NON-SURGICAL TREATMENT OF FELINE HYPERTHYROIDISM: OPTIONS AND CONSIDERATIONS

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1 Vlaams Dier ge nees kun dig Tijd schrift, 2007, 76, Re view article 69 NON-SURGICAL TREATMENT OF FELINE HYPERTHYROIDISM: OPTIONS AND CONSIDERATIONS Niet-chi rur gi sche be han de ling van hy pert hy re o ïdie bij de kat: op ties en over we ging en 1 I. van Hoek, 2 K. Pe re mans, 1 T. Wael bers, 2 E. Van der meu len, 1 S. Da mi net 1 De part ment of Me di ci ne and Cli ni cal Bi o lo gy of Small Ani mals, Fa cul ty of Ve te ri na ry Me di ci ne, Ghent Uni ver si ty, Sa lis bu ry laan 133, B-9820 Me rel be ke 2 De part ment of Me di cal ima ging of Do mes tic Ani mals, Fa cul ty of Ve te ri na ry Me di ci ne, Ghent Uni ver si ty, Sa lis bu ry laan 133, B-9820 Me rel be ke, Bel gi um ing rid.van hoek@ugent.be ABSTRACT Feline hyperthyroidism is currently the most diagnosed endocrine disorder in cats. It is caused by benign ade no ma tous hy per pla sia of the thy roid gland in 98% of the ca ses. The two ma jor non-sur gi cal tre at ment op ti ons, administration of antithyroid drugs and radioiodine therapy, are reviewed in this article. Before treatment is initiated, special attention should be given to renal and cardiovascular function. Antithyroid drugs contain thiourylenes, which block the syn the sis of thy roid hor mo nes. The ra py should be star ted at a con ser va ti ve dose with mo - ni to ring of the pa tient for side ef fects. Ra di oi o di ne is ta ken up by the hy per ac ti ve cells of the thy roid tu mor. The decay with emission of β-particles causes local destruction of the surrounding follicle cells. Radioiodine is conside red the tre at ment of choi ce in most cats. SAMENVATTING Hyperthyreoïdie bij de kat is momenteel de meest gediagnosticeerde endocriene aandoening bij de kat. De aandoening wordt veroorzaakt door goedaardige adenomateuze hyperplasie van de schildklier in 98% van de gevallen. De twee belangrijkste niet-chirurgische behandelingen, de toediening van schildklierremmers en de radiojoodtherapie worden in dit artikel besproken. Alvorens met de therapie wordt gestart, verdienen de nierfunctie en cardiovasculaire functie speciale aandacht. Schildklierremmers bevatten thiourylenen die de synthese van schildklierhormonen blokkeren. De therapie dient gestart te worden met een conservatieve dosis en de patiënt wordt voor nevenwerkingen opgevolgd. Radiojood wordt opgenomen door de hy per ac tie ve cel len van de schild klier tu mor. Het ver val met de uit stra ling van β-partikels veroorzaakt een lokale destructie van omgevende follikelcellen. Radiojoodtoediening wordt beschouwd als de beste behandelingsoptie bij het merendeel van de patiënten. INTRODUCTION In about 98% of the ca ses the ex ces si ve pro duc ti on and secretion of thyroid hormones causing thyrotoxicosis in feline hyperthyroidism is due to benign adenomatous hy per pla sia of the thy roid gland (Mee king, 2005). Thy roid glands of hy pert hy roid cats con tain sing le or multiple hyperplastic nodules ranging in size from less than 1 mm to 3 cm in one lobe in +/- 30% of the ca ses (uni - la te ral af fec ti on) or in both lo bes in +/- 70% of the ca ses (bilateral affection) (Holzworth et al., 1980). Occasionally (2%) malignant tumors are observed. The etiology of feline hyperthyroidism is likely to be multifactorial. Environmental fac tors such as fee ding of can ned food or the use of cat lit - ter (Kass et al., 1999; Edin bo ro et al., 2004), overexpression of on co ge nes such as c-ras (Merryman et al., 1999), and al - tered G protein expression (Ward et al., 2005) have been as - sociated with the disease. Hyperthyroid cats are usually older than 10 years. Commonly observed clinical signs

