Welfare hiding right in front of us

Hi there Mia!

When you address someone as I did above, do you put a comma between “there” and “Mia”? Maybe this is a grammar question for a grammar website (or I could just Google it), but I’m wondering if people put that comma in? 

I used to put in the comma, but then I was told it sounded like, “Hi there (paauuse) Mia!"

(source)

HI! How awesome to have those definitions out in the open. Prior to my program in Applied Animal Behaviour and Animal Welfare, I hadn't considered that welfare could be defined or explicitly explored through the scientific method. But, when welfare’s in the title of your program, it’s bound to come up (but why the word animal 2 times! Was that really necessary?) I find that in general conversations, we talk about and around welfare: "How are you doing? How's your dog doing? How are you feeling," even though we might not necessarily realize that the responses are welfare-based in nature.

WSPA made a Concepts in Animal Welfare online course (available to anyone for free). I particularly like how they describe thinking about welfare. If someone asks you how you are feeling, at the moment, your welfare might be mighty fine in some areas but not so groovy in others. Our welfare, and the welfare of others, moves on a continuum.

(source)

Maybe this person should get a new chair and open or close a window.
 
So I think about welfare along this continuum from really good to middle-of-the-road to not-so-good, and different factors can come out in different places. Then, on top of everything, we have to consider welfare from the perspective of the other.

For example, if I just broke my leg falling down the stairs, I’m probably going to freak the #@!&@*!! out. But if a rabbit hurts himself, we might not know anything has happened because as a prey species, it's not in his best interest to freak the #@!&@*!! out. 

It’s not to say that he doesn’t experience pain, he just wasn’t built to make a big scene like I will. If the rabbit in pain made a scene, that could attract attention and he could end up someone's easy dinner. Best to hide it. 

But for me, maybe it’s adaptive to make a big scene so that someone will come help me? Or, maybe the big scene has the opposite effect and makes other people want to stay away? Or maybe a lawyer would see me in my state of chaos and distress and weigh the benefits of helping me against the risk of a possible lawsuit. Humans are complicated...

What's interesting about dogs is that less-than-awesome welfare states can sometimes be hidden right in front of us. 

(source)

A while back, I attended an outdoor, end-of-summer dog event called WoofStock. Dogs and people meandered about. It was hot. I saw a crowd of people, and I went over (because that's what we do). 

A man was carrying a Pug, and boy was that tongue hanging out of that dog's mouth. Everyone was cramming in to look at the, “Oh-So-Cute” dog! I was left wondering, Why isn’t he walking around like all the other dogs? He too has the gift of 4 legs. 

I researched brachycephalic dogs, and found that through decades of breeding, we have created (and maintained) a dog who can have difficulty breathing and whose tongue doesn’t fit in its mouth. I pulled the research together and wrote a blog post on Dog Spies called, Where Should Dogs Put Their Tongues? 

I hope you agree that I don't think it's "pick on pug" day. I'm just looking at the question of welfare from three different directions: (1) how do dogs look; (2) what do we find aesthetically pleasing and (3) do certain physical attributes offer particular challenges?

Sometimes what we humans like and find attractive & aesthetically pleasing is not in dogs' best interests. For example, what's the welfare of the above Pug? Some might look at this dog and say, What a cute face! But is he enjoying where his tongue is?

Bye for now!

Julie 

Oechtering, G., Schlüter, C. & Lippert, J. (2010). Brachycephaly in dog and cat: a "human induced" obstruction of the upper airways, Pneumologie, 64 (07) 452. DOI: 10.1055/s-0030-1255513 http://www.ncbi.nlm.nih.gov/pubmed/20632241

Asher, L., Diesel, G., Summers, J.F., McGreevy, P.D. & Collins, L.M. (2009). Inherited defects in pedigree dogs. Part 1: Disorders related to breed standards, The Veterinary Journal, 182 (3) 411. DOI: 10.1016/j.tvjl.2009.08.033 www.sciencedirect.com/science/article/pii/S1090023309003645

© Julie Hecht 2012

Thyroid Tumors Grow Progressively Larger in Most Hyperthyroid Cats Treated with Methimazole

As I discussed in my last post (Managing Hyperthyroid Cats That Become Unresponsive to Methimazole), methimazole blocks thyroid hormone secretion from a hyperthyroid cat's thyroid tumor (usually a benign tumor). However, in cats treated with methimazole, it is quite common for hyperthyroid cats on methimazole treatment to need higher dosages of methimazole over time, as the thyroid adenoma continues to grow larger and increases its secretion of thyroid hormone (1-3).

