amount of encircling, indistinct, pale basophilic cytoplasm. These cells display mild anisocytosis and anisokaryosis. No infectious organisms are observed. 
• This is an epithelial cell tumor and cytologically it appears to be benign. This is likely a thyroid gland tumor; if so, the majority of thyroid tumors in cats are benign adenomas. Rarely, thyroid carcinomas occur in cats and are very difficult to distinguish from adenomas cytologically. Histopathology is required to specifically identify the origin of these epithelial cells. It should be emphasized that other epithelial cell tumors other than thyroid tumors in this area have similar cytologic appearance.

I spoke with a consultant at the lab, who recommended just monitoring the mass rather than surgical removal, as it appears to be benign. The owner doesn't want surgery unless the mass is likely to cause the cat problems in the future. 

Is it reasonable to just monitor the cat rather than treat? I've heard about enormous thyroid masses that can become cystic and develop into thyroid carcinoma so I don't want that to happen. While we can certainly monitor for growth and deal with the mass if it gets larger, I'd like to remove it now if it's pretty much guaranteed to continue to grow and has potential to cause issues in the future.

Thanks for your advice!

My Response:

First of all, as the pathologist indicates, we can not make a definitive diagnosis of thyroid adenoma based on cytology alone. If this is thyroid adenoma, the tumor will likely continue to grow with time (1,2), as you have already seen in this case. It's also possible for an adenoma to become cystic (3), which can make treatment much more complicated.

Finally, in addition to tumor growth, it is also possible to see transformation from thyroid adenoma into carcinoma with time (2,4,5). Based on my studies, this would most likely occur in cats with long-standing hyperthyroidism treated with methimazole (longer than 3-4 years) (5). Since this cat is so young, he certainly has a long time to develop thyroid tumor growth and hyperthyroidism.

That all said, not all cats with a thyroid mass will become hyperthyroid (6-8), and not all of these thyroid tumors will continue to grow rapidly, become cystic, or transform into a malignancy. However, if this was my cat, I would certainly like to know if the mass is a thyroid adenoma or another type of tumor. In this cat, that should be the first step in managing this cat — we need to know what it is before we can recommend the "best" treatment.

Is the cervical mass of thyroid origin?
If the owner doesn't want to do surgery to remove the mass and submit the tissue for histopathology (the gold standard means of confirming the diagnosis), then the next best test to determine if the mass is of thyroid origin would be thyroid scintigraphy (9-11).

Figure 1: Thyroid scintigraphy in a normal cat

On a normal thyroid scan, only the 2 normal thyroid lobes, salivary glands, and stomach take up the injected radionuclide (see Figure 1). Therefore, if this is not a thyroid tumor (but another type of tumor), it will not be seen on the thyroid scan.

It is also possible that we could have a nonfunctional thyroid tumor that would fail to have any thyroid uptake, but these are very rare, especially in cats. If that were the case, we would only see a single thyroid lobe on the scan— not the 2 normal thyroid lobes, as shown in Figure 1.

Figure 2: Thyroid scintigraphy in a cat with a right thyroid adenoma. 

So the bottom line is this: if the mass takes up radionuclide on thyroid scan (Figure 2), then we know it's a thyroid tumor (most likely an adenoma). If we see two normal thyroid lobes and the mass doesn't take up any of the radionuclide (Figure 1), then the tumor is not of thyroid origin and must be surgically removed to get the answer.

Radioiodine treatment of non-function thyroid tumors
If the thyroid scan does confirm thyroid tumor, and it displays normal to enhanced radionuclide uptake (Figure 2), then the tumor could be treated with radioiodine, even if the cat was not hyperthyroid.

However, if the normal thyroid lobe also takes up some of the injected radionuclide, we may want to consider suppressing the normal thyroid lobe by giving exogenous L-thyroxine for a week or two to shut off pituitary TSH secretion (12). In these cats, I like to repeat the thyroid scan after administration of L-T4 to ensure that the normal lobe no longer takes up the radionuclide. If it does, that means that it will likely take up the administered I-131 and the cat will become hypothyroid.

No treatment with periodic monitoring
Now if the owner does not want to do a thyroid scan (or scintigraphy is not available in your area) and surgical removal is still out, then you have no other option other than to monitor thyroid hormone values and tumor size.