2 70 Vlaams Diergeneeskundig Tijdschrift, 2007, 76 Figure 1. Enlarged thyroid nodule of a hyperthyroid cat. include polyphagia, polyuria, polydipsia, weight loss, behavioral changes like hyperactivity, an unkempt hair coat and gastrointestinal signs. An atypical presentation with the pre sen ce of anor exia and le thar gy is pos si ble as well, which may be re la ted to the chro ni ci ty and se ve ri ty of the disease (Bucknell, 2000) or an underlying disorder complicating the hyperthyroidism. Clinical signs can be less pronounced when the disease is diagnosed early (Broussard et al., 1995). Clinical examination reveals a pal pa ble cer vi cal no du le (s) in more than 90% of hy per - thy roid cats (Tho day and Moon ey, 1992; Nors wort hy et al., 2002). Fi gu re 1 shows a lar ge cer vi cal no du le in a cat diagnosed with hyperthyroidism. Tachycardia and systolic he art mur mur are pre sent in 60 and 30%, res pec ti ve ly, of hy pert hy roid cats (Tho day and Moon ey, 1992). Di ag - nosis is confirmed by measurement of an increased serum total T4 (TT4) concentration. Feline hyperthyroidism is currently the most diagnosed endocrine disorder in geriatric cats (Meeking, 2005). It was first re por ted in cats in 1979 (Pe ter son, 1979). Therapeutic options include administration of radioiodine ( I) or antithyroid drugs such as methimazole, and thyroidectomy. Each has spe ci fic ad van ta ges and dis ad van - tages, which are sum ma ri zed in Ta ble 1. The ad mi ni stra - tion of I and thyroidectomy are in principle irreversible me thods. The use of an ti thy roid drugs is re ver si ble. Se - veral factors can influence the choice of therapy. Indeed, preference of the owner, availability of I therapy, and the pre sen ce of a skil led sur ge on are all im por tant con si - de ra ti ons. Fur ther mo re, the age of the pa tient and, more Table 1. Advantages and disadvantages of treatments currently available for feline hyperthyroidism. Tre at ment Advan ta ges Di sad van ta ges Anti thy roid drugs Ra di oi o di ne tre at ment Thy roi dec to my in ex pen si ve no need for sur ge ry, anest he sia or hos pi ta li za ti on in de fi ni te and re ver si ble one tre at ment ra pid cure no need for anest he sia re la ti ve ly easy and in ex pen si ve sur ge ry no need for sop his ti ca ted fa ci li ties side ef fects need for dai ly me di ca ti on and clo se mo ni to ring not per ma nent need for sop his ti ca ted fa ci li ties hos pi ta li za ti on time de pen dant on ex cre ti on of ra di o ac ti vi ty anest he tic risk pos si ble re ci di ves when not all tis sue is re mo ved com pli ca ti ons are fre quent

3 Vlaams Dier ge nees kun dig Tijd schrift, 2007, importantly, the presence of concomitant disease such as cardiovascular or renal dysfunction must be taken into ac count when a the ra py is cho sen (Kint zer, 1994). The major non-surgical treatment options available, antithyroid drugs and I, will be re vie wed in this ar ti cle. Spe ci al con si de ra ti ons Special consideration must be given to renal function be fo re ini ti a ting any type of tre at ment. The re is a com pli - cated relationship between hyperthyroidism and renal function in cats. Evaluating renal function in a hyperthyroid cat is dif fi cult but im por tant at the same time. First, cats with hyperthyroidism are geriatric patients and in this population chronic renal failure (CRF) is frequently observed. Second, hyperthyroidism can mask CRF. Indeed, hyperthyroidism increases the glomerular filtration rate (GFR), thereby decreasing serum creatinine concentration and BUN. Serum creatinine can also be decreased by the progressive weight loss and reduction in muscle mass observed with hyperthyroidism. A decline in GFR and an in cre a se in BUN and cre a ti ni ne have been re por ted as soon as 6 days af ter suc ces sful tre at ment of hyperthyroidism, regardless of type of therapy (DiBartola et al., 1996; Adams et al., 1997). Hyperthyroidism may con tri bu te to the de ve lop ment and pro gress of re nal disease by causing hyperfiltration followed by glomerulosclerosis. At present the following recommendations can already be made: a cat presented with hyperthyroidism and mild azotemia, isosthenuria, small irregular kidneys, or proteinuria must be considered at risk of developing re nal fail ure af ter tre at ment. The pre sen ce of the se symp toms pledges for a reversible treatment to evaluate the effect of treatment on renal function before considering any irreversible treatment. Assessment of cardiovascular function is also important in cats with hyperthyroidism. Cats with hyperthyroidism experience an increased susceptibility to arrhythmias, tachycardia, hypertension, signs of congestive heart failure and ventricular hypertrophy. Hyperthyroidism has a direct effect on the myocardium, vasculature and peripheral tissues, which results in