PBS Article Covers Our Paper About Organophosphate Esters (OPEs), Housecats and Hyperthyroidism

In addition to covering our recently published paper, this PBS article also mentioned my article in NY Times Magazine.

From the PBS post:

In the study, published July 10 in Environmental Science & Technology, researchers outline a connection between hyperthyroidism in indoor cats to organophosphate esters (OPEs), which have since supplanted PBDEs.

As manufacturers voluntarily phased out PBDEs because of health concerns in both pets and humans, OPEs were substituted in a range of household products to meet fire safety regulations.

Some research has pointed to OPEs as potential hormone disruptors. And if OPEs are making their way into house cats, those chemicals might be affecting humans, too.

New Chemicals in Environment (Organophosphate Esters) Linked to Hyperthyroidism in Cats

Dr. Peterson was involved in a recent study which linked the use of flame retardants and other common household compounds to hyperthyroidism in cats.




This study, published in Environmental Science & Technology, used silicone pet tags to monitor feline exposure to various chemicals and compounds found throughout the home. These silicone tags were attached to a standard cat collar (see photo above), and most owners reported that wearing the silicone tags didn't bother their cat at all.




The concern, in general, is that cats are being exposed to OPEs inside the home. OPEs (organophosphate esters) are one type of flame retardant, a chemical alternative to PDBEs. PDBEs began appearing as flame retardants in the 1970s and have been associated with hyperthyroidism in cats in a number of studies, as well as being harmful to humans. PDBEs were phased out beginning in 2004, and OPEs were substituted by manufacturers as an alternative flame retardant. 




This study is the first time we've taken a hard look at OPEs and how they affect cats.

From one of the press releases: "In the mid-1970s, manufacturers began to put polybrominated diphenyl ethers (PBDEs) into textiles, polyurethane foam, plastics, and electronics. But in 2004, U.S. manufacturers started voluntarily phasing out these flame retardants amidst environmental and health concerns. Alternatives including organophosphate esters (OPEs), such as tris(1,3-dichloroisopropyl) phosphate (TDCIPP), were added instead, but recent research suggests these flame retardants, like PBDEs, can act as endocrine disruptors. Prior research suggested a link between PBDE levels and feline hyperthyroidism, but so far OPEs have not been examined in this context."




A direct quote from this study: "To our knowledge, this is the first study to investigate bioavailable household OPE exposures between hyperthyroid and non-hyperthyroid cats."




Conclusion: Higher concentrations of harmful compounds were found on the tags of cats in homes with air fresher use (versus no air freshener use), as well as modern residences build after 2005 (versus pre-1989), and on the tags of cats who spend more time on upholstered furniture. 




More directly, harmful compounds were found in higher concentration on the tags of hyperthyroid cats, versus on the tags of non-hyperthyroid cats, indicating a higher level of exposure to the compounds (such as OPEs) in the environments of the cats who have become hyperthyroid.

Diagnosing Feline Hyperthyroidism: Not Always as Simple as One Might Believe

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

Diagnosing feline hyperthyroidism: It's not always as simple as it seems

Don't rely too heavily on T4 concentrations since cats can have a false elevation.

In his presentation, “Diagnosis of hyperthyroidism: A critical evaluation of our current available tests,” Mark Peterson, DVM, DACVIM, discussed some of the pitfalls in relying too heavily on thyroid (thyroxine, or T4) testing alone. While a total T4 concentration will be enough to make an accurate diagnosis of hyperthyroidism in more than 90% of cases, he warned to always pay attention to the clinical signs and physical examination findings. There are cats that can have a false elevation in their T4 concentration, so supportive clinical signs as well as a palpable thyroid nodule will help rule in or rule out the diagnosis.

When it comes to successfully palpating for evidence of a thyroid nodule, Peterson detailed a few of his favorite techniques:

• Stand behind the cat with the cat facing away from you—the cat feels less stressed if it can’t see you. Peterson also puts the cat in a basket with a towel so the cat feels more secure and is less squirmy. Use your thumb and index finger to gently run the length of the trachea from the larynx to the thoracic inlet.
• Alternatively, with the cat in the same position, turn its head to the left and palpate. Repeat with the cat’s head turned in the other direction.

Examine the cat from behind, with the cat facing the owner.

For patients in which a thyroid nodule can be palpated but there are no clinical signs and there is no elevation in T4 concentration, he recommends monitoring signs at home and rechecking the level in six to 12 months.