If the mass continues to grow, then surgical or radiation treatment should be strongly considered. If the cat develops hyperthyroidism at some time in the future, then medical treatment could also be considered. However, in such a young cat, I'd still recommend definitive treatment. Who would want to give methimazole to a young cat for up to 15 years or even longer, especially when we know that the thyroid tumor will continue to growth larger over time?

References:

1. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
2. 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. 
3. Hofmeister E, Kippenes H, Mealey KL, et al. Functional cystic thyroid adenoma in a cat. J Am Vet Med Assoc 2001;219:190-193. 
4. Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. J Feline Med Surg 2009;11:116-124. 
5. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. J Vet Intern Med 2012;26:1523. 
6. Norsworthy GD, Adams VJ, McElhaney MR, et al. Palpable thyroid and parathyroid nodules in asymptomatic cats. J Feline Med Surg 2002;4:145-151. 
7. Ferguson D, Freeman R. Goiter in apparently euthyroid cats In: August JR, ed. Consultations in Feline Internal Medicine. St. Louis: Elsevier Saunders, 2006.
8. Boretti FS, Sieber-Ruckstuhl NS, Gerber B, et al. Thyroid enlargement and its relationship to clinicopathological parameters and T4 status in suspected hyperthyroid cats. J Feline Med Surg 2009;11:286-292. 
9. Daniel GB, Brawnier WR. Thyroid scintigraphy In: Daniel GB, Berry CR, eds. Textbook of Veterinary Nuclear Medicine. 2nd ed. Harrisburg, PA: American College of Veterinary Radiology, 2006;181-199.
10. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. J Vet Intern Med 2012;26:754.
11. Feeney DA, Anderson KL. Nuclear imaging and radiation therapy in canine and feline thyroid disease. Vet Clin North Am Small Anim Pract 2007;37:799-821, viii. 
12. Szumowski P, Rogowski F, Abdelrazek S, et al. Iodine isotope 131-I therapy for toxic nodular goitre: treatment efficacy parameters. Nucl Med Rev Cent East Eur 2012;15:7-13. 

Cystic Thyroid Carcinoma in a Hyperthyroid Cat

Hyperthyroid cat with cystic thyroid tumor

My patient is a difficult hyperthyroid cat with a huge cystic thyroid mass, and I need your advice about how to best treat this cat.  This is a 14-year-old, F/S DSH that has been treated for 2 years with methimazole (5-7.5 mg per day). About 6 months ago, the referring veterinarian noticed that the cat had developed a small cystic thyroid mass in the mid-cervical region, but this cystic tumor has continued to rapidly expand and now extends from the mandible to below the thoracic inlet (Figure 1).

Figure 1: Large Cystic Thyroid Mass

The thyroid mass is easy to palpate, with one large right-sided mass palpable just caudal to the mandible (approximately 2 cm x 1 cm x 1cm) and a second, very extensive irregular mass extending from the larynx to the thoracic inlet (approximately 7 cm x 6 cm x 2 cm) (Figure 1). The cystic thyroid mass is soft and fluctuant in some regions.

Surgical resection was attempted but unsuccessful. Biopsy of the mass identified thyroid adenoma/adenomatous hyperplasia. However, a pulmonary nodule was also identified on a chest film so thyroid carcinoma is still suspected, especially given the large size of the mass.

Since surgery, the cat has continued to lose weight and has now developed a poor appetite. The cystic fluid continues to accumulate within the thyroid mass, and the cat has experienced  2 episodes of severe dyspnea and now has developed mild right-sided Horner's syndrome. The dyspnea was relieved by drainage of some of the cyst fluid. The cystic fluid was somewhat hemorrhagic (Figure 2), and the cat is now slightly anemic.

Figure 2: Cystic fluid removed
from thyroid mass

Routine blood work revealed mild azotemia, dilute urine specific gravity (1.018), and mild non-regenerative anemia (PCV, 23.6%). Cardiac and abdominal ultrasonography was noncontributory. The systolic blood pressure was normal at 140 mmHg.

The cat has been referred to me for radioiodine therapy to treat the cat's large cystic mass and poorly-controlled hyperthyroid state, and to determine whether any other causes could explain or be contributing to her weight loss and poor appetite.

