Treating Hyperthyroidism
World Small Animal Veterinary Association World Congress Proceedings, 2013
Carmel T. Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS
University College Dublin Veterinary Hospital, UCD, Belfield, Dublin, Ireland

For many years, surgical thyroidectomy and thyroid ablation using radioactive iodine have been the most popular and effective curative methods available for feline hyperthyroidism. Medical management is non-curative, but offers a practical option for many patients. It is frequently used in cats, both for long-term control and prior to surgery, to decrease the metabolic and cardiac complications associated with anaesthetising hyperthyroid cats. Recently, the advent of an iodine-restricted diet offers an alternate management for hyperthyroidism.

Antithyroid Drugs

Methimazole and carbimazole are the drugs most frequently used for preoperative and long-term medical management of hyperthyroidism because of their consistent and potent effect in lowering thyroid hormone concentrations. Both are actively concentrated by the thyroid gland where they inhibit thyroid hormone production. Carbimazole is converted to methimazole and only methimazole accumulates in the thyroid gland. A 5-mg dose of carbimazole is equivalent to 3 mg of methimazole. Methimazole is available as both human and veterinary formulations [Felimazole (2.5 and 5 mg), Dechra Veterinary Products]. Carbimazole is also available as a preparation for human use. More recently, a novel once daily controlled-release formulation (10 or 15 mg tablets) was licenced for cats in Europe [Vidalta (10 and 15 mg), Intervet Schering Plough]. Based on relative bioavailability and conversion, 15 mg of this preparation is equivalent to approximately 7.5 mg of conventional methimazole. Administration with food significantly enhances absorption.

Today, cats are less severely affected with hyperthyroidism and currently the recommended starting dose for methimazole is 2.5 mg and for carbimazole is 5 mg administered twice daily. The starting dose for controlled-release carbimazole is 15 mg administered once daily. In mild cases (defined as total T4 concentration between 50 and 100 nmol/L), a lower dose of 10 mg daily is recommended.

The length of time to achieve biochemical euthyroidism is relatively rapid occurring within a week, at least in most cases. However, cats are usually not reassessed until after 10 days (controlled-release formulations) or 3 weeks (conventional tablets). A serum total T4 concentration is measured and if within the low end or below the reference range, thyroidectomy can be performed administering the last dose on the morning of surgery. For severely affected cats, even if biochemical euthyroidism is achieved, a longer course of preoperative therapy may be required before the animal is considered a reasonable surgical candidate. The dose is adjusted as for long-term maintenance. If euthyroidism has not been achieved, the dose of methimazole or carbimazole can be altered in 2.5 to 5 mg increments, reassessing the cat again in two to three weeks. Lack of owner or cat compliance should first be eliminated as a reason for a failure of therapy.

For long-term management, once euthyroidism has been achieved, the daily dosage is adjusted aiming for the lowest possible dose that effectively maintains euthyroidism. Achieving this is limited by available tablet size, as neither conventional nor controlled-release formulations can be broken or crushed. Methimazole can be continued at a dose of 2.5 mg twice daily. Although divided doses are most effective in rapidly inducing euthyroidism, it has been reported that at four weeks there is no significant difference in the percentage of cats achieving euthyroidism using 2.5 mg administered twice daily versus 5 mg administered once daily. Consequently, administering 5 mg of methimazole chronically may be attempted. Experience suggests that once daily dosing with 2.5 mg is also efficacious in many cats. Conventional carbimazole has been recommended chronically at a dose of 5 mg administered twice daily, but continuing with once daily therapy may also be effective. Further increasing the dosing interval results in recurrent hyperthyroidism. For controlled-release carbimazole, the majority (approximately 90 %) can be effectively maintained on doses between 10 and 20 mg daily. A few cases require lower doses (10 mg every other day) and only rarely do cats require higher doses.

In many cats, antithyroid drug therapy results in serum total T4 concentrations below the reference interval. Clinical signs of hypothyroidism rarely develop, and surgical risks are not increased. However, emerging evidence suggests that this should be avoided long-term and dose adjustments are made such that the serum total T4 is maintained in the lower half, but not below, the reference interval.

