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.

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