My problem list for this cat includes the following:

• Hyperthyroidism
• Huge cystic thyroid tumor
• Secondary dyspnea and Horner's syndrome due to the compressive effects of the cystic mass
• Chronic kidney disease (IRIS Stage 2)  
• Mild poorly-regenerative anaemia
• Pulmonary nodule (my differentials include a thyroid metastatic lesion, primary pulmonary tumor, or metastatic lesion from an unrelated tumor).

Although the thyroid biopsy was read out as thyroid adenoma, the behavior of this cat's thyroid tumor is more suggestive of carcinoma.  Therefore, I am planning to treat her as a thyroid carcinoma with high-dose (30 mCi) radioiodine next week. I know that I'll have to drain the cystic fluid just prior to her I-131 treatment to minimize the respiratory complications. I plan to maintain her methimazole during treatment given the duration of her disease and size of the tumor.

Do you agree with my treatment protocol? Do these large cystic masses respond to treatment with radioiodine or do they behave differently? What is your experience with this sort of tumor?

This is the largest (hypersecretory) thyroid mass I have seen, and the owners are very realistic about the guarded prognosis and possible complications of treatment. But we really have nowhere else to go other than radioiodine (she was referred to me by a surgeon!).

My Response:

In cats with long-term hyperthyroidism, the development of cystic thyroid masses are not uncommon (1,2). Most of these cysts never become extremely large and the cats remain asymptomatic (i.e., no signs related to the compressive effects of the cystic tumor).

Cystic thyroid nodules have been associated with thyroid carcinoma in dogs, as well as thyroid adenomas or carcinomas in cats (1-5). It is also possible for cats to develop a nonfunctional cystic thyroid adenoma (6-9).

This cat will indeed be a challenge to manage and successfully cure. Here are my thoughts and responses to your questions:

Huge cystic mass extending from her mandible into mediastinum with a solitary pulmonary nodule
Many cats with advanced or chronic hyperthyroidism will develop a large thyroid tumor that can fall through the thoracic inlet into the anterior mediastinal area (10). Similarly, when cats develop thyroid carcinoma, local invasion of tumor tissue into the cranial thoracic area is very common. However, metastasis as a solitary pulmonary nodule would be very rare with thyroid carcinoma.

Therefore, if the pulmonary nodule in this cat is located in the lateral and/or caudal lung lobes, I would say that thyroid metastasis is quite unlikely.

Does the surgical biopsy rule out thyroid carcinoma in this cat?
Confirming thyroid carcinoma in some cats can be difficult. In one study of 8 cats with thyroid carcinoma (5), 2 cases had mixed adenomatous and carcinoma lesions on the same tissue section of their thyroid biopsies. This suggests that carcinoma can arise from a background of benign thyroid neoplasia, at least in some cats.

Therefore, the pathologic finding of thyroid adenoma (adenomatous hyperplasia) can never totally exclude concurrent carcinomatous tissue in a hyperthyroid cat.

The suggestion that thyroid adenoma can transform to thyroid carcinoma makes some sense, since most cats with carcinoma have severe, long-standing hyperthyroidism associated with a large tumor volume (10).  Given that this cat has a huge goiter and has been hyperthyroid for over 2 years, that would make thyroid carcinoma more likely. In any case, given that the thyroid cyst is so large in this cat, very large doses of 131-I would be required to destroy the tumor tissue, even if the cystic thyroid tumor is benign.

Draining the cystic fluid from the thyroid tumor
Of course, you must drain the cystic fluid in order to minimize and relieve the cat's dyspnea. But after you treat with I-131, you need to be prepared to do this in an ongoing fashion during the cats hospitalization.

In other words, the radioiodine will not have immediate effects and the cystic fluid will likely continue to accumulate for at least a few weeks after treatment.

Tumor behavior in hyperthyroid cats with large cystic masses
In this cat, I would expect a fair to good response after radioiodine treatment, with resolution of the hyperthyroidism and a marked decrease in size of the thyroid mass.

However, I have had a number of cats with large cystic masses ultimately require surgical resection to prevent recurrence of cystic fluid following cure of their hyperthyroidism (and return to euthyroid state). In these cats, the cystic fluid continues to accumulate, despite a decrease in the size of the adenomatous mass.