No one has yet studied the long-term effects of nutritional management with a low-iodine diet (i.e., Hill's y/d) on thyroid tumor growth in these hyperthyroid cats. However, the same progressive growth of the thyroid tumor would be expected on a low-iodine diet, since the thyroid tumor remains and is free to continue to grow progressively larger with time.

Figure 1: Hyperthyroid cat who has developed a very large thyroid tumor after 3 years of methimazole treatment. Notice the swollen neck, which turned out to be a massive thyroid carcinoma.

After months to years of methimazole treatment, many of these cats will develop a very large, palpable thyroid tumor (Figure 1) and will become difficult to regulate, even with high daily doses of oral or transdermal methimazole (3-5). Some cats eventually become completely refractory to methimazole, so alternative treatment modalities must be considered.

With enough time and as the disease progresses, the benign thyroid adenoma characteristic of early feline hyperthyroidism can also transform into malignant thyroid carcinoma in some cats (5,6). Again, methimazole or other antithyroid drug therapy (including Hill's y/d) does nothing to the thyroid tumor pathology and cannot stop this from happening.

Radioiodine therapy can be used to successfully treat cats with all sizes of benign and malignant thyroid tumors, but is best used on cats with small benign tumors. Cats with small thyroid tumors are easier to cure with lower radioiodine doses, resulting in shorter hospitalization times.

Video Animation: Thyroid Growth on Methimazole

The animation below describes the continued growth of the initially benign thyroid tumors causing hyperthyroidism in cats during their medical management with methimazole (Tapazole).

This video was done by my colleague and friend, Dr. Michael Broome, Director of Advanced Veterinary Medical Imaging in Orange Country, California. We have been long-term collaborators on clinical research issues pertaining to cats with hyperthyroidism, and we continue to work closely together on this common disorder (4,5).




References:

1. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
2. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
3. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 American College of Veterinary Internal Medicine Forum. 2011;104-106.
4. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2012; 26:754.
5. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. Proceedings of European College of Veterinary Internal Medicine; 2012.
6. Hibbert A, Gruffydd-Jones T, 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.

Managing Hyperthyroid Cats that Become Unresponsive to Methimazole

Antithyroid drugs (methimazole or carbimazole) are commonly used as the primary means of long-term therapy for cats with hyperthyroidism. During chronic treatment (i.e., over a period of many weeks to years), many cats will develop a "resistance" to this medication. These cats will need progressively higher daily dosages of methimazole (or carbimazole) in order to keep serum thyroid hormone values within the normal, reference range limits (1-3).

The purpose of this post is to address the following questions:

• What's the highest methimazole dose that can be given?
• What causes this methimazole resistance during long-term antithyroid drug treatment?
• Could this be caused by thyroid cancer?
• What other treatments should be considered?

What's the Highest Methimazole Dose That Can Be Given to Cats?
There is no maximum dose of methimazole for cats.  However, when methimazole doses approach 10 to 15 mg twice daily (20-30 mg/day) and the serum T4 remains high, it is advisable to consider other treatment options (see below).

However, several issues should be first considered.

1. First, ensure that the tablets are consistently being put into the cat's mouth and that the cat is swallowing the pills. Many cats will learn to hold the pill in their mouth and spit it out later when the owner is not watching.  If the medication is given in food, it is common for cats to "eat around" the pill and not swallow it. If oral medication becomes an issue in treatment,  transdermal methimazole can be considered (4,5). 
2. Secondly, the problem may be the use of generic formulations of methimazole, which are not always as bioavailable or effective as brand-name products (Felimazole; Tapazole). A change to a brand-name product can sometimes be helpful.
3. Third, gastrointestinal problems (e.g., inflammatory bowl disease) could be affecting methimazole absorption. If the cat has chronic vomiting or diarrhea, a workup for primary intestinal disease might be required.
4. Finally, we must consider the possibility that a thyroid cancer (carcinoma) has developed, which generally is less responsive to the methimazole than benign thyroid tumors (see below).

Other than the last issue, most of these problems would have been addressed early on in the course of medical management. So these issues are typically not the cause of the methimazole resistance that we see in hyperthyroid cats treated chronically with antithyroid drugs.

Why is the Dose of Methimazole Increasing?
After methimazole (or carbimazole) is administered, the thyroid gland takes up and concentrates the antithyroid from the circulation. Once within the thyroid, methimazole works by inhibiting the production of T4 and T3 from the hyperthyroid cat's thyroid tumor (4,5).