increased myocardial protein synthesis, alteration of myosin subtype, less efficient energy conversion and upregulation of β-receptors (Kienle et al., 1994). Nonselective (propranolol) or selective (atenolol) β-adre no re cep tor bloc king agents can be used, if nee ded, for symptomatic treatment of tachycardia, polypnea, hypertension, hyperexcitability and signs of congestive heart failure. Atenolol has the advantage of requiring a once-daily dosing regimen. In humans, propranolol has the additional effect of inhibiting peripheral conversion of T4 to T3 (How et al., 1980). The pharmacokinetic profile of propranolol is altered by hyperthyroidism. Reduced do ses should be gi ven when it is ad mi nis te red oral ly, and the pa tient should be clo se ly mo ni to red when ma - king dose adjustments based on cardiac response (Jacobs et al., 1997). Beta-re cep tor bloc king agents can also be used as an aid in treating hyperthyroidism with antithyroid medica- Table 2. Important drugs in therapy of feline hyperthyroidism. Ge ne ric name Clas si fi ca ti on Tra de name Indi ca ti on Do sa ge Thi a ma zo le (met hi ma zo le) Thi ou ry le ne Fe li ma zo le Hypert hy roi dism mg/cat/day Ate no lol Beta 1 - (and Beta 2 at high Te nor min Car di ac arrhythmia, mg/cat PO sid do ses) adre no cep tor hy pert hy roi dism, an ta go nist hy per ten si on Propra no lol Beta 1 - and Beta 2 Inder al Car di ac arrhytmia s, mg/cat PO tid adre no cep tor hy per trop hic car di o my o pa thy, an ta go nist hy per ten si on, re ver se cli ni cal fe a tu res of thy ro toxi co sis Amlo di pi ne Cal ci um chan nel Amlor Hy per ten si on, hy per ten si ve cri sis mg/kg PO sid bloc ker Nor vasc

4 72 Vlaams Diergeneeskundig Tijdschrift, 2007, 76 ti on, or alo ne when an ti thy roid drugs are not to le ra ted and the pa tient is awai ting sur ge ry or I treatment. Because they do not act on the thy roid gland it self, they can be gi ven up to the mo ment of I treatment (Mooney, 2001). A study by Kobayashi (1990) reported an incidence of hypertension in hyperthyroid cats of 87%. A recent study revealed that this percentage of hyperthyroid cats with hypertension at diagnosis has been overestimated in the past and re por ted an in ci den ce of 12% (Syme and Elli ot, 2003). In the same re cent stu dy, ho we ver, 23% of the ini - tially normotensive cats developed hypertension during the ini ti al 6 months of tre at ment. The re a son for this ob - ser va ti on is still unk nown, but it clear ly points out the need for monitoring blood pressure, even after successful treatment of hyperthyroidism. Impor tant drugs used in the the ra py of fe li ne hy perthyroidism are summarized in Table 2. TREATMENT WITH ANTITHYROID DRUGS Mode of ac ti on Thiourylenes are antithyroid drugs derived from a sulfur-containing parent compound called thiouracil. Thiourylenes are actively concentrated in the thyroid, where they ex hi bit their the ra peu tic ef fect by bloc king the syn - thesis of thyroid hormones. More specifically, they block the thyroidperoxidase catalyzed reactions (oxidation of iodide and iodination of tyrosyl residues in thyroglobulin) and the coupling of iodotyrosines to iodothyronines. Thiourylenes also interfere with this coupling by binding to and altering the structure of thyroglobulin. These action sites are shown in Figure 2. Thiourylenes have no influence on the iodide uptake mechanism of the thyroid cell (iodide pump) or the release of previously formed thyroid hormones (Trepanier, 1990; Mooney, 2001). The most commonly known thiourylenes are methimazole (MMI), a synonym for the pharmaceutical compound thiamazole, and propylthiouracil (PTU). Another agent is carbimazole (CBZ), a carbethoxy derivative of MMI which is not a true thi ou ry le ne it self, but an in ac ti ve pro-drug. However, CBZ is almost completely bio-activa ted to an equim ole cu lar amount of MMI af ter ad mi ni - stration. It was developed originally in the search for a drug with a longer duration of activity compared to MMI (Pe ter son and Au coin, 1993; Tre pa nier, 1990). On a mo - lar ba sis, MMI and CBZ have the same po ten ti al, but CBZ has a greater molecular weight, which necessitates a hig her dose rate in or der to ob tain an ef fect equi va lent to MMI. A dose of 10 mg CBZ is ap proxi ma te ly equi va