Peterson also noted that there are different cut-off values from laboratory to laboratory. This means that a T4 concentration that is normal at one laboratory, may actually be elevated at another. This serves as another reminder of the importance of the physical examination and clinical signs when trying to diagnose hyperthyroidism.

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

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

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

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

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

My Response:

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

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

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

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

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

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

References:

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

Top Endocrine Publications of 2014: The Feline Thyroid Gland

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

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

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

References:

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

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. 

Hyperthyroidism in Guinea Pigs: An Emerging Disease

PAPER REVIEW

Hyperthyroidism in Four Guinea Pigs: Clinical Manifestations, Diagnosis, and Treatment

by F. Künzel, B. Hierlmeier, M. Christian, and M. Reifinger

Journal of Small Animal Practice 2013; 54:667-671.

Background

Only limited information regarding hyperthyroidism in guinea pigs has been reported, much of which has been published as a general review article (1-3). Therefore, veterinarians may not be aware of this disease, resulting in under-diagnosis of this condition.

The purpose of this case series by Künzel et al. (4) is to describe the results of diagnosis, treatment, and outcome of guinea pigs with hyperthyroidism. The goal was to provide additional information about this disease to help clinicians dealing with guinea pigs that may be suspected of having this disease.

Case Series of 4 Guinea Pigs Suffering from Hyperthyroidism

Signalment: Hyperthyroidism was diagnosed in four guinea pigs (3 females and 1 male), ranging in age from 3 to 6 years. These 4 cases represented 1.3% of guinea pigs examined at the University clinic during the same 2.5-year period.

Clinical features: Clinical signs reported in all guinea pigs included weight loss despite the maintenance of a normal appetite.   Polyuria was noted in 2 of the 4 cases.

Physical examination findings: Physical examination revealed evidence for weight loss and a palpable mass in the ventral cervical region in all guinea pigs. Additional findings in individual guinea pigs included unkempt hair coat, tachycardia and tachypnea.

Serum chemistry results and thyroid hormone determinations: All 4 of the guinea pigs showed elevated serum alanine aminotransferase (ALT) activity. The diagnosis of hyperthyroidism was confirmed by demonstration of increased serum total thyroxine (T4) concentrations in all guinea pigs, as measured by chemiluminescent technique (5).

Treatment: Surgical thyroidectomy was attempted in 1 case but the guinea pig died during anesthetic induction. Histopathology confirmed thyroid adenoma.

The other 3 guinea pigs were treated with methimazole, using starting doses of 1-1.4 mg/kg/day. Based on clinical signs and results of follow-up serum T4 values, the final methimazole doses ranged from 2-3 mg/kg every 24 hours in 2 cases and 2.5 mg/kg every 8 hours in the third guinea pig. In this latter case, radioactive iodine treatment was eventually performed.

Response to treatment: All 3 of the treated guinea pigs showed progressive weight gain as serum T4 concentrations fell to within the reference interval. However, all died of unknown causes 18-28 months following initial treatment.

My Bottom Line:

Hyperthyroidism in guinea pigs represents a relatively new addition to the list of differential diagnoses for weight loss in guinea pigs (2-4). In many ways, the description and management of hyperthyroidism in these 4 guinea pigs mimics the situation we had with feline hyperthyroidism in the early 1980’s, as we were just starting to routinely recognize this common disease in cats (6,7).

The signalment (middle-aged to senior), clinical signs (weight loss despite a good appetite) and physical exam findings (palpable thyroid nodule) displayed by these guinea pigs are all remarkably similar to those of the typical hyperthyroid cat. The finding of a high total T4 concentration was diagnostic in all of these 4 guinea pigs, as it is in over 90% of hyperthyroid cats.

Treatment with methimazole was successful in management of 3 of the 4 guinea pigs. However, on a body weight basis, much higher daily doses were needed for the guinea pigs, at least compared to the typical hyperthyroid cat.  Use of radioiodine therapy also appears to be a safe and promising treatment for guinea pigs suffering from hyperthyroidism (2,5). However, more work needs to be done before this becomes an accepted therapeutic approach for hyperthyroidism in the guinea pig.

