In clinically hyperthyroid cats, is I-131 treatment superior to thyroidectomy in normalising serum T4 level?

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Appraisal, application and reflection

Summary

Hyperthyroidism is the most common endocrinopathy diagnosed in senior and geriatric cats with a prevalence of 8.7% in cats >10 years of age reported in the UK (Stevens et al., 2014). Management of the disease must be considered on an individual basis considering a multitude of factors including but not limited to the underlying thyroid pathology, concurrent disease especially chronic kidney disease, severity and duration of disease, response to previous treatments, owner finances, available facilities and cat compliance. Radioiodine therapy and thyroidectomy provide definitive therapies for hyperthyroidism.

Many studies that were appraised defined the response to radioiodine therapy and thyroidectomy by the proportion of cats with thyroxine (T4) values within normal reference interval. Many of the studies do not include thyroid stimulating hormone (TSH) analysis so subclinical hypothyroidism could be missed in some cats. Currently, no assay is available that has the sensitivity to detect low TSH levels in cats, but it is possible that a proportion of cats with normal T4 levels may have subclinical hyperthyroidism (normal T4 levels but low TSH levels). This was a limitation that should be considered in answering the PICO and designing future studies.

Post-procedure follow-up of thyroid parameters is a relatively new component in the long-term management and study of feline hyperthyroidism. Generally, more recent papers had incorporated the follow-up period into their study design. The follow-up times varied following radioiodine therapy and thyroidectomy from the hours post-therapy to longer-term follow-ups over years. Peterson et al. (1995) showed that 81.3% cats (422/519) had normal T4 levels 2–3 months following radioiodine therapy, increasing to 87.1% cats (437/502) 6–12 months after radioiodine therapy. When considering the PICO, the length of follow-up should be considered and more prospective studies are needed to clarify the definitive effect of either radioiodine or thyroidectomy on T4 levels in extended follow-up periods.

One limitation across most of the papers reported is that the study populations were identified from referral level practice. It is possible that referral populations may be less reliable in predicting behaviours in primary care populations. Referral practices offer more technical diagnostics and therapies, and often treat patients with more complicated hyperthyroidism. Further studies are needed to look at the long-term outcome of cats managed in primary care setting, especially since thyroidectomy is offered in many practices when radioiodine is not an option for owners. It may be beneficial to also include qualitative studies to understand owner perspectives, concerns and commitment in managing hyperthyroidism long-term.

Radioiodine Therapy

There was a considerably higher number of publications about the follow-up period to radioiodine therapy in cats with hyperthyroidism, compared to surgery. These studies were mainly cohort studies and the majority were prospective in nature, strengthening the evidence of their conclusions. Of 12 papers reporting T4 levels 6 months after radioiodine therapy, approximately 40–87% cats had normal T4.

There was only one randomised controlled trial. In this approximately 85% of cats were euthyroid up to 4 years following treatment (Théon et al., 1994). Peterson et al. (2018) demonstrated in a prospective cohort study that 79.8% cats (209/262) were euthyroid (normal T4 and TSH) 6 months following radioiodine therapy. Although this study distinguished between euthyroid and sub-clinically hypothyroid cats, persistently hyperthyroid cats were excluded from their statistics and longer-term T4 levels were not reported. There were numerous retrospective studies, which by nature provide weaker evidence supporting the PICO. However, many of these retrospective studies had strict inclusion criteria, large population sizes and the power to follow-up longer-term responses. A retrospective study by Chun et al. (2002) in a study population of 193 cats found that over 150 had normal T4 levels 12 months after radioiodine therapy, or 77.7% (a similar finding to the prospective study by Peterson et al., 2018). Finch et al. (2019) found that five cats that were hyperthyroid 1 month after radioiodine therapy were euthyroid by 6 months in a relatively small population of 25 cats. A limitation of most of these papers, especially the retrospective studies, was that they were mainly testing other variables including radioiodine dosing or pre-radioiodine T4 stabilisation.