lent to 6.1 mg of MMI. In Belgium, only Felimazole (Thiamazole) tablets of 5 mg are registered for treatment of hyperthyroidism in cats. Methimazole has a bitter taste, but Felimazole is sugar-coated to simplify administration. Propylthiouracil is very po tent in bloc king thy roid hor mo ne syn the sis but is no long er re com men ded for use in cats be cau se of severe side effects. These include anorexia, vomiting, lethargy, immune mediated hemolytic anemia and thrombocytopenia (Peterson et al., 1984). Figure 2. Synthesis of thyroid hormones and action sites of thiourylenes. MMI: methimazole, TGB: Thyroglobulin, TPO: Thyroid Peroxidase, MIT: mono-iodotyrosine, DIT: di-iodothyrosine T3: L-tri-iodothyronine, T4: L-thyroxine

5 Vlaams Dier ge nees kun dig Tijd schrift, 2007, Cli ni cal ap pli ca ti on The goal of the ra py is to main tain se rum TT4 con cen - tra ti on in the lo wer half of the nor mal range with the mi - nimal dose necessary to achieve this effect. Antithyroid drugs like MMI can be used eit her as short-term or longterm therapy. Short-term therapy is applicable for patients who need or can be ne fit from im pro ve ment of sys - temic dysfunctions caused by the hyperthyroidism prior to surgery or I tre at ment, and for pa tients sus pec ted of chronic renal disease. A euthyroid state will resolve these systemic dysfunctions and will unmask underlying renal fail ure if pre sent. Long-term the ra py with MMI is sui ted for the se pa tients with un mas ked re nal fail ure and for pa - tients for whom sur ge ry or I therapy is not advisable and/or accessible. The advantages of long-term therapy are that it re qui res neit her sur gi cal skills nor the avai la bi - lity of I tre at ment. Owners be ne fit not only from the ab - sen ce of hos pi ta li za ti on, but also from the spre ad cost and the ready availability of the drugs compared to surgery or I treatment. When treatment with antithyroid drugs is used, the patient rarely suffers from hypothyroidism or hypoparathyroidism, it can receive medication from its ow ner, and it can be tre a ted up to an old age. This type of therapy is indefinite and any positive or negative effect of the drug en coun te red by the pa tient is al most al ways re - versible upon its discontinuation (Kintzer, 1994; Feldman and Nel son, 2004). Ho we ver, a ma jor draw back of this the ra py is the need for dai ly oral ad mi ni stra ti on, which can be dif fi cult, es pe ci al ly in cats. Anti thy roid drugs are not cytotoxic and adenomatous thyroid cells will continue to grow des pi te the ef fect of an ti thy roid drugs. This may re - quire dose adjustments during treatment, which contributes to the need for fol low-up (Beh rend, 1999). Do sa ge Until a few ye ars ago, the ge ne ral ly ac cep ted pro to col for an ti thy roid drug tre at ment was a high star ting dose of MMI of mg/day di vi ded into two or three do ses (Peterson et al., 1988) or CBZ 15 mg/day di vi ded in three do ses with an 8 hour dose in ter val (Moon ey et al., 1992). To day, the se high do ses are re qui red in only a small per - centage of the patients because cats with hyperthyroi - dism are di ag no sed ear lier, when they ex hi bit less se ve re symptoms (Broussard et al., 1995). The dose nee ded de - pends on the se ve ri ty of the hy pert hy roid sta te, so af ter early diagnosis a lower more conservative starting dose can be used with a lo wer oc cur ren ce of side-ef fects. Cur - rent ly, mg/cat/day MMI is the re com men ded star - ting dose, with in cre a ses of do ses if the re is an in ade qua te initial response (Trepanier, 2006). The clinical signs of euthyroidism become apparent in the patient only after biochemical euthyroidism has been established. Often serum TT4 concentration is below the re fe ren ce range but the re are no signs of cli ni cal hy po thy - roi dism. This can be ex plai ned by a re la ti ve ly high se rum free T4 concentration, compared to total T4 concentration. In addition, the concentration of the more metabolically ac ti ve T3 tends to re main wit hin the re fe ren ce range (Mooney et al., 1992). Adver se re ac ti ons Adverse reactions occur in approximately 10-15% of cats tre a ted with a mo de ra te to high dose of MMI (10 to 15 mg/day) (Pe ter son et al., 1988) or CBZ (15 mg/day) (Mooney et al., 