References:

1. Mayer J, Hunt K, Eshar D, et al. Thyroid scintigraphy in a guinea pig with suspected hyperthyroidism. Exotic DVM 2009;11:25-29.
2. Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in Guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509-523. 
3. Brandao J, Vergneau-Grosset C, Mayer J. Hyperthyroidism and hyperparathyroidism in guinea pigs (Cavia porcellus). Vet Clin North Am Exot Anim Pract 2013;16:407-420. 
4. Kunzel F, Hierlmeier B, Christian M, et al. Hyperthyroidism in four guinea pigs: clinical manifestations, diagnosis, and treatment. J Small Anim Pract 2013; 54:667-671. 
5. Muller K, Muller E, Klein R, et al. Serum thyroxine concentrations in clinically healthy pet guinea pigs (Cavia porcellus). Vet Clin Pathol 2009;38:507-510. 
6. Peterson ME, Johnson JG, Andrews LK. Spontaneous hyperthyroidism in the cat. Spontaneous hyperthyroidism in the cat. Proceedings of the American College of Veterinary Internal Medicine 1979: 108.
7. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. J Am Vet Med Assoc 1983;183:103-110. 

Unmasking Kidney Disease In Hyperthyroid Cats after Treatment

I have two hyperthyroid cats that both had "completely normal" kidney function until we started treating with methimazole. On treatment, the serum T4 concentrations in both cats have come down nicely to 1.2 and 2.0 µg/dl, respectively (reference interval, 1.0-4.0 µg/dl), so these values are within the low-normal range, which is what I aim for after treatment.

In the first cat, the serum creatinine has increased from 1.2 mg/dl up to 2.0 mg/dl, whereas the serum creatinine value in the second cat rose from 1.5 mg/dl up to 2.5 mg/dl. Based on the IRIS staging system, both cats could be classified as having stage 2 chronic kidney disease (CKD).

How do I manage such hyperthyroid cats that develop "new" CKD after treatment? Should I lower the methimazole or stop it all together in order to help improve the kidney function?

My Response:

Hyperthyroidism and CKD are both very common problems of the older cat and may occur concurrently in the same patient (1,2). Because hyperthyroidism increases the glomerular filtration rate (GFR) and renal blood flow (RBF), the kidney disease may be masked and only revealed once the cat is rendered euthyroid (3-5). As you know, that's what happened in these two feline patients.

However, it is very important to understand that treatment of hyperthyroidism doesn't cause new kidney problems; the CKD was already present in your cats before the methimazole treatment, but the serum creatinine values were normal, in part due to the high GFR associated with hyperthyroidism. Now that you have the hyperthyroidism under control, the lowering of circulating thyroid hormone concentrations has also resulted in a drop in GFR, unmasking the underlying CKD that was already there.

Management of hyperthyroid cats that develop kidney disease after treatment
So what do we do with hyperthyroid cats like your two patients here— cats that develop mild CKD after treatment of hyperthyroidism with methimazole?

It was once thought that if azotemia developed following medical treatment, then it would be best to stop the methimazole and leave the hyperthyroidism untreated (or at least under-treat it) to maximize renal function. This recommendation has now been widely abandoned, with the realization that hyperthyroidism could actually be causing renal injury in these cats through the process of glomerular hyperfiltration (1,2,6). This increase in glomerular pressure has been associated with proteinuria and evidence of tubular damage, which could result in progressive renal injury. In other words, hyperthyroidism has the potential to exacerbate these processes and worsen, rather than help, renal function.

On the other hand, it's also important not to over control hyperthyroidism. In other words, we don't want the post-treatment T4 concentrations to go too low because iatrogenic hypothyroidism will make the azotemia worse (7). Even mild degrees of hypothyroidism can worsen the azotemia in susceptible cats. This means that the serum T4 value does not have to be below reference range — even a serum T4 in the lower third of the reference range may be too low, especially if the serum TSH is high, diagnostic for mild hypothyroidism (8).

Because of this association between development of iatrogenic hypothyroidism and worsening of azotemia, my "goal" in treating cats with hyperthyroidism is to reduce the total T4 concentration into the middle of the reference range (e.g., 2.0-3.0 µg/dl with your lab). So in your first cat, you may want to lower the methimazole dose and allow the serum T4 to come up into the mid-normal range. This may help increase GFR and improve kidney function in that cat. One recent study found that restoration of euthyroidism in cats with iatrogenic hypothyroidism resulted in a significant reduction in serum creatinine concentration, with azotemia resolving in half of the cats (9).