Many of these cystic masses which are deemed "unresectable" before radioiodine treatment will become much easier to remove with surgery after treatment.  Use of radioiodine renders the cyst relatively avascular, thereby making this surgical procedure much more successful.

References:

1. Hofmeister E, Kippenes H, Mealey KL, et al. Functional cystic thyroid adenoma in a cat. J Am Vet Med Assoc 2001;219:190-193. 
2. Phillips DE, Radlinsky MG, Fischer JR, et al. Cystic thyroid and parathyroid lesions in cats. J Am Anim Hosp Assoc 2003;39:349-354. 
3. Wisner ER, Nyland TG. Ultrasonography of the thyroid and parathyroid glands. Vet Clin North Am Small Anim Pract 1998;28:973-991. 
4. Turrel JM, Feldman EC, Nelson RW, et al. Thyroid carcinoma causing hyperthyroidism in cats: 14 cases (1981-1986). J Am Vet Med Assoc 1988;193:359-364. 
5. Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. J Feline Med Surg 2009;11:116-124. 
6. Liptak JM. Unilateral extracapsular thyroidectomy for a non-functional cystic thyroid adenoma. Aust Vet Practit 1996;26:174-177. 
7. Lynn A, Dockins JM, Kuehn NF, et al. Caudal mediastinal thyroglossal duct cyst in a cat. J Small Anim Pract 2009;50:147-150. 
8. Reed TP, Brisson BA, Schutt LK. Cystic ectopic lingual thyroid tissue in a male cat. J Am Vet Med Assoc 2011;239:981-984. 
9. 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. 
10.  Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. Congress Proceedings, 22nd ECVIM-CA Congress (The European College of Veterinary Internal Medicine – Companion Animals) 2012;224.

Radioiodine-Induced Bone Marrow Suppression in Dogs and Cats

In our feline practice, we have have a radioiodine facility and have been treating hyperthyroid cats for a few years. One of my colleagues recently told me that myelosuppression can occur following radiodine treatment. I have never appreciated this in the cats I've treated, nor have I seen it reported. However, it has apparently been reported in dogs treated with very large doses of radioiodine for thyroid carcinoma (1,2).

I'd appreciate your thoughts on this topic. Do you ever see radioiodine-bone marrow suppression in your cats?

My Response:

After administration of radioiodine to a patient (human, dog or cat) with hyperthyroidism, the thyroid gland receives the highest radiation dose because it actively takes up and concentrates the I-131 (3). Other tissues, such as the salivary glands, stomach wall, and bladder also receive a radiation dose higher than that of the total body since these organs will also concentrate iodine. However, the radioiodine uptake in these tissues is much less than that of the thyroid.  The other body organs (such as the bone marrow) will receive a "cross-fire" dose — i.e., radioactivity from photons emitted from the thyroid and, to a much lesser degree, from the salivary glands and stomach  (Fig. 1) (3,4).

Figure 1: Most of the administered dose of I-131 concentrates in the thyroid, but other nearby tissues will receive a much smaller "cross-fire" dose from the gamma radioactivity (photons) emitted from the thyroid tumor.

In general, radiation doses received by the organs that do not normally concentrate iodine, including the bone marrow, are very small; however, the radiation dose delivered to the marrow may be clinically significant if a large enough radioiodine dose was administered to the patient. For example, human patients with Graves' disease or toxic nodular goiter treated with routine doses of radioiodine (e.g., 15 mCi) will not develop myelosuppression (5).

However, patients with thyroid carcinoma are generally treated with very high doses (e.g., 150 mCi to 1000 mCi of 131-I). In this subgroup of patients, severe leukopenia and thrombocytopenia are well-recognized potential adverse effects of high-dose radioiodine administration (6-8).

Dogs with thyroid carcinoma
In dogs with thyroid carcinoma treated with high-doses of radioiodine, bone marrow suppression can develop (1,2,9). Transient hematologic abnormalities (e.g., leukopenia and thrombocytopenia) are most common, but severe and permanent radioiodine-associated myelosuppression has also been reported (1).