It is imperative to understand that methimazole treatment blocks T4 and T3 production from the hyperthyroid cat's thyroid tumor but does not cure the disease. In cats treated with methimazole, the underlying cause of the hyperthyroidism (a benign thyroid tumor called an adenoma) remains intact. It is, therefore, quite common for hyperthyroid cats on methimazole treatment to need higher dosages of methimazole over time, as the thyroid adenoma continues to grow larger or increases its secretion of thyroid hormone (1-3,6).

Figure 1: Hyperthyroid cat that has developed a large thyroid tumor
after 18 months of methimazole treatment

After months to years of treatment, many of these cats will develop a very large, palpable thyroid tumor (Figure 1) and will become difficult to regulate, even with high daily doses of oral or transdermal methimazole. Some cats eventually become completely refractory to methimazole, so alternative treatment modalities must be considered.

Could This Be Thyroid Cancer?
With enough time and as the disease progresses, the benign thyroid adenoma characteristic of early feline hyperthyroidism can also transform into malignant thyroid carcinoma in some cats (7,8). Again, methimazole or other antithyroid drug therapy does nothing to the thyroid tumor pathology and cannot stop this from happening.

Figure 2: The thyroid scan on the left is from a cat that has become unresponsive to methimazole after 3 years of treatment.  This cat has massive thyroid tumors located both in the neck area but also extending well into the chest cavity (compare to normal thyroid scan on right). This is considered diagnostic for thyroid carcinoma.

As someone who does thyroid imaging and radioiodine treatment, I commonly see cats that have been treated for years with antithyroid drugs and now have very large to huge thyroid tumors. In about 10% of these cats with severe, long-standing hyperthyroidism, the diagnosis is thyroid carcinoma with extension of tumor or metastasis into the chest (Figure 2). It's quite likely that transformation of the tumor from adenoma to carcinoma has occurred in these cats. This may be the natural evolution of the disease; however, antithyroid drugs have been shown to be carcinogenic in rodents, it is possible that the drug treatment is playing a role.

Do All Hyperthyroid Cats Exhibit Progressive Growth of Their Thyroid Tumor(s)?
Fortunately, all cats do not show accelerated tumor growth on methimazole. In a few cats, the thyroid tumor grows very slowly or not at all (7). Most cats, however, definitely have an increase in thyroid size over time. And some cats show a rapid increase in size, just within a few months.

Unfortunately, in a newly diagnosed hyperthyroid cat, we have no way to determine how fast the thyroid tumor is going to grow or its potential for malignant transformation.

What Other Treatments Should Be Considered in Cats Unresponsive To Methimazole?
In cats that develop large thyroid tumors and become resistant to the effects of methimazole, we have 3 options for treatment: radioiodine, surgical thyroidectomy, or nutritional management with a low-iodine diet (Hill's y/d).  Of these 3 options, radioiodine is the treatment option of choice.

Surgery has a major advantage over methimazole and nutritional therapy because the large, potentially malignant thyroid masses are removed and the cat is potentially cured (9). However, complications of surgery are intensified in cats with large thyroid masses. First of all, these larger tumors are very vascular, may be invasive, and can bleed during the surgical procedure. This can make it difficult to identify the parathyroid glands, which must be preserved to prevent a low serum calcium from developing postoperatively. In addition, many of these cats have thyroid tumors that now extend into the thoracic cavity or have metastasized. Therefore, complete surgical removal of all thyroid tumor tissue may not be possible.

In most cats with severe hyperthyroidism and large thyroid masses, the use of nutritional management is not successful in normalizing thyroid hormone concentrations, similar to the methimazole. Even if this form of therapy did successfully lower serum T4 values to normal, the large and potentially malignant thyroid tumors remain, enabling them to continue to grow and possibly metastasize.

Although use of radioiodine is generally successful in treating cats that have been unresponsive to methimazole, these cats can be much more difficult to cure with a single dose of radioiodine than are cats with smaller thyroid tumors or recently diagnosed hyperthyroidism (1-3). Cats with huge benign or malignant tumors require much larger doses of radioiodine to ablate (10 to 30 mCi) the thyroid tumor(s) than do the typical recently diagnosed cats with mild to moderately hyperthyroidism (2 to 6 mCi).  Because these cats have been treated for months to years, they also tend to be older and have many more complications, mainly because of the concurrent diseases (e.g., renal disease) that are common in older cats.

References:

1. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
2. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
3. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 American College of Veterinary Internal Medicine Forum. 2011;104-106.
4. Trepanier LA. Medical management of hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:22–28.
5. Trepanier LA. Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North American Small Animal Practice 2007;37:775-788.
6. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2012; 26:754.
7. 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. Proceedings of European College of Veterinary Internal Medicine; 2012.
8. Hibbert A, Gruffydd-Jones T, 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.
9. Radlinsky MG. Thyroid surgery in dogs and cats. Veterinary Clinics of North American Small Animal Practice 2007;37:789-798.

