Stijn J.M. Niessen, DVM, PhD, DECVIM, PGCertVetEd, FHEA, MRCVS
Senior Lecturer Internal Medicine, Royal Veterinary College, University of London, London, UK; Research Associate, Newcastle Medical School, Newcastle, UK; Consultant, Veterinary Information Network, Davis, CA, USA
For many clinicians, treatment options for feline hyperthyroidism have never been as diverse as they currently are. This also means clinicians have more options to discuss with owners of newly diagnosed hyperthyroid cats and more complicated decisions need to be made. It is probably fair to say that expert opinions about their relative efficacy are at times equally diverse, especially when it comes to the dietary management of the disease. This lecture will attempt to illustrate that each treatment modality actually could present the optimal choice for a specific cat-owner combination by discussing their advantages and disadvantages. The lecture will use case examples and adopt an unbiased approach being guided by recent study data.
What Are Our Main Options?
The currently most effective available treatment options are: 1. thyroidectomy; 2. methimazole or carbimazole treatment; 3. ultra-low iodine diet; and 4. radioactive iodine. The open minded up-to-date clinician should discuss all these options with the care-taker of a newly diagnosed hyperthyroid cat, before instituting the chosen therapy, especially since not all cats and not all owners are the same. The optimal treatment for an individual cat-owner combination might be different from case to case. Below are examples of cases where each treatment modality provides a good solution.
The 8-Year-Old Healthy Domestic Short-Haired Cat
In a young, seemingly healthy cat, a treatment option that is permanent and does not require ongoing treatment is usually preferable, both from a medical and a financial point of view. Methimazole or carbimazole treatment or low-iodine dietary management are of course still possible, though would not fulfil the above criteria.
Additionally, some hypothesise that it is possible for adenomatous thyroid glands to transform into a carcinomatous process when given enough time, further emphasising the possible benefit of curing the disease as soon as possible by removing the adenomatous tissue, versus merely inhibiting the production of hormone and leaving the tissue in place. One report followed 1572 hyperthyroid cats which were divided into 5 groups based on interval from diagnosis to 131I treatment. When the estimated thyroid volumes in the 5 groups of cats were compared, a progressive, significant increase in median tumour volume occurred the longer the wait between diagnosis and permanent treatment. Additionally, the prevalence of cats with areas of increased radionucleotide uptake within the thoracic cavity also increased progressively from 5.1% to 26.1%. Finally, the prevalence of suspected thyroid carcinoma also increased progressively from 0.7% to 21.7%. These results confirm the suspicion that hyperfunctional thyroid tissue continues to grow and enlarge over time and provide circumstantial evidence that transformation from benign disease into thyroid carcinoma occurs more often the longer a cat is controlled medically. Thyroidectomy and radioactive iodine are therefore logical choices in the relatively young and healthy cat.
The higher up-front costs of both modalities are usually offset by the lack of need of ongoing treatment and monitoring for many years to come. Thyroidectomy in experienced hands will only rarely be associated with postoperative hypocalcaemia (< 5%), although obviously success rates vary with the experience of the surgeon. The need for a general anaesthetic usually means that preoperative stabilisation is required with either methimazole, carbimazole, atenolol or low-iodine diet to at least ensure the patients are cardiovascularly stable. It should be emphasised that in the majority of cases (70%) both thyroid lobes will be affected and hyperthyroidism returns in time when unilateral thyroidectomy is performed. Bilateral removal is therefore advocated (either staged or during one procedure). Many textbooks and experts will refer to radioactive iodine as the gold-standard treatment for hyperthyroidism in the cat. Indeed treatment with radioactive iodine is simple, safe and effective, without the need of such anaesthetic is reasonably well behaved cats. The radioisotope 131I is most frequently used and after subcutaneous (most popular), intravenous or oral administration will concentrate in the thyroid gland. Since only the adenomatous or hyperplastic (or rare carcinomatous) thyroid tissue will take up the radioactive iodine, the healthy thyroid tissue, which is dormant through suppression induced by negative feedback, will usually be spared, ready to gradually start functioning again when the excess thyroid concentrations (and negative feedback) subside. The 131I emits predominantly (90%) beta-rays (10% gamma) which have a very limited penetration depth (0.6 to 2 mm) ensuring the sparing of euthyroid tissue in most cases. Dosing schedules vary across institutions, though are often based on clinical image (more severely affected cats receive more), total thyroxine concentration (the higher the plasma concentration, the higher the dose) and size of the thyroid nodule (the bigger, the higher the dose). Ultimately, most cats are treated with doses between 50 and 200 MBq. Nevertheless, more recent research suggests a possible role for lower dose treatment, especially given the realisation that overdosing could increase the prevalence of post-treatment hypothyroidism, which in turn seems associated with an increased incidence of renal azotaemia and mortality.