As discussed previously, more prospective data is needed throughout the follow-up period following radioiodine therapy, with controls including using the same testing laboratory for T4 values, to identify the true proportion of cats that have normal T4, iatrogenic hypothyroidism or persistent hyperthyroidism after treatment.

Thyroidectomy

Only five publications were evaluated exploring how thyroidectomy influenced long-term T4 levels after surgery, specifying euthyroid status. Three of these papers were published prior to 2000 where long-term T4 monitoring was not incorporated into study objectives.

The most recent publication by Covey et al. (2019) reported 13/68 (19%) were euthyroid 6 months after bilateral thyroidectomy and 19/23 (83%) were transiently euthyroid 595–1955 days after bilateral thyroidectomy; a value similar to the proportion of cats with normal T4 levels following radioiodine therapy. Only 23 cats were analysed long term in this retrospective study, which by nature is a weaker form of evidence. The study reported a high proportion of recurrent hyperthyroidism 10/23 (44%) in cats after surgery and over time cats were more likely to revert from euthyroidism to hyperthyroidism. Although a smaller population size, the study measures TSH to confidently distinguish between euthyroidism and hypothyroidism. The remaining four studies measured T4 levels in cats receiving both unilateral and bilateral thyroidectomy. DiBartola et al. (1996) found that T4 levels were significantly lower following bilateral thyroidectomy but did not report the normal reference interval.

Interestingly they did not find a significant difference between T4 levels between day 30 and day 90 post-surgery. There was also no significant difference between surgery and radioiodine therapy in this study. Graves et al. (1994) found that 46% (6/13) cats were euthyroid following bilateral thyroidectomy and the remaining were hypothyroid 30 days after surgery. Birchard et al. (1984) followed 85 cats prospectively, which increases the strength of the evidence. There were relatively small numbers of cats in each group; 32 receiving unilateral thyroidectomy and 53 receiving bilateral thyroidectomy. It was found that all cats had T4 within the reference interval 48 hours following surgery but four cats from the bilateral thyroidectomy group relapsed into hyperthyroidism within 8–44 months after surgery. Although the exact number was not included, the study reported that the majority of cats had below normal T4 2–3 months after unilateral thyroidectomy but did not require T4 supplementation since cats did not show outward clinical signs of hypothyroidism. The importance of long-term thyroid evaluation is important following either unilateral or bilateral thyroidectomy to identify subclinical hypothyroidism and hyperthyroid remission.

Naan et al. (2006) found that all cats that had undergone unilateral thyroidectomy were in remission long-term. True unilateral disease was confirmed with thyroid imaging and as such, unilateral thyroidectomy was very successful on long-term thyroid evaluation. Only nine cats had true unilateral disease and the study was retrospective. In bilateral disease, many cats have asymmetrical thyroid enlargement with one lobe being very enlarged and one lobe minimally enlarged. Unilateral thyroidectomy may restore euthyroidism in these cats and it could take many months before the remaining lobe grows enough for hyperthyroidism to recur (Peterson, 2011). A prospective study with more cats may be difficult to perform since radioiodine is more widely available and associated with higher remission and fewer clinical signs. The 81 cats that received bilateral thyroidectomy remained in remission 13 months following surgery.

A large proportion of studies did not measure TSH levels, alongside T4 levels, in cats following either thyroidectomy or radioiodine therapy. Without TSH levels, it is difficult to distinguish between euthyroidism and subclinical hypothyroidism following treatment. Finch et al. (2019) measures T4 and TSH levels and found that 20% cats developed overt or subclinical hypothyroidism within 12 months of radioiodine therapy.

Conclusion

In answer to the PICO, there is more evidence available from observational studies showing that radioiodine therapy is more effective at normalising T4 levels compared to unilateral or bilateral thyroidectomy. It is relatively new for studies to incorporate long-term T4 monitoring in their study designs, particularly focusing on hyperthyroidism remission and iatrogenic hypothyroidism. More studies are required with a prospective or randomised design with larger sample sizes and lifelong thyroid evaluation to improve the evidence-base available. This is especially important in determining the long-term effect of thyroidectomy on T4 values, as fewer papers are available.

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