While antithyroid dugs are routinely administered orally, compliance can be problematic, particularly in fractious or inappetent cats. Drug absorption is also potentially affected by concurrent intestinal disease and there are obvious difficulties in cats that vomit. Methimazole and carbimazole can be formulated in a pluronic lecithin organogel (PLO) or as a lipophilic preparation for transdermal application. This may provide a useful alternative to oral administration and several studies have shown reasonable efficacy. Recommendations for starting doses and follow-up adjustments are similar for transdermal and oral administration. Whilst undoubtedly an option for treating hyperthyroidism, there are no transdermal products specifically available for use in cats except in Australasia. Custom formulation increases expense of therapy and stability of the product is not guaranteed. It remains unclear whether there is true transdermal absorption or direct ingestion of the drug.

Most clinical adverse reactions occur within the first three months of therapy. Mild clinical side effects of vomiting, with or without anorexia and depression, occur in approximately 10 to 15 % of cats, usually within the first three weeks of therapy. In most cases, these reactions are transient and do not require drug withdrawal. Self-induced excoriations of the head and neck have occasionally been described, usually within the first six weeks of therapy. Permanent withdrawal of the drug together with symptomatic therapy is usually required although there are anecdotal reports of recovery without drug withdrawal. More serious haematological complications occur in less than 5 % of cases and include agranulocytosis and thrombocytopenia, either alone or concurrently, or, more rarely, immune-mediated haemolytic anaemia. A hepatopathy characterized by marked increases in liver enzymes and bilirubin concentration occurs in less than 2 % of cats. Withdrawal of the medication and symptomatic therapy is required.

Surgical Thyroidectomy

Surgical thyroidectomy is an effective treatment for hyperthyroidism. In practice, it is often considered the treatment of choice, particularly if radioactive iodine is unavailable. The majority (>70 %) of cats require bilateral thyroidectomy. If a unilateral thyroidectomy is carried out, future monitoring for recurrence of the condition is required. Routine bilateral thyroidectomy, whilst increasing the risk of post-operative complications, obviates the need for decision making at the time of surgery. However, ectopic thyroid tissue should be considered if hyperthyroidism persists after routine thyroidectomy.

Two main techniques (modified intra- or extracapsular) have been described for thyroidectomy, both of which attempt to preserve the cranial (external) parathyroid gland and maintain eucalcaemia. There is no significant difference in the rate of postoperative hypocalcaemia or recurrence between the two techniques and both are considered equally appropriate for bilateral thyroidectomy in cats. The final choice is usually dependent on personal preference and experience.

The most significant post-operative complication is hypocalcaemia that occurs within one to five days of surgery. Other complications include haemorrhage, Horner's syndrome, laryngeal oedema or paralysis, voice change and recurrence. It is difficult to accurately assign a risk for hypocalcaemia and recurrence in a cat undergoing bilateral thyroidectomy as it is highly operator dependent. In one study of the modified intracapsular technique performed by an experienced surgeon, a low rate of postoperative hypocalcaemia (< 6 %) and recurrence (5 %) was found.

Radioactive Iodine

Treatment with radioactive iodine is simple, safe and effective and is possibly the best treatment for most hyperthyroid cats. The radioisotope most commonly used is 131I, which, like stable iodine, is concentrated by the thyroid gland. 131I can be administered intravenously or orally, but the subcutaneous route is preferred. The dose is based on the severity of the clinical thyrotoxicosis, the size of the thyroid gland and a circulating total T4 concentration. Most cats are treated with doses between 50 and 200 MBq. A single treatment induces euthyroidism in over 90 % of treated cats. There are few complications of 131I therapy. Persistent hyperthyroidism can be successfully managed with a repeat injection, although in some cats euthyroidism spontaneously develops within weeks to months of treatment. Permanent hypothyroidism is rare as is recurrence after successful treatment and other side effects are minimal. Several drawbacks exist. Facilities for 131I are only available in a few referral centres and post-treatment hospitalization times are usually approximately 2 to 4 weeks.

The long-term prognosis for cats treated with radioiodine is excellent with median survival times exceeding two years.

Restricted Iodine Diets

Recently, a restricted iodine diet has been marketed for the control of hyperthyroidism (Hill's y/d). Exclusively feeding this diet has been shown to normalize thyroid hormone concentrations in mildly affected animals. However, although an attractive option, no large-scale studies have been completed to date.