Finally, if you unmask kidney disease after treatment of a hyperthyroid cat, this also means that you should take steps to attempt to slow the progression of CKD, just as you would in a geriatric cat with CKD alone. These steps may include one or more of the following, depending on secondary factors and stage of the CKD (10,11):

• Antibiotics, if urinary tract infection
• Antihypertensives, if hypertensive
• Low-phosphate diet
• Phosphorus binders
• Calcitriol or ACE-inhibitors, if necessary
• Subcutaneous fluids

Survival times of hyperthyroid cats that develop mild CKD after treatment
In most cats that develop newly-diagnosed azotemia after treatment for hyperthyroidism, the CKD is mild (usually IRIS stage 2) and associated with few clinical signs other than mild polyuria and polydipsia. Owners of cats that have developed azotemia still report that treatment of the hyperthyroidism has improved the clinical condition of their cat, as shown by weight gain and resolution of other clinical signs of hyperthyroidism.

The survival time of cats that develop azotemia following treatment of hyperthyroidism does not differ from those that do not develop any azotemia (7). This fact may be surprising to many practicing veterinarians who naturally assume that the development of CKD is associated with a worse prognosis. However, CKD progresses relatively slowly in cats, and only about half of all cats diagnosed with mild CKD will ultimately succumb to the disease (12). Many CKD cats die because of unrelated causes.

Survival times of hyperthyroid cats that are azotemic prior to treatment
The situation is completely different in cats that are already clearly azotemic (serum creatinine >2 mg/dl), even before any treatment for hyperthyroidism has been given. In general the survival of this group of cats with azotemic CKD prior to treatment is poor. In one study, the median survival time for azotemic cats was only 178 days; however, survival times in that study was very variable,  ranged from 0 days up to 1,505 days (4.1 years) (13).

Bottom Line:

Hyperthyroid cats that develop "new" CKD after treatment are common, but the azotemia is generally mild and we should not withhold methimazole treatment in those cats. However, we don't want to induce iatrogenic hypothyroidism, and steps should be taken to address the underlying CKD. Unless prior azotemia was present, the prognosis of most treated cats with mild CKD is good to excellent.

References:

1. Langston CE, Reine NJ. Hyperthyroidism and the kidney. Clin Tech Small Anim Pract 2006;21:17-21.  
2. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743.  
3. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Res 1994;55:1745-1749.  
4. Boag AK, Neiger R, Slater L, et al. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Vet Rec 2007;161:711-715.  
5. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domest Anim Endocrinol 2009;36:45-56.  
6. Syme H. Are methimazole trials really necessary? In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
7. 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.  
8. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compendium 2013;35:E4. 
9. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255. 
10. Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 2012;42:669-692.
11. Polzin DJ. Chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract 2011;41:15-30. 
12. Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 2000;41:235-242.
13. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 

Top Endocrine Publications of 2013: The Feline Thyroid Gland

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

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

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

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

References:

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

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

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

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

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

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

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

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

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

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

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

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

My Response:

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

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

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

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

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

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

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

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

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

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

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

References:

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

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. 

Diagnosing Subclinical Hyperthyroidism in Cats

I have a quick question about a "problem" case, a 9-year old M/C DSH. This cat has lost about 3 pounds over the last year, but weighed 22 pounds last year so the owner has been trying hard to get the cat to lose weight.

The cat came in for his recheck last week. His physical examination was normal and we ran a routine blood panel (CBC, serum chemistry panel, and total T4). His serum T4 was high-normal at 3.7 µg/dl (reference range, 0.8-4.0 µg/dl). I then added on a free T4 by dialysis, which came back as slightly high at 54 pmol/L (10-50 pmol/L). Looking back in his records, his free T4 concentrations were also slightly high when checked a year ago (58 pmol/L).

This cat is not clinical at all otherwise for hyperthyroidism. He has strange seizure-like episodes, about once every 3 months, but these have been happening since he was a young cat. There has been no change in these episodes.

My gut is telling me that because this cat is not clinical and his thyroid values have remained stable over the last year, we probably should not treat hyperthyroidism at this time. However, I wanted to get your opinion and see if you think that this cat is indeed hyperthyroid, and if so, if he may be a candidate for I-131 at this time.

My Response:

In our studies, we have found that up to 30% of cats that present like this (asymptomatic, high-normal T4, slightly high free T4 concentration) will be normal when evaluated by thyroid scintigraphy (1-3). So basically, this cat certainly could be in the preclincal stages of becoming hyperthyroid, but it's also very possible that the free T4 is falsely high and he is euthyroid.