1992). If adverse reactions occur during tre at ment with MMI, it is al most al ways in the first 4 to 8 weeks of tre at ment, which ex plains the clo se mo ni to ring needed in that period (Peterson et al., 1988; Tre pa nier et al., 2003). The most im por tant cli ni cal side ef fects du ring the first weeks of tre at ment are anor exia, vo mi ting and le - thar gy. The se are usu al ly trans ient and may re sol ve des - pite continued administration. When the gastrointestinal signs are more se ve re and per sist, an eva lu a ti on of the li - ver function is advised. Apparent hepatic toxicity occurs in less than 2% of cats tre a ted with mg/day MMI (Peterson et al., 1988). Hepatopathy is characterized by gastrointestinal signs, icterus and altered serum alanine transferase (ALT) and serum alkaline phosphatase (SAP) concentrations. Hepatopathy requires discontinuation of MMI ad mi ni stra ti on. It will take days or even weeks for all clinical and biochemical problems to resolve and alternative therapies should be considered for further treatment of hy pert hy roi dism in the se cats (Kint zer, 1994). Another serious clinical side effect is self-induced excori a ti on of the skin of head and neck, as shown in Fi gu re 3. Fi gu re 3. Exco ri a ti on of the skin of the head of a hy pert hy - roid cat tre a ted with MMI.

6 74 Vlaams Diergeneeskundig Tijdschrift, 2007, 76 This side effect requires discontinuing MMI administration, although these cutaneous lesions may be partly responsive to glucocorticoid treatment. Again, alternative therapies for hyperthyroidism need to be considered in these cases (Peterson et al., 1988). He ma to lo gi cal side ef fects can be mild, or they can be more se ri ous with need for ces sa ti on of the ra py. Mild he - matological changes occur in 16% of cats treated with MMI. They include lymphopenia, eosinophilia and transient leucopenia (Peterson et al., 1988; Feld man and Nel son, 2004). The se can be iso la ted or re la ted to gas - trointestinal signs. More serious side effects occur in approxi ma te ly 3% of cats tre a ted with MMI (Pe ter son et al., 1988). These include severe thrombocytopenia associated with a bleeding tendency, and agranulocytosis associated with fever, anorexia, lethargy and localized or systemic infections. Relatively rare but serious side effects include immune mediated hemolytic anemia (IMHA) with a positive Coombs test, and coagulopathy, which is unassociated with thrombocytopenia. Cats with coagulopathy and a normal pla te let count can have a pro long ed proteins induced by vi ta min K ab sen ce or antagonists (PIVKA) clot ting time (Randolph et al., 2000). Some hy pert hy roid cats may already have abnormal coagulation profiles prior to treatment. In the stu dy by Ran dolph et al. (2000), 3 cats (n=20) had 1 or more ab nor mal co a gu la ti on test at the on set of the stu dy, alt hough none had evi dent blee ding ten den - cies. The cau se of this is not known, but it is spe cu la ted that decreased vitamin K absorption associated with the fat malabsorption seen in some hyperthyroid cats resulted in abnormal pretreatment PIVKA clotting times. These serious side effects require the discontinuance of MMI therapy and supportive care such as intravenous fluids, blood transfusions and/or antibiotic therapy. In the study by Peterson et al. (1988), more than 50% of the cats tre a - ted with MMI for long er than 6 months de ve lo ped po si ti - ve an ti nu clear an ti bo dy (ANA) test re sults. The risk for ANA s appears to increase with longer duration of MMI tre at ment and with hig her dai ly do ses of MMI. The im - por tan ce of the se fin dings is unk nown, sin ce none of the cats from this stu dy sho wed any signs of a lu pus-like syn - drome. The side ef fects re la ted to CBZ the ra py are si mi lar to tho se re la ted to MMI the ra py (Moon ey, 1998; Beh rend, 1999; Buc knell, 2000). In CBZ tre a ted cats, 10% have mild side ef fects with vo mi ting oc cur ring wit hin the first 3 weeks of the ra py, with or wit hout anor exia and le thar gy. Carbimazole is tasteless (Cooper, 1984), which may account for the lo wer in ci den ce of vo mi ting. In 5% of the ca ses tre a ted with CBZ, mild and trans ient lymphopenia, eosinophilia or leucopenia occurs, without the need for discontinuation of