How to Manage Hyperthyroid Cats that Become Resistant to Methimazole

I have a 19-year old female DSH cat who was diagnosed with hyperthyroidism 5 years ago. I chose not to do the radioactive treatment because that treatment required her being away for several days. I didn't want to do surgery to remove the thyroid gland because she was very weak at the time of the initial diagnosis. 

Therefore, I have been treating her with methimazole over all these years. Initially, her daily dosage was 5 mg (divided twice daily). Over the years, it has become necessary to increase this first up to 10 mg/day, then to 15 mg (daily doses divided into 2-3 doses per day). This 15-mg dosage was effective at controlling her hyperthyroidism for a short time, but now her serum thyroid value is high again. Because of the persistent hyperthyroidism, many of her clinical signs have returned. She has lost weight, despite the fact that her appetite has increased.  I have just increased the methimazole dose up to 10 mg twice a day (20 mg/day) but this still does not appear to be helping.  Now I am worried about the effects of the medicine on her kidneys.

Do cats just become accustomed to the methimazole and always need an increasing amount?  How high can we go with the dosage of the methimazole?  

Thank you. 

My Response: 

This scenario that you are describing isn't that uncommon in cats treated with methimazole on a long-term basis. All hyperthyroid cats, as you may know, have one or more thyroid adenomas (benign thyroid tumors), which will continue to grow larger with time (1-7).

Thyroid scans of hyperthyroid cats, illustrating that all of these cats will have a thyroid tumor that will continue to grow larger over time. In some cats, these tumors will become very large or huge, which can lead to "resistance" to methimazole.

How methimazole works to control hyperthyroidism
Methimazole and other antithyroid drugs work by being taken up by the thyroid tumor where the drugs inhibit thyroid hormone production and secretion (1-4,7). Therefore, most hyperthyroid cats will require higher dosages of methimazole to inhibit thyroid hormone secretion as their goiters become larger and the thyroid tumor volume increases.

The methimazole does not change the tumor pathology and cannot stop the tumor from growing (5,6).  In some of these cats, the thyroid adenoma also may transform into a thyroid carcinoma as the disease progresses (6,8). Again, methimazole does nothing to the tumor pathology and cannot stop this from happening.

Why methimazole may become ineffective with time
In answer to one of your questions, hyperthyroid cats do not just become accustomed to the methimazole and need an increasing amount. There is a good explanation for the dose increases and why the drug will fail to work in some cats, especially in those treated chronically.

After use of medical treatment for a number of months to years, many hyperthyroid cats will have fairly large palpable goiters (thyroid enlargement). Because of the large goiter size, these cats can be difficult to regulate and make euthyroid, even when very high daily doses of oral or transdermal methimazole are administered (7). The reason for this is simple— with time, we just can't give a dose of methimazole that is high enough to block thyroid secretion from all of the thyroid tumor cells. In other words, the cat just has too much thyroid tumor tissue and thyroid oversecretion can no longer be adequately suppressed by the methimazole.

How high can we go with the methimazole dose in this cat?
So, what do you do?  The dose of methimazole needed to control hyperthyroid cats is based on what it takes to lower the serum T4 concentration into the reference range, so there is not an upper limit to what methimazole dosage can be used. I've gone as high as 30 mg per day in some cats, although the incidence of side effects tends to be higher as you raise the dose (7). So in your cat, I would continue to raise the dose up to 25 mg and then 30 mg/day, as needed. If this fails to completely control the hyperthyroidism, addition of other drugs such as beta-adrenergic blockers (e.g., atenolol) and/or L-carnitine could also be considered (9, 10).

If your cat was younger, I would strongly recommend definitive therapy (i.e., surgery or radioiodine) in order to remove or destroy the thyroid tumor(s). However, at 19-years of age, that may no longer be feasible, depending on your cat's overall clinical condition.

My Bottom Line:
The underlying cause of hyperthyroidism in all affected cats is a hyperfunctional thyroid tumor. Unless surgically removed or irradiated with radioiodine, these thyroid tumors will tend to grow larger with time, as the disease progressed. If methimazole is used as initial treatment, the drug may eventually become ineffective, even when higher dosages of the drug are used.

Overall, I believe that we should be curing the thyroid tumor in the hyperthyroid cat with definitive treatments, not just controlling the hyperthyroid state for the rest of the cat's life with methimazole. In most hyperthyroid cats, especially those that are young to middle-aged, the use of surgical thyroidectomy or radioiodine are, therefore, the treatments of choice. I do not generally recommend using methimazole on a long-term basis, unless we don't believe that the cat will live for another couple of years. Both surgery and radioiodine can be more difficult in cats with large goiters and severe hyperthyroidism, so early definitive therapy is always best.

References:

1. Peterson ME. Hyperthyroid diseases In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Fourth ed. Philadelphia: WB Saunders Co, 1995;1466-1487.
2. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
3. Mooney CT, Peterson ME. Feline hyperthyroidism In: Mooney CT, Peterson ME, eds. Manual of Canine and Feline Endocrinology Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;199-203.
4. Peterson ME. Hyperthyroidism in cats In: Rand JS, Behrend E, Gunn-Moore D, et al., eds. Clinical Endocrinology of Companion Animals. Ames, Iowa Wiley-Blackwell, 2013;295-310.
5. Gerber H, Peter H, Ferguson DC, et al. Etiopathology of feline toxic nodular goiter. Vet Clin North Am Small Anim Pract 1994;24:541-565.  
6. Peterson M. Hyperthyroidism in cats: What's causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 2012;14:804-818. 
7. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 ACVIM Forum; 2011 June 15–19; Denver, CO. American College of Veterinary Internal Medicine, pp 104–106.
8. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. J Vet Intern Med 2012;26:1523.
9. Peterson ME. Alternative medical treatments for hyperthyroid cats. Conference Proceedings North American Veterinary Conference (NAVC) Conference 2012: Small Animal & Exotics Proceedings 2012;852-858.
10. Peterson ME. Alternative Medical Treatments for Hyperthyroid Cats. Animal Endocrine Clinic blog, September 13, 2012.