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. 

Relationship Between Stomatitis and Hyperthyroidism in Cats?

My patient is a 12-year-old, male hyperthyroid cat who had a full mouth extraction done 4 years ago because of severe oral disease. Since that time, this cat had required Depo-medrol injections every 1-2 months to help keep the stomatitis under control.

About a year ago, the cat developed hyperthyroidism and was treated with radioiodine. Since that time, he has remained euthyroid. But unexpectedly, his stomatitis has also completely resolved, and no further steroid treatment has been needed.

Nothing else changed in the household — i.e., no diet changes, no other medications, and this has always been an indoor cat. I am happy for the cat (and the owner), but am curious if you have an explanation to explain the apparent connection between the stomatitis and hyperthyroidism?

My Response

I've seen a few hyperthyroid cats over the years whose concurrent oral disease improved after they were treated with radioiodine. I do not know for certain why their oral lesions sometime respond so well to correction of the hyperthyroid state.

Are some hyperthyroid cats iodine deficient?
One theory is that some of these hyperthyroid cats are iodine deficient (even on a "normal" iodine diet) because of their increased need for iodine to make thyroid hormone (1). Once we cure them with radioiodine, their need for iodine goes down because now they are no longer making excess amount of thyroid hormone.

Figure 1. Chemical structure of thyroxine.
Notice that each T4 molecule contains 4 atoms of iodine atoms 

Remember that each T4 molecule contains 4 iodine atoms (Figure 1), whereas each T3 molecule contains 3 iodine atoms.

Salivary glands normally concentrate iodine
Iodine appears to be very important for oral health (2,3). Normally, the salivary glands have the capacity to concentrate iodide as well as the thyroid tissue. The iodide is then secreted into saliva such that its salivary concentration has been reported to vary from 20 to 100 times that found in the serum (4,5).

Figure 2. Thyroid scintigraphy of a normal cat.
Notice the similar uptake of the tracer in the thyroid lobes and salivary glands. Also note that the stomach also concentrates the radionuclide to some extent (area of uptake on bottom of scan image).

In proof of this, remember that the salivary glands can be seen to concentrate ("take up") radioiodine with thyroid scintigraphy very well (see Figure 2) —equal to the thyroid glands in a normal cat (6-8).

Iodine deficiency and immunity
Based on a number of studies in man and other species, it's clear that iodine has many extra-thyroidal functions in the body. Iodine plays an important role in the immune response. It also has anti-inflammatory and anti-oxidative actions (2,3,9-12).

Bottom Line

Marked variation of iodine levels between cat foods have been reported in studies of commercial foods, in which the iodine content between foods varied by a factor of 30-fold (13-15). It also possible that some cats would be consistently fed a low-iodine diet for prolonged periods, leading to an iodine-deficient state.

So it is possible that this cat has been chronically iodine deficient, which may have become worse when hyperthyroidism developed. By treating the hyperthyroidism, the total body need for iodine would be expected to decrease. So that might explain why the stomatitis improved after correction of the hyperthyroidism with radioiodine.

Again, I'm not talking about the use of low-iodine diets (y/d) for hyperthyroidism here, but that diet could, at least theoretically, make the oral disease worse in these cats.

References:

1. Wakeling J, Elliott J, Petrie A, et al. Urinary iodide concentration in hyperthyroid cats. American Journal of Veterinary Research 2009;70:741-749. 
2. Venturi S, Venturi M. Iodine in evolution of salivary glands and in oral health. Nutrition and Health 2009;20:119-134. 
3. Brownstein, D. Iodine: Why you need it, Why you can't live without it. Medical Alternative Press; 3rd edition. 2004.
4. Myant NB. Iodine metabolism of salivary glands. Annals of the New York Academy of Sciences 1960;85:208-214.
5. Mason DK, Harden R McG, Alexander WD. The salivary and thyroid glands: A comparative study in man. British Dental Journal 1967;122:485-489. 
6. Beck KA, Hornof WJ, Feldman EC. The normal feline thyroid. Technetium pertechnetate imaging and determination of thyroid to salivary gland radioactivity ratios in 10 normal cats. Veterinary Radiology & Ultrasound 1985;26:35-38. 
7. Peterson ME, Becker DV. Radionuclide thyroid imaging in 135 cats with hyperthyroidism. Veterinary Radiology 1984;25:23-27.
8. Broome MR. Thyroid scintigraphy in hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:10-16.
9. Marani L, Venturi S, Masala R. Role of iodine in delayed immune response. Israeli Journal of Medical Science 1985;21:864. 
10. Venturi S, Venturi M. Iodine, thymus, and immunity. Nutrition 2009;25:977-979.
11. Miller DW. Extrathyroidal benefits of iodine. Journal of American Physicians and Surgeons 2006;11:106-110. 
12. Ware CM, Wishner LA. The lipid antioxidant properties of iodine compounds. Lipids 1968;3:182-183.
13. Johnson LA, Ford HC, Tarttelin MF, et al. Iodine content of commercially-prepared cat foods. New Zealand Veterinary Journal 1992;40:18-20. 
14. Ranz D, Tetrick M, Opitz B, et al. Estimation of iodine status of cats. Journal of Nutrition 2002;132 (suppl 2):1751S-1753S. 
15. Edinboro CH, Scott-Moncrieff JC, Glickman LT. Feline hyperthyroidism: potential relationship with iodine supplement requirements of commercial cat foods. Journal of Feline Medicine Surgery 2010;12:672-679. 