Indeed, hypothyroid cats that develop azotaemia after treatment (with any modality) seem to experience shorter survival times (median 456 days, range 231–1589 days) than those that remain non-azotaemic (median survival 905 days, range 316–1869 days). Peterson and Broome (2014) treated 131 cats with mild hyperthyroidism and small thyroid volume with low doses of 131I (median 68 MBq). Before treatment, the serum T4 concentrations ranged from 3.5–20.8 µg/dl (median, 6.2 µg/dl, reference range, 0.8–4.0 µg/dl. After treatment median T4 concentrations normalised and at 3 months, T4 values were within normal limits in 125 cats (95%), low in 4 (3%), and persistently high in only 2 (1.5%). In 3 of the 4 cats with low T4 values, hypothyroidism was confirmed by measuring a high endogenous TSH. Results of this recent study therefore confirm once again radioactive iodine to be a safe and effective treatment option though also suggest a push for the use of low dose radioiodine treatment (≤ 75 MBq), especially when thyroid tumour volume is modest. If iatrogenic hypothyroidism does develop (diagnosed through documenting clinical signs, low T4 and, ideally, high endogenous TSH), treatment with L-thyroxine (0.1 mg once to twice daily) is indicated. The dosage should be adjusted based on post-pill serum T4 and cTSH determinations and correct dosing should normally result in improvement of azotaemia.
A recent study assessing owners' feelings (n = 158) about radioactive iodine treatment reported a moderate level of concern about treatment hospitalisation length, which included the possibility of the cat being unhappy 130 (82.3%), owner missing the cat 102 (64.6%), inappetence 50 (31.6%), other pets missing the cat 32 (20.3%), development of comorbid disease 28 (17.7%) and side effects 25 (15.8%). Nevertheless, owners assessed their cat's quality of life on a scale of 1 (very poor) to 10 (excellent), as 4 pre-radioiodine and 9 post-radioiodine. Overall, 91.7% were happy with their decision to choose 131I, confirming acceptability of this modality to owners.
Finally, should a cat not respond to the first injection (in the author's clinic approximately 2% of cases), a second injection usually proves effective, unless we are in fact dealing with the rare occurrence of a thyroid carcinoma.
The 18-Year-Old Healthy Domestic Short-Haired Cat - Easy to Pill
Given the prevalence of chronic kidney disease (CKD) in the elderly cat population (30–40%) this patient represents a slightly different scenario. If we also take into account the lack of sensitivity of blood creatinine for the detection of (mild) CKD, especially in those patients with reduced muscle mass (therefore reduced creatinine concentrations) and hyperthyroidism (which increases glomerular filtration rate) the possibility of such patient having masked CKD is real. Any post-hyperthyroidism treatment drop in GFR could therefore unmask the CKD resulting in worsening clinical signs and even uraemic crises. Adding to this the fact that such 18-year old cat is unlikely to live many more years and might pose an anaesthetic challenge, the relative financial investment into the treatment might further influence the treatment decision cat owner and clinician make together. If tolerated by the cat, methimazole or carbimazole treatment or feeding a low-iodine diet will represent possibly good alternative choices in this case scenario.
The antithyroid drugs of choice are carbimazole (which also comes in a once daily slow-release formulation) and methimazole. Methimazole should be initiated at a starting dose of 2.5–5 mg/cat q 12 hours and then titrated to effect. Most cats (90%) become euthyroid within 2–3 weeks. A low starting dose and meticulous monitoring of urine specific gravity, urea and creatinine, can be advantageous in such elderly cat with concerns over renal failure. Should one find that more than 20 mg/cat q 12 hours is needed to control the T4, it is unlikely that higher doses would work either and an alternative modality (radioactive iodine, surgery, diet) should be considered instead of further raising the dose. The starting dose for once daily slow-release carbimazole is 15 mg/cat SID, though in mild cases (mild to modest increase in T4) 10 mg often is effective. Side effects are unfortunately not uncommon, though usually mild, and have been reported to occur in up to 20% of medically treated cases. Most common side-effects include gastrointestinal signs (anorexia, vomiting, lethargy), facial pruritis, icterus, and bleeding diatheses. Haematological abnormalities develop in 5–15% of cats and may include agranulocytosis and thrombocytopenia. For this reason, monitoring should ideally include haematology, basic biochemistry and T4 concentration every 2–4 weeks for the first 3 months of therapy.