Effects on the Renal System

Hyperthyroidism is known to increase glomerular filtration rate (GFR), decrease circulating creatinine concentration and mask underlying renal disease. Decreased GFR, increased serum urea and creatinine concentration and development of overt clinical signs of renal disease have all been reported after successful treatment of hyperthyroidism, irrespective of therapeutic modality. Its prevalence has been estimated at approximately 33 %. The decline in GFR is detectable within one month of treatment of the hyperthyroidism, but remains stable for at least 6 months thereafter. Assessment of GFR before treatment can act as a predictor of post-treatment renal failure with a low GFR in hyperthyroidism indicating an increased risk for post-treatment azotaemia. However, techniques for assessment of GFR are not widely used in practice. In their absence, accurate prediction of impending renal failure is difficult. Routine pre-treatment parameters, such as serum urea or creatinine concentrations, and urine specific gravity have not been considered consistently useful. Because of these difficulties, trial therapy using either methimazole or carbimazole has been recommended with reassessment of renal function once euthyroidism is achieved. If no marked deterioration occurs, then a more permanent therapeutic option for hyperthyroidism may be selected. However prudent this may be, its necessity is questionable, given that treatment for the hyperthyroidism is required whatever the outcome. Interestingly, the survival of cats that develop azotaemia is no different to those that remain non-azotaemic after treatment of hyperthyroidism (MST of 595 compared with 584, respectively). The treatment of cats with pre-existing renal insufficiency is complicated given that it significantly adversely affects survival. Initially low and then increasing doses of methimazole have been suggested in such cats, but there is limited evidence to support this. Concurrent therapy should always be instituted for renal insufficiency and careful monitoring carried out. Maintenance of a mildly hyperthyroid state, while anecdotally recommended, is questionable given that hyperthyroidism may in itself be damaging to renal function. In treated cats, avoidance of hypothyroidism is important because it may have its own detrimental effects on GFR. In support of this, a recent study has found that iatrogenic hypothyroidism appears to contribute to the development of azotaemia in treated hyperthyroid cats and adversely affects survival.

Table 1: The advantages and disadvantages of medical and radioactive iodine management

Medical management

Radioactive iodine therapy

Surgical thyroidectomy

Advantages

Practical option

Curative with one single treatment

Curative

Effective and safe

Effective and safe

Effective

Few specific contra-indications

Minimal adverse effects

No special radiation facilities required

Rapid return to euthyroidism

Rapid return to euthyroidism

Avoids isolation and need for daily therapy

Oral and transdermal applications

Subcutaneous route

  

Avoids prolonged hospitalisation and surgery

Avoids surgery and need for daily medication

Disadvantages

Dependent on owner and cat compliance

Few facilities available

Experience necessary

Transient effect

High up-front costs

Medium up-front costs

Adverse reactions can occur

Prolonged hospitalisation

High risk of postoperative complications

Optimal dosing avoiding hyper and hypothyroidism can be difficult to attain

Not applicable for cats requiring intensive management of concurrent conditions

Decision on unilateral vs. bilateral can be difficult

Question of transformation to thyroid carcinoma long term

Hypothyroidism may develop albeit transiently

Pretreatment required

References

1.  Frenais R, Burgaud S, Horspool LJ. Pharmacokinetics of controlled-release carbimazole tablets support once daily dosing in cats. J Vet Pharmacol Ther. 2008;31:213–219.

2.  Frenais R, Rosenberg D, Burgaud S, et al. Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidism. J Small Anim Pract. 2009;50:510–515.

3.  Hill KE, Gieseg MA, Kingsbury D, et al. The efficacy and safety of a novel lipophilic formulation of methimazole for the once daily transdermal treatment of cats with hyperthyroidism. J Vet Intern Med. 2011;25:1357–1365.

4.  Williams TL, Peak KJ, Brodbelt D et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med. 2010;24:863–869.

5.  Williams TL, Elliott J, Syme HM Association of iatrogenic hypothyroidism with azotemia and reduced survival in cats treated for hyperthyroidism. J Vet Intern Med. 2010;24:1086–1092.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Carmel T. Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS
University College Dublin Veterinary Hospital, UCD
Belfield, Dublin, Ireland


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