Does Iodine Deficiency Cause Thyroid Disease in Cats?

Although only first described in cats in the last 1970s (1), today hyperthyroidism is clearly the most common endocrine disorder of cats, being detected at rates as high as 2% of all cats examined (2). Cats certainly live longer today than they did 35 years ago when we first described the disease, but it is highly unlikely that this epidemic of hyperthyroidism is solely the result of the aging cat population.

Other factors must be involved: the most likely candidates include deficiencies or excesses in the cat's diet or the chronic exposure to one or more "thyroid-disrupting" chemicals present in the environment, drinking water, or diet (2).

Is Diet the Cause of Feline Hyperthyroidism?

All epidemiologic studies of cats with hyperthyroidism reported to date have identified commercial cat food diets as a risk factor for developing the disease (3-10). One of these studies suggested that particular flavors of canned food (fish, liver, and giblets) may be involved (5), and another incriminated cans with plastic linings in easy-open (pop-top) lids (8), which may contain the thyroid disruptor chemical bisphenol-A (BPA).

Soy isoflavones, a well-known goitrogen that inhibits thyroid hormone synthesis (11,12), are also known to be present in many dry cat foods (13). Finally, most recently, iodine deficiency has "resurfaced" as a candidate for development of goiter and subsequent hyperthyroidism in cats (6,14).

Dietary Iodine Excess or Deficiency

Because of the clear association between diet and hyperthyroidism, several studies have attempted to implicate iodine in the cause or progression of the disease. The iodine content of cat food has always been extremely variable. However, a definite trend for adding lower amounts of iodine to cat food has occurred over the last 30 years as the recommended dietary iodine requirements for cats has changed (14).

In the mid-1980s, shortly after hyperthyroidism was first reported, most commercial cat food diets were found to contain very high amounts of iodine, often up to 10 times the recommended level (15). Subsequently, the recommendations for iodine supplementation to cat food diets were lowered (16).

By the early 1990’s, another study reported that only 10% of the cat food tested had iodine concentrations that exceeded the upper limit of recommended iodine concentrations, whereas about 25% of the foods had iodine concentrations that were below the level of detection (17). In that study, the widest variation in iodine content was in canned food, whereas dry food diets were less variable.

Similar findings in the variation of iodine levels between cat foods were reported in another study of commercial foods in 2002, in which the iodine content between foods varied by a factor of 30-fold (18). Again, however, the average iodine content of commercial cat foods was lower than they had been in the 1980s.

Thus, between the 1980s and early 2000s, iodine concentrations appeared to range between non-detectable and extremely high levels in a variety of canned foods. Large variations in iodine concentration among cat foods may reflect the widely different iodine concentrations of ingredients used (e.g., glandular tissue, fish), as well as the amounts of iodine added to the foods by the different manufacturers.

The role that iodine plays in the development of hyperthyroidism remains unclear, but it can be postulated that wide swings in iodine intake over time may contribute to the development of thyroid disease in cats (19-21). It also possible that some cats will be consistently fed a low iodine diet, which would also predispose a cat to thyroid hyperplasia and goiter (22,23).

Could Iodine Deficiency Now Be Contributing to the Disease?

Iodine deficiency is a known cause of thyroid hyperplasia and goiter in man and all animals, including cats (22-25). Iodine is a key element needed in the synthesis of thyroid hormones. As a consequence, inadequate iodine intake leads to low circulating thyroid hormone concentrations, which spurs the pituitary gland to increase its secretion of TSH (Figure 1). Persistently high circulating TSH concentrations will lead to thyroid hyperplasia and possibly goiter (22,23).  It's possible that with enough time and continued stimulation, the hyperplastic thyrocytes may become autonomous, leading to adenomatous hyperplasia and then to thyroid adenoma. As these tumors continue to grow and function independent of TSH control, hyperthyroidism would ensue leading to suppression of pituitary TSH secretion. In some cats, transformation of adenomatous hyperplasia/adenoma to thyroid carcinoma will occur (26).