Overall, the obvious advantages of oral antithyroid drug therapy include the low up-front costs, no need for anaesthesia, and avoidance of a surgical procedure under anaesthetic or isolation following radioactive iodine. Additionally, it allows more careful titrating of treatment effect compared to all other treatment modalities, which is of particular interest, when dealing with a cat with the possibility of significant co-morbidities and especially renal disease. If renal status worsens significantly, and especially if the associated clinical picture deteriorates, the dose can be immediately reduced (or treatment temporarily completely halted) resulting in a subsequent increase in GFR. For this reason methimazole or carbimazole have been used as a test to evaluate the effect of restoring euthyroidism on renal function, a sort of "sneak preview" prior to choosing thyroidectomy or radioiodine. However, the necessity of this approach in cats without pre-treatment azotaemia is currently being questioned. Critics argue that it has been shown that hyperthyroidism itself can, in the long-term, be detrimental to the renal function through a variety of mechanisms. Therefore, clinicians should always try to opt for definitive treatment unless there is a strong chance of immediate deterioration (which would be the case in IRIS Sage 3 and 4 CKD cases). This line of thinking is substantiated by a study showing that survival of cats that do develop azotaemia is not shorter than those that do not develop azotaemia after treatment of hyperthyroidism (median survival azotaemia developers 595 days 584 days for those that did not develop azotaemia) after treatment. Overall, definitive therapy with 131I or surgery should probably be avoided in cats in the higher IRIS Stages (3 or 4), unless taking many precautions including considering immediate post-procedure supplementation (controversial).
The 12-Year-Old Domestic Short-Haired Cat with IRIS Stage 1–2 Renal Disease - Nightmare to Pill
This perhaps is the most difficult patient type to decide upon. Using topical methimazole might be of interest here, since it still allows some titration of the treatment effect, despite it being less reliable in terms of bioavailability compared to oral formulation. Topical treatment enables administration in those cats whose owners cannot administer tablets. Additionally, topical treatment has been associated with fewer gastrointestinal side-effects. The methimazole is usually compounded into a Pluronic lecithin organogel (concentration 5 mg/0.1 ml), which is then applied to the non-haired portion of the pinna (owner needs to wear gloves). Given the risk of deterioration of renal status the reversibility of treatment.
A second option to consider for the last two types of patients might include feeding an ultra-low iodine diet. Two main conditions need to be fulfilled for this treatment modality to be successful from a hyperthyroidism point-of-view: the cat would need to a. like the food and b. eat this food exclusively. Given the novelty of this treatment option, extensive data, and especially long-term follow-up data, are lacking. A 2013 study documented its use in 225 cats, although a high drop-out rate was reported. Due to loss of follow-up, presented data only included 68 of the original 225 cats (30%) after 2 months of treatment. Clinical signs and circulating T4 concentrations decreased significantly in this smaller group within 4 weeks of starting the diet and were within the reference interval in 51/68 cats at week 8. The most common reason for failure to control the hyperthyroidism seems access to other iodine-containing food, with even the smallest amounts being able to induce treatment failure (these small amounts will be present in snacks, human food treats, some medications or alternative water sources). Dietary management will therefore be difficult in outdoor cats or cats with the need for other dietary intervention, such as those with atopy or inflammatory bowel disease. The currently available low-iodine diet (Hill's y/d) is acceptable for early renal disease cases, given its modest amount of phosphorus and high-quality protein content (36% dry-matter basis). However, in more severe renal disease cases, a truly restricted protein renal diet is needed. Diligent follow-up (e.g., blood urea, creatinine and phosphorus, urine protein measurements) is recommended in renal disease cases according to established internationally agreed guidelines (see IRIS website).
The dietary route might also be of benefit to other cats not suitable to definitive options or antithyroid medication, because of concurrent non-thyroidal illness, adverse reactions to methimazole/carbimazole and/or owner finances or whilst waiting for surgery or radioactive iodine treatment. Disadvantages of the dietary route include the fact that the thyroid adenoma is being left in place with this option and therefore this does not represent a definitive curative option. Additionally, titration is not possible with this option, should renal disease be unmasked, whereas this is possible by reducing the dose of antithyroid medication (though in more marked renal disease cases a lower protein diet would be advisable).
In the treatment of feline hyperthyroidism, more options are available than ever before. Rather than seeing this as a dilemma or to split the veterinary community into camps, it can only be welcomed as an opportunity to pick and choose the treatment option of choice for each cat-owner combination according to the individual circumstances. It is difficult to make a 100% wrong decision, though appreciating the intricacies of each modality with regards to costs, availability, long-term effect, reversibility, compliance and possible complications will enable clinicians to end up with a happy owner and a happy cat.
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