Almost all dogs that develop bone marrow suppression have been treated with doses greater than 4 mCi/kg body weight, so it has been recommended not to exceed that dose limit, if possible (1). A higher incidence of bone marrow suppression is also seen in dogs retreated with high-dose radioiodine therapy, so the cumulative 131-I dose may also be an important factor in bone marrow suppression.  In any case, careful and close monitoring is recommended for all dogs treated with high-dose radioiodine.

Cats with hyperthyroidism and thyroid carcinoma
In contrast to dogs, I have never seen a hyperthyroid cat treated with radioiodine develop bone marrow suppression. That's true even in cats with thyroid carcinoma that are treated with 131-I doses as high as 30 to 40 mCi (10-12), which represents a dose range of approximately 5 to 10 mCi/kg on a body weight basis.

For some reason, the feline bone marrow appears to be more resistant to the radiation effects than is the canine marrow. However, this may simply relate to the fact that hyperthyroid cats tend to be much more severely affected than are the dogs with thyroid carcinoma. Therefore, most feline thyroid tumors will take up and concentrate much more of the administered 131-I dose than do canine thyroid tumors (10-15); as more of the administered dose is delivered to the thyroid, this leaves less circulating activity that will be delivered to the rest of the body, including the bone marrow.

References:

1. Turrel JM, McEntee MC, Burke BP, et al. Sodium iodide I-131 treatment of dogs with nonresectable thyroid tumors: 39 cases (1990-2003). J Am Vet Med Assoc 2006;229:542-548. 
2. Adams WH, Walker MA, Danie lGB, et al. Treatment of differentiated thyroid carcinoma in 7 dogs utilizing 131-I. Vet Radiol Ultrasound 1995;36:417-424.
3. Wyszomirska A. Iodine-131 for therapy of thyroid diseases. Physical and biological basis. Nucl Med Rev Cent East Eur 2012;15:120-123. 
4. Lamart S, Bouville A, Simon SL, et al. Comparison of internal dosimetry factors for three classes of adult computational phantoms with emphasis on I-131 in the thyroid. Phys Med Biol 2011;56:7317-7335. 
5. Silberstein EB, Alavi A, Balon HR, et al. The SNMMI practice guideline for therapy of thyroid disease with 131-I 3.0. J Nucl Med 2012;53:1633-1651. 
6. Alexander C, Bader JB, Schaefer A, et al. Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med 1998;39:1551-1554. 
7. de Keizer B, Hoekstra A, Konijnenberg MW, et al. Bone marrow dosimetry and safety of high 131-I activities given after recombinant human thyroid-stimulating hormone to treat metastatic differentiated thyroid cancer. J Nucl Med 2004;45:1549-1554. 
8. Robbins RJ, Schlumberger MJ. The evolving role of 131-I for the treatment of differentiated thyroid carcinoma. J Nucl Med 2005;46 Suppl 1:28S-37S. 
9. Peterson ME, Kintzer PP, Hurley JR, et al. Radioactive iodine treatment of a functional thyroid carcinoma producing hyperthyroidism in a dog. J Vet Intern Med 1989;3:20-25. 
10. Turrel JM, Feldman EC, Nelson RW, et al. Thyroid carcinoma causing hyperthyroidism in cats: 14 cases (1981-1986). J Am Vet Med Assoc 1988;193:359-364. 
11. Peterson ME, Becker DV. Radioiodine treatment of 524 cats with hyperthyroidism. J Am Vet Med Assoc 1995;207:1422-1428. 
12. Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. J Feline Med Surg 2009;11:116-124. 
13. Rijnberk A. Hyperthyroidism in the dog and its treatment with radioactive iodide. Tijdschrift voor diergeneeskunde 1966;91:789-794.
14. Rijnberk A. Thyroid tumors and hyperthyroidism in dogs. In: Clinical Endocrinology of Dogs and Cats. Dordrecht/Boston:Kluwer Academic Publishers, 1996;55-59.
15. 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.

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. 

Surgical Thyroidectomy: A Useful Treatment Option for Dogs with Thyroid Carcinoma?

Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994–2010)

Joanne L. Tuohy, Deanna R. Worley, and Stephen J. Withrow

Journal of the American Veterinary Medical Association 2012;241:95–103

Tumors of the thyroid gland are the most common endocrine neoplasm of the dog. Thyroid carcinomas, while responsible for approximately 50–70% of all thyroid tumors diagnosed at postmortem examination, account for up to 90% of thyroid tumors detected during life (1-3). Therefore, all thyroid masses detected upon physical examination must be presumed to malignant until proven otherwise.

In dogs suffering from thyroid carcinoma, the likelihood for metastasis is high, with up to 38% of dogs having gross metastatic disease at the time of initial evaluation (4,5). The most common site for metastasis is the lungs, with other sites being the regional lymph nodes, jugular veins, and heart (1-3). Tumor size appears to be predictive of metastasis; in 1 study, dogs with tumor volumes < 21 cubic cm had a significantly lower risk of metastasis (2). The finding of vascular invasion by neoplastic cells is also suggestive of potential metastasis (5). Bilateral thyroid tumors are typically larger than unilateral tumors. In accord with that, one study reported that bilateral tumors were 16 times more likely to metastasize than unilateral thyroid tumors (6).

Treatment options for canine thyroid carcinoma include surgical resection, external radiation therapy, radioiodine therapy, and chemotherapy (7). The choice of treatment for a particular dog with a thyroid gland tumor depends on tumor size, vascularity, and invasiveness; whether the tumor is fixed or mobile upon palpation; and most importantly, whether gross metastatic disease is present (7-10). External beam radiation and radioiodine treatment are indicated for dogs deemed to have nonresectable tumors, such as fixed, deeply invasive, or bilateral tumors (3,6,7,11-14). Metastatic disease can be potentially treated with radioiodine or chemotherapy (7,15-18). Surgical thyroidectomy can be considered in thyroid tumors that are not large or invasive, with no evidence of metastasis (8-10).

To date, however, there are no published guidelines for surgical management of dogs with freely movable thyroid gland tumors. The purpose of the study reported by Tuohy et al (10) was to evaluate the outcome of resection of simultaneous discrete bilateral mobile thyroid gland carcinomas in dogs.  The hypothesis of this study was that dogs with bilateral, mobile thyroid gland carcinoma would be amenable to a single bilateral thyroidectomy procedure, even when parathyroid glandular tissue was not preserved and hypoparathyroidism would be likely. A second hypothesis of this study was that bilateral tumor development does not always necessitate a need for adjuvant chemotherapy in order to obtain prolonged survival.

Objective of this study—To evaluate the outcome of resection of simultaneous discrete bilateral mobile thyroid gland carcinomas in dogs.

Design— Retrospective case series.

Animals— 15 dogs with resected simultaneous discrete bilateral mobile thyroid gland carcinomas. The dogs ranged in age from 7.6 to 11.9 years, with 10 breeds affected.  Seven of the dogs were females, and 8 were castrated males.

Procedures— Medical records (from 1994-2010) were searched for dogs with the appropriate diagnosis and treatment. Information collected included signalment, clinical signs, diagnostic test results, tumor mobility (mobile tumor identified by movement ≥ 1 cm in all planes during palpation), complications, adjuvant treatments, and outcome.

Results— Prior to surgery, serum thyroxine (T4) concentrations were assessed in 10 of the 15 dogs. Four dogs had low serum T4 concentrations (<1.0 μg/dL), and 2 dogs had high serum T4 concentrations (7.4 and 4.5 μg/dL); these dogs had no associated clinical signs. Four dogs were euthyroid (2.0 and 1.6 μg/dL). None of the dogs were treated with supplemental L-T4 prior to thyroidectomy.

Preoperatively, 6 dogs underwent ultrasound examination of the cervical region, 2 had thyroid scintigraphy, and 3 had computed tomographic (CT) scans.

Mobile, discrete, bilateral thyroid gland carcinomas were removed in all dogs. Among the 15 dogs, complete parathyroidectomies were necessary in 9; parathyroid tissue was reimplanted in 4 and preserved in 2. Complications included hemorrhage and laryngeal nerve trauma, but without serious consequences. Thirteen dogs received calcitriol with or without supplemental calcium after surgery.

In the immediate postoperative period, hypocalcemia developed and was corrected in 11 dogs. At the last study followup, 7 dogs continued to receive calcitriol with or without supplemental calcium, and 8 dogs required long-term thyroid hormone treatment.