Fig. 1: Pathogenesis of thyroid hyperplasia & goiter in chronic iodine deficiency.  Although simple goiter caused by iodine deficiency is well-documented, it is not known for certain if iodine deficiency, at least by itself, can lead to the development of true thyroid tumors and hyperthyroidism.

So, based on the trend to lower iodine levels in cat food over the last two decades, could iodine deficiency be contributing to the explosion in hyperthyroid cases that we are seeing today? In support of that reasoning, a recent case-control study reported that cats consuming commercial foods which were relatively deficient in iodine were more than 4 times as likely to develop hyperthyroidism compared with cats that ate iodine-supplemented foods (6,14).

In another study supporting the possible role of iodine deficiency in the pathogenesis of this disease, hyperthyroid cats had lower-than-normal urinary iodine excretion. Following successful treatment for hyperthyroidism, urinary iodine excretion in these cats increased into the normal range (27). The investigators hypothesized that the hyperthyroid cats may have had a pool of stored iodine that was excreted in the weeks following treatment. They suggested that if the urinary iodine concentrations of their hyperthyroid cats reflected iodine intake while the disease was developing, inadequate iodine intake may be a risk factor for hyperthyroidism.

Does Iodine Deficiency Act Synergically with Other Goitrogens or Thyroid Disruptors?

It is difficult to envision how iodine deficiency, excess, or wide fluctuations in iodine intake would be solely responsible for the thyroid adenomatous changes and the development of hyperthyroidism in cats. However, we must remember that most, if not all, hyperthyroid cats are also exposed to other goitrogens or thyroid disruptors in the water, diet, or the environment (e.g., BPA and PBDE) throughout their lifetime (2,8,28). Thus, iodine deficiency may act together with these other goitrogens in a synergistic or cooperative manner to effect multiple sites of thyroid hormone metabolism or action; over time, this may lead to the adenomatous thyroid changes characteristic of hyperthyroidism.

In support of this reasoning, studies in rats demonstrate that soy isoflavones are not highly goitrogenic when added to the diet alone, but soy will consistently induce thyroid hyperplastic and adenomatous changes in the presence of iodine deficiency (29,30). In other words, soy can cause goiter, but only in animals or humans consuming diets that are only marginally adequate in iodine, or in those who are otherwise predisposed to developing goiter because of other factors.

Could Hill's Prescription y/d Diet Make this Situation Worse?

Hill's y/d diet (31), clearly being an ultra-low, iodine deficient diet is effective in lowering serum T4 values in hyperthyroid cats. Since these cats already have developed the thyroid adenomatous hyperplasia and thyroid adenoma(s) responsible for hyperthyroidism, we do not have to worry about inducing thyroid disease in these cats — they already have it!

But, will lowering T4 and T3 secretion in these hyperthyroid cats lead to increases in circulating TSH and continued stimulation of thyroid growth and proliferation in some cats? Will this TSH stimulation cause transformation of benign adenomatous thyroid tissue to carcinoma, as has been documented to occur in some hyperthyroid cats (26)?

The short answer is this: we simply do not know.  The long-term safety studies needed to answer this question have not yet been done. Because Hill's y/d is not a drug (although it's certainly being marketed as a replacement for methimazole), the company is not required to do the these safety studies, and it's fairly clear that they have no intension of paying to have them done.

Nevertheless, it would definitively be prudent NOT to feed y/d to clinically normal cats, since even mild decreases in thyroid hormone secretion could stimulate TSH secretion (22,23). Again, this could lead to thyroid hyperplasia, goiter, and would definitely predispose the cat to developing hyperthyroidism in the future (Figure 1).