How to Dose and Monitor Hyperthyroid Cats on Methimazole

Antithyroid drugs, including methimazole and carbimazole, are medications that treat an overactive thyroid (hyperthyroidism) by blocking the thyroid gland's ability to make thyroid hormone. Carbimazole is a "pro-drug" since, after its absorption, it is converted to "active" methimazole in the body; therefore, these drugs can be considered equivalent (1).

Over the 25 years since we first reported the use of methimazole for treatment of cats with hyperthyroidism (2), I have had repeated questions from veterinarians and cat owners about the use of once or twice-daily dosing regimes. In addition, I've had many questions regarding the best time to monitor a hyperthyroid cat's serum thyroid concentrations during methimazole treatment.

The purpose of this post is to review how these drugs actually work to lower serum T4 and T3 values. In addition, I'll provide an overview of my current protocols for dosing and monitoring hyperthyroid cats treated with these drugs.

How Do Antithyroid Drugs Work? What's the Mechanism of Action?
After administration, the thyroid gland takes up and concentrates methimazole from the circulation. Once within the thyroid, methimazole works by inhibiting the production of T4 and T3 from the hyperthyroid cat's thyroid tumor.

More specifically, methimazole blocks thyroid hormone synthesis by inhibiting thyroid peroxidase, an enzyme involved in the oxidation of iodide to iodine, incorporation of iodine into thyroglobulin, and coupling of tyrosine residues to form T4 and T3 (2-7). Methimazole does not block the release of preformed thyroid hormone, so there is generally a delay of 2 to 4 weeks  before serum T4 concentrations return to normal after initializing therapy.

It is important to remember that antithyroid drugs, such as methimazole, do not destroy the thyroid tumor, decrease it's size, or slow the progressive thyroid tumor growth that is characteristic for this disorder. Because the thyroid tumor continues to grow larger over time despite methimazole therapy, the need for higher doses should be anticipated during long term treatment in many cats (6-8).

How Long Does a Dose of Methimazole "Last" After Its Given? 
After oral administration, studies show that methimazole has a relatively short half-life in the circulation—only 2.3 hours and 4.7 hours in hyperthyroid and normal cats, respectively (9,10).  But we must remember that this drug does not work to lower T4 by remaining in the circulation. Rather, this antithyroid drug is taken up by the thyroid gland, the site where it acts to inhibit the production of thyroid hormones.  In accord with that, normal cats show sustained suppression of serum thyroid hormone concentrations for up to 24 hours after a single dose of methimazole (11), proving that this drug inhibits T4 production far beyond its known half-life in the circulation.

Unfortunately, once-daily dosing with methimazole will not be adequate in most cats with hyperthyroidism. In one study of 40 hyperthyroid cats (12), once-daily dosing was much less effective than use of twice-daily administration (the total daily dose given was the same in both groups of cats). In that study, only 54% of cats become euthyroid (i.e., normal thyroid state) after 2 weeks with once daily treatment, whereas 87% of cats became euthyroid with twice-daily administration (12).  Therefore, I strongly recommend twice daily dosing of methimazole to help ensure better control of the cat's hyperthyroid state.

If once-daily treatment is insufficient and twice-daily treatment causes compliance issues, a sustained carbimazole formulation (Vidalta, MSD Animal Health) can be tried at 10 to 15 mg, once a daily (13). However, this drug is not approved for use in the USA and is currently only available in Europe.

For more information about carbimazole and Vidalta, see my last post on Antithyroid Drug Treatment for Hyperthyroidism: Brand Name, Generic, or Compounded Drug? 

Initial Methimazole Dose 
The initial methimazole doses used vary depending on the cat’s pretreatment serum T4 value and the size of the thyroid tumor. In general, however, most cats are started on 1.25 mg to 2.5 mg of methimazole, administered twice daily (4-7). This dose is adjusted according to T4 measurements (see below), as well as the cat's clinical response.

In cats that fail to respond and remain hyperthyroid, the daily doses are slowly titrated upwards to lower serum T4 concentrations into the desired range.  For more information about making dose adjustments, see my blog post on: Treating Cats with Hyperthyroidism: Antithyroid Drugs.

Best Time to Collect Blood (Post-Pill) for Monitoring Cats on Methimazole?
Although one might expect that protocols for monitoring cats on methimazole would be standardized among veterinarians, this is not the case.  Some have stated that the time of serum T4 sampling in relation to the administration of the antithyroid drug is not important, even in cats on once-daily methimazole (11).