Serum total T4 concentrations, as assessed at the end of the immediate postoperative period, were low in 4 dogs, within reference range in 4 dogs, and slightly high in 2 dogs. Serum total T4 concentrations in 5 dogs were not determined. Eleven dogs received thyroid hormone treatment (ie, L-T4) whereas 3 dogs did not.

Six dogs received adjuvant chemotherapy. Local tumor recurrence or de novo distant metastasis was not detected at each dog’s last follow-up examination. Median survival time was 38.3 months. Three dogs were lost to follow-up, 8 survived (4.3 to 77 months after surgery), and 4 died of unrelated causes.

Thyroid hormone replacement therapy had a significant effect on overall survival time; median survival time was 38.3 months among  the 11 dogs that received L-T4 and 17.5 months among 3 dogs that did not receive L-T4 (Figure 1). Otherwise, there were no significant effects of chemotherapy or administration of supplemental calcitriol or calcium among the dogs.

Figure 1: Survival curve for dogs that were given L-T4 supplementation (dashed line; n = 11) and dogs that were not given L-T4 following surgery (solid line; 4)

Conclusions and Clinical Relevance— In dogs with thyroid gland carcinomas undergoing bilateral thyroid lobectomies, a successful outcome can be expected, even when parathyroid gland tissue cannot be preserved. The role of adjuvant chemotherapy in treatment outcome was not clearly defined.

My Bottom Line

This study by Tuohy et al (19) suggests that surgical resection is a viable treatment option for dogs with bilateral mobile thyroid gland carcinoma and that a good prognosis can be expected. Thyroid tumor mobility was the most important criterion for determining feasibility of successful resection in these dogs. The size of these tumors did not impact resection or patient survival, nor was preservation of parathyroid gland tissue critical.

Should adjunct chemotherapy or radiotherapy be given to dogs with thyroid carcinoma?
Vascular or lymphatic invasion (or both) by tumor cells was commonly detected during histologic examination of excised thyroid carcinomas (i.e., in 9 of the 15 dogs). This finding suggests that these affected dogs could benefit from adjuvant chemotherapy or external radiotherapy because such invasive tumors likely have a higher risk of metastasis.

None of the dogs in this study received adjuvant external radiotherapy or radioiodine therapy, so neither of these treatments could be evaluated. However, 6 dogs did undergo adjuvant chemotherapy (doxorubicin only or with carboplatin), but their survival time did not differ from the other dogs that did not receive any chemotherapy. This finding highlights the need for more definitive studies on the role of adjuvant chemotherapy in the treatment of thyroid gland carcinoma in dogs.

Postoperative thyroid hormone treatment for dogs with thyroid carcinoma?
After bilateral thyroidectomy, one would expect serum T4 and T3 levels to decrease into the subnormal  range within 1 to 2 days after surgery. If normal or high T4 values are found in the postoperative period (as reported in 6 dogs of this report), functional thyroid metastasis should be suspected and other follow-up tests of thyroid function (e.g., serum thyroid panel, thyroid uptake and scintigraphy) performed. Why 6 of the dogs of this study had normal to slightly high serum T4s in the "immediate" postoperative period is unclear since no additional follow-up information was reported. It is certainly possible — and even likely— that repeat thyroid testing done at a later date would have revealed low serum T4 values.

In human patients, administration of large doses of thyroid hormone is commonly used as an adjunct treatment after surgery, with the goal of inducing mild hyperthyroidism and completely suppressing circulating TSH to low or undetectable levels (20-22). Circulating TSH can serve as a growth factor to stimulate growth of residual tumor cells; therefore, suppression of TSH may prevent or slow the regrowth of carcinoma tissue in patients with residual neoplastic disease.

In this study, it was interesting that thyroid hormone supplementation appeared to improve survival time in the 11 dogs treated (see Figure 1). Unfortunately, it is not known if TSH suppression was achieved in these dogs since the dose(s) of L-T4 given to these dogs was not provided, and follow-up post-pill serum thyroid hormone or TSH values were not reported. However, two things are very clear— it can be difficult to produce iatrogenic hyperthyroidism in dogs with L-T4 supplementation and that high doses would be needed to completely suppress TSH secretion (23,24).