References

1. Peterson ME, Johnson JG, Andrews LK. Spontaneous hyperthyroidism in the cat. Proceedings of the American College of Veterinary Internal Medicine 1979:p. 108.
2. Peterson ME, Ward CR. Etiopathologic findings of hyperthyroidism in cats. Veterinary Clinics of North America Small Animal Practice 2007;37:633-645. 
3. Scarlett JM, Moise JN, Rayl J. Feline hyperthyroidism: a case controlled study. Preventative Veterinary Medicine 1988; 6:295-309. 
4. Kass PH, Peterson ME, Levy J, et al. Evaluation of environmental, nutritional, and host factors in cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1999;13:323-329. 
5. Martin KM, Rossing MA, Ryland LM, et al. Evaluation of dietary and environmental risk factors for hyperthyroidism in cats. Journal of the American Veterinary Medical Association 2000;217:853-856. 
6. Edinboro CH, Scott-Moncrieff JC, Glickman LT. Review of iodine recommendations for commercial cat foods and potential impacts of proposed changes. Thyroid 2004;14:722.
7. Edinboro CH, Scott-Moncrieff JC, Glickman LT. Environmental risk factors for feline hyperthyroidism: pet cats as potential sentinels for public health. Thyroid 2004;14:759.
8. Edinboro CH, Scott-Moncrieff JC, Janovitz E, et al. Epidemiologic study of relationships between consumption of commercial canned food and risk of hyperthyroidism in cats. Journal of the American Veterinary Medical Association 2004;224:879-886. 
9. Olczak J, Jones BR, Pfeiffer DU, et al. Multivariate analysis of risk factors for feline hyperthyroidism in New Zealand. New Zealand Veterinary Journal 2005;53:53-58. 
10. Wakeling J, Everard A, Brodbelt D, et al. Risk factors for feline hyperthyroidism in the UK. Journal of Small Animal Practice 2009;50:406-414. 
11. Doerge DR, Sheehan DM. Goitrogenic and estrogenic activity of soy isoflavones. Environmental Health Perspectives 2002;110(Suppl 3):349–353.
12. Doerge DR, Chang HC. Inactivation of thyroid peroxidase by soy isoflavones, in vitro and in vivo. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2002;777: 269-279. 
13. Court MH, Freeman LM. Identification and concentration of soy isoflavones in commercial cat foods. American Journal of Veterinary Research 2002;63:181-185. 
14. Edinboro CH, Scott-Moncrieff JC, Glickman LT. Feline hyperthyroidism: potential relationship with iodine supplement requirements of commercial cat foods. Journal of Feline Medicine Surgery 2010;12:672-679. 
15. Mumma RO, Rashid KA, Shane BS, et al. Toxic and protective constituents in pet foods. Am J Vet Res 1986;47:1633-1637. 
16. Dzanis DA. The Association of American Feed Control Officials dog and cat food nutrient profiles: substantiation of nutritional adequacy of complete and balanced pet foods in the United States. Journal of Nutrition 1994; 124 (suppl): 2535S–2539S. 
17. Johnson LA, Ford HC, Tarttelin MF, et al. Iodine content of commercially-prepared cat foods. New Zealand Veterinary Journal 1992;40:18-20. 
18. Ranz D, Tetrick M, Opitz B, et al. Estimation of iodine status of cats. Journal of Nutrition 2002;132 (suppl 2):1751S-1753S. 
19. Tarttelin MF, Johnson LA, Cooke RR, et al. Serum free thyroxine levels respond inversely to changes in levels of dietary iodine in the domestic cat. New Zealand Veterinary Journal 1992; 40:66–68. 
20. Tarttelin MF, Ford HC. Dietary iodine level and thyroid function in the cat. Journal of Nutrition 1994;124: 2577S-2578S. 
21. Kyle AH, Tarttelin MF, Cooke RR, Ford HC. Serum free thyroxine levels in cats maintained on diets relatively high or low in iodine. New Zealand Veterinary Journal 1994;42:101–103. 
22. Scott PP, Greaves JP, Scott MG. Nutrition of the cat. 4. Calcium and iodine deficiency on a meat diet. British Journal of Nutrition 1961;15:35–51. 
23. Roberts AH, Scott PP. Nutrition of the cat. 5. The influence of calcium and iodine supplements to a meat diet on the retention of nitrogen, calcium, and phosphorus. British Journal of Nutrition 1961;15:73–82. 
24. Delange FM, Ermans AM. Iodine deficiency. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid: a fundamental and clinical text. Philadelphia: Lippincott-Raven, 1996; 296–316.
25. Zimmermann MB. Iodine deficiency. Endocrine Reviews 2009;30(4):376-408. 
26. Hibbert A, Gruffydd-Jones, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. Journal of Feline Medicine and Surgery 2009; 11:116-124. 
27. Wakeling J, Elliott J, Petrie A, et al. Urinary iodide concentration in hyperthyroid cats. American Journal of Veterinary Research 2009;70:741-749. 
28. Dye JA, Venier M, Zhu L, et al. Elevated PBDE levels in pet cats: sentinels for humans? Environmental Science and Technology 2007;41:6350-6356. 
29. Ikeda T, Nishikawa A, Imazawa T, et al. Dramatic synergism between excess soybean intake and iodine deficiency on the development of rat thyroid hyperplasia. Carcinogenesis 2000;21:707-713. 
30. Ikeda T, Nishikawa A, Son HY, et al. Synergistic effects of high-dose soybean intake with iodine deficiency, but not sulfadimethoxine or phenobarbital, on rat thyroid proliferation. Japan Journal of Cancer Research 2001; 92: 390-395. 
31. http://www.hillspet.com/products/pd-feline-yd-dry.html