However, I strongly disagree with that recommendation. We know that the suppressive effect of methimazole on thyroid secretion is highly variable among hyperthyroid cats, depending on the severity of their disease and size of their thyroid tumor. In addition, we also know that twice daily dosing is more effective and that once daily therapy is less likely to be successful in treatment (12).

The protocol that I use for my hyperthyroid cats is to have the methimazole dosed twice a day (morning and night) and then collect the post-treatment serum T4 sample sometime during the day. Ideally, it would make the most sense to me to take the sample around 6 hours post-pill (half-way between the two methimazole administration times), but the "exact" timing does not appear to  critical.

However, I would recommend that one be consistent in the timing of the post-pill test sample. In other words, do not have your cat tested once in the morning (an hour after the methimaole was given) and then compare those results to another testing time when the sample was collected late in the afternoon (11 hours after the methimazole was administered). In other words, we should try to monitor the post-methimazole serum thyroid hormone values at the same time each hospital visit.

What's the Ideal Serum T4 Concentration for Cats on Methimazole? 
It is important to keep the serum T4 concentration within the mid-normal range and not have even mildly high or high-normal values on methimazole. For example, if the T4 reference range is listed as 0.8-4.0 μg/dl (10-50 nmol/L), my goal is maintain the T4 values between 1.5-2.5 μg/dl (20-32 nmol/L). Recent research indicates that hyperthyroidism may contribute to the development or progression of chronic renal disease in cats (14-16).  Leaving a hyperthyroid cat untreated (or poorly regulated with methimazole or carbimazole) may therefore be detrimental to long-term kidney function and is never recommended.

During long-term treatment, it is also important to avoid inducing hypothyroidism, which may be deleterious to the cat’s kidney function (25,26). If hypothyroidism is suspected, a complete thyroid panel is recommended, including determination of the serum concentrations of total T4, free T4, T3, and TSH (see my previous blog posts on diagnostic testing for more information about these tests). The findings of low serum free T4 with high TSH concentrations is diagnostic for iatrogenic hypothyroidism; in those cats, the daily dose of methimazole  should be decreased.

References:

1. Peterson ME, Aucoin DP. Comparison of the disposition of carbimazole and methimazole in clinically normal cats. Research in Veterinary Science 1993;54:351–355. 
2. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150-157. 
3. Peterson ME: Hyperthyroidism, In: Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Fifth Edition). Philadelphia, WB Saunders Co. 2000; pp 1400-1419. 
4. Trepanier LA. Medical management of hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:22–28.
5. Trepanier LA. Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North American Small Animal Practice 2007;37:775-788.
6. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
7. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
8. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 American College of Veterinary Internal Medicine Forum. 2011;104-106.
9. Trepanier LA, Peterson ME, Aucoin DP. Pharmacokinetics of intravenous and oral methimazole following single- and multiple- dose administration in normal cats. Journal of Veterinary Pharmacology and Therapuetics 1991;14:367–373.
10. Trepanier LA, Peterson ME. Pharmacokinetics of methimazole in normal cats and cats with hyperthyroidism. Research in Veterinary Science 1991;50:69–74.
11. Rutland BE, Nachreiner RF, Kruger JM. Optimal testing for thyroid hormone concentration after treatment with methimazole in healthy and hyperthyroid cats. Journal of Veterinary Internal Medicine 2009;23:1025-1030. 
12. Trepanier LA, Hoffman SB, Kroll M, et al. Efficacy and safety of once versus twice daily administration of methimazole in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 2003;222:954–958.
13. Frenais R, Rosenberg D, Burgaud S, et al. Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidism. Journal of Small Animal Practice 2009;50:510-515. 
14. Lapointe C, Bélanger MC, Dunn M, et al. N-acetyl-beta-D-glucosaminidase index as an early biomarker for chronic kidney disease in cats with hyperthyroidism.  Journal of Veterinary Internal Medicine 2008;22:1103-1110. 
15. 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. Domestic Animal Endocrinology 2009;36:45-56.  
16. van Hoek I, Meyer E, Duchateau L, et al. Retinol-binding protein in serum and urine of hyperthyroid cats before and after treatment with radioiodine. Journal of Veterinary Internal Medicine 2009;23:1031-1037. 
17. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. Journal of Veterinary Internal Medicine 2010;24:863-869. 
18. Williams T, Elliott J, Syme H. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. Journal of Veterinary Internal Medicine 2010;24:1086-1092.