Determination of free T4 is far from being a perfect test, and a diagnosis of hyperthyroidism should NEVER be based on the finding of a high free T4 alone (1,2,4). This is especially true in a cat like this one, that presents without a palpable thyroid nodule or clinical features of thyroid disease.

So you and the owners have 2 options at this time:

1. Do a thyroid scan (scintigraphy) to better define the cat's thyroid function (1-3,5,6). If the thyroid lobes are of normal size and display normal thyroid uptake of the radionuclide, we can definitely rule out hyperthyroidism. If, on the other hand, a small hyperfunctional thyroid adenoma is found, then we know that the cat has early hyperthyroidism and could be treated.
2. The second option is to continue to monitor the cat every 3-6 months (body weight, heart rate, neck palpation, and complete thyroid profile, including serum concentrations of total T4, free T4, and TSH). If hyperthyroid, the serum T4 and free T4 should continue to go higher, where as the TSH should be undetectable (1,2,7,8). If the serum TSH is found to be measurable, that goes against hyperthyroidism since even mild increases in circulating T4 and T3 should feedback to the pituitary to shut off TSH secretion.

Thyroid scintigraphy in a normal cat (on right) and cat with preclinical hyperthyroidism (on left).
Notice that the hyperthyroid cat has a small left thyroid adenoma with complete suppression of the right thyroid lobe. In cats with unilateral hyperthyroid disease, this lack of radionuclide uptake by the normal thyroid lobe is due to the fact that circulating TSH becomes suppressed in almost all hyperthyroid cats, even those with mild disease.

Either option is acceptable - just depends on what the owner wants to do. The cat is not going to be hurt by waiting, as long as he is closely monitored. At 9-years of age, he is still on the young side for being hyperthyroid, but about 5-10% of my cats are less than 10-years, so it's very possible that he is just preclinical at this time and will develop overt signs of hyperthyroidism within the next year.

References:

1. Peterson ME. More than just T4: Diagnostic testing for hyperthyroidism in cats. J Fel Med Surg 2013;15:765-777. 
2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet 2013;35:E3.
3. Peterson ME, Broome MR. Radioiodine for feline hyperthyroidism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014.
4. Peterson ME, Melian C, Nichols R. Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease. J Am Vet Med Assoc 2001;218:529-536. 
5. Broome MR. Thyroid scintigraphy in hyperthyroidism. Clin Tech Small Anim Pract 2006;21:10-16. 
6. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. J Vet Intern Med 2012;26:754.
7. Wakeling J, Elliott J, Syme H. Evaluation of predictors for the diagnosis of hyperthyroidism in cats. J Vet Intern Med 2011;25:1057-1065. 
8. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Can Vet J 2010;51:33-34. 

Fluctuation in Serum Thyroid Hormone Concentrations: An Issue in Diagnosis of Feline Hyperthyroidism?

Examining a cat with hyperthyroidism

I am writing this email to you because of your recent article published in the Journal of Feline Medicine and Surgery about diagnostic testing for hyperthyroidism (1). In that paper, you mentioned that hyperthyroid cats can show fluctuation of serum T4 and T3 concentrations (2), leading to difficulty in diagnosis in some cats.

My question is this: When, in your opinion or experience, is the best moment of the day (or the best conditions), to get the blood samples for thyroid hormone analysis to avoid this fluctuation problem?

Thanks! Looking forward to hearing from you.

My Response:

Unfortunately, there is no way to predict if and when this fluctuation in T4 and T3 will occur. So collecting blood samples at a particular time of day would not be helpful.

Remember, however, that this fluctuation is only of clinical importance in cats with very mild hyperthyroidism; in these cats, the serum T4 value may vary from the upper third of the reference range limits to just slightly above normal. In cats with more advanced stages of hyperthyroidism, fluctuation in circulating T4 concentration will occur throughout the day and over a period of a few days, but all T4 values will be high (1-3). Thus, in most hyperthyroid cats, the fluctuation in circulating thyroid hormone levels will not contribute to problems in the diagnosis.

References:

1. Peterson ME. Diagnostic testing for hyperthyroidism in cats: more than just T4. J Fel Med Surg 2013;15:765-777.  
2. Peterson ME, Graves TK, Cavanagh I. Serum thyroid hormone concentrations fluctuate in cats with hyperthyroidism. J Vet Intern Med 1987;1:142-146. 
3. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: Hyperthyroidism. Compend Contin Educ Vet 2013;35:E1-E6.

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.