In the end, it's really impossible to know if the L-T4 therapy really had any true suppressive effect on thyroid carcinoma regrowth or on the dog's survival.  That all said, it remains an interesting observation, and high-dose thyroid hormone suppressive therapy certainly deserves to be investigated as an adjuvant  treatment for dogs with thyroid carcinoma.

References

1. Brodey RS, Kelly DF. Thyroid neoplasms in the dog. A clinicopathologic study of fifty-seven cases. Cancer 1968;22:406-416. 
2. Leav I, Schiller AL, Rijnberk A, et al. Adenomas and carcinomas of the canine and feline thyroid. Am J Pathol 1976;83:61-122.  
3. Barber LG. Thyroid tumors in dogs and cats. Vet Clin North Am Small Anim Pract 2007;37:755-773. 
4. 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. 
5. Harari J, Patterson JS, Rosenthal RC. Clinical and pathologic features of thyroid tumors in 26 dogs. J Am Vet Med Assoc 1986;188:1160-1164.  
6. Theon AP, Marks SL, Feldman ES, et al. Prognostic factors and patterns of treatment failure in dogs with unresectable differentiated thyroid carcinomas treated with megavoltage irradiation. J Am Vet Med Assoc 2000;216:1775-1779.  
7. Peterson ME: Hyperthyroidism and thyroid tumor in dogs. In: Melian C, Perez Alenza MD, Peterson ME, Diaz M, Kooistra H (eds): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008, pp 113-125. 
8. Klein MK, Powers BE, Withrow SJ, et al. Treatment of thyroid carcinoma in dogs by surgical resection alone: 20 cases (1981-1989). J Am Vet Med Assoc 1995;206:1007-1009. 
9. Liptak JM. Canine thyroid carcinoma. Clin Tech Small Anim Pract 2007;22:75-81. 
10. Radlinsky MG. Thyroid surgery in dogs and cats. Vet Clin North Am Small Anim Pract 2007;37:789-798, viii.  
11. Pack L, Roberts RE, Dawson SD, et al. Definitive radiation therapy for infiltrative thyroid carcinoma in dogs. Vet Rad Ultrasound 2001;42:471-474. 
12. Brearley MJ, Hayes AM, Murphy S. Hypofractionated radiation therapy for invasive thyroid carcinoma in dogs: a retrospective analysis of survival. J Small Anim Pract 1999;40:206-210. 
13. Brearley MJ. Radiation therapy for unresectable thyroid carcinomas. J Am Vet Med Assoc  2000;217:466-467. 
14. Mayer MN, MacDonald VS. External beam radiation therapy for thyroid cancer in the dog. The Can Vet J 2007;48:761-763.  
15. Worth AJ, Zuber RM, Hocking M. Radioiodide (131-I) therapy for the treatment of canine thyroid carcinoma. Aust Vet J 2005;83:208-214. 
16. Turrel JM, McEntee MC, Burke BP, et al. Sodium iodide I 131 treatment of dogs with nonresectable thyroid tumors: 39 cases (1990-2003). J Am Vet Med Assoc 2006;229:542-548. h 
17. Fineman LS, Hamilton TA, de Gortari A, et al. Cisplatin chemotherapy for treatment of thyroid carcinoma in dogs: 13 cases. J Am Anim Hosp Assoc 1998;34:109-112. 
18. Jeglum KA, Whereat A, Young K. Chemotherapy of canine thyroid carcinoma. Compend Contin Educ Pract Vet 1983;5:5:96–98. 
19. Tuohy JL, Worley DR, Withrow SJ. Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). J Am Vet Med Assoc 2012;241:95-103. 
20. Clark OH. TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 1981;5:39-47. 
21. Deasy J, Prichard RS, Evoy D, et al. The role of thyrotropin suppression in patients with differentiated thyroid carcinoma. Ir Med J 2010;103:202-205. 
22. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid 2010;20:135-146. 
23. Piatnek DA, Olson RE. Experimental hyperthyroidism in dogs and effect of salivariectomy. Am J Physiol 1961;201:723-728. 
24. Kaptein EM, Hays MT, Ferguson DC. Thyroid hormone metabolism. A comparative evaluation. Vet Clin North Am Small Anim Pract 1994;24:431-466.