therapy. Excoriations of the skin are des cri bed ra re ly and oc cur du ring the first 6 weeks of tre at ment, along with the need for dis con ti nu a - tion of therapy. More serious side effects like agranulocytosis or thrombocytopenia have not yet been described for the use of CBZ, but the pos si bi li ty of de ve lo ping the se side ef fects may still exist (Moon ey, 1998; Buc knell, 2000), therefore monitoring is still advised. Mooney et al. (1992) suggested that the incidence of adverse reactions using CBZ com pa red to MMI is lo wer. Ho we ver, the num ber of cats in clu ded was small and a low dose re gi me was used in this stu dy (Moon ey et al., 1992). Side ef fects are less fre quent and less se ve re at re la ti - ve ly low MMI do ses of mg/day com pa red to the re - la ti ve ly high do ses of mg/day. When MMI is star - ted at 2.5 to 5 mg/cat/day, ad ver se re ac ti ons are seen in only 5% of the cats tre a ted (Chap man et al., 2005). The following protocol is suggested in the literature to control hyperthyroidism gradually with minimal occurrence of side ef fects (Moon ey, 1998; Chun et al., 2002; Feld man and Nel son, 2004). A tri al the ra py for 4 weeks is star ted with a re com men ded ini ti al dose of 2.5 mg MMI twi ce a day for 2 weeks. After 2 weeks the ow ner is con tac ted for fol low-up about side ef fects. When no side ef fects are re - por ted, the dose should be in cre a sed to 3.75 mg twi ce a day for an ad di ti o nal two weeks. After this tri al pe ri od, the veterinarian is consulted for a complete history, phy - sical examination and blood work, including hematology, serum biochemistry and serum TT4 concentration. According to these results, three different therapeutic deci si ons can be made, de pen ding on the se rum TT4 con - centration. First, serum TT4 concentration can be within or near the nor mal re fe ren ce range. The dose is then best main tai ned for anot her 2 to 6 weeks, af ter which the ve te - rinarian is consulted for examining the patient and determi ning the need for a fur ther dose ad just ment. Se cond ly, if af ter this ini ti al 4 week tri al pe ri od the se rum TT4 con - cen tra ti on is be low the re fe ren ce range, the dose must be re du ced by 25% to 50% and the cat must be rechec ked 4 to 8 weeks la ter. Fi nal ly, if the se rum TT4 con cen tra ti on 4 weeks after initiating therapy is still above reference range, the do sa ge should be in cre a sed eve ry 2 weeks by 2.5 mg per day, to a maxi mum of 20 mg/day. Most cats will be con trol led with a dose of 5 or 7.5 mg/day (Pe ter - son et al., 1988). Nonetheless, this effective dose requirement va ries be tween cats. With this low-dose pro to col, clinical improvement may be delayed, occurring 2-6 weeks after normalization of serum TT4 concentration. Tablets of 5 mg MMI (Fe li ma zo le ) should not be di vi ded into smaller doses due to the coating. Therefore initial therapy is of ten star ted with a dose of 5 mg once a day.

7 Vlaams Dier ge nees kun dig Tijd schrift, 2007, The se rum half life of MMI in cats is only in the range of several hours after oral administration (Trepanier et al., 1991), but MMI may pos si bly be con cen tra ted in the thy roid gland in cats as it is in hu mans, which le ads to prolonged antithyroid effects (Okuno et al., 1987). It has recently been demonstrated that once daily therapy is adequate in many cats but that twi ce dai ly ad mi ni stra ti on of MMI le ads to a good con trol of the hy pert hy roi dism in a lar ger num ber of cats (Tre pa nier et al., 2003). A dif fe rent low-dose pro to col is ad vi sed when CBZ is used. In this case it is re com men ded to give 2.5 mg twi ce a day for 7 days and then 5 mg twi ce a day for 3 weeks. After this period, the veterinarian needs to be consulted for the same as ses sments as for MMI af ter the 4 week tri al pe ri od, and dose ad just ments can be made if ne ces sa ry (Feld man and Nel son, 2004). No net he less, for long-term tre at ment of hy pert hy roid cats, a re gi men of 5 mg twi ce a day is recommended (Mooney et al., 1992; Moon ey, 1998). A trial therapy with antithyroid drugs prior to a definite treatment such as I or sur ge ry is nee ded when con cur - rent renal insufficiency is suspected. A lower starting dose of 1.25 mg once or twi ce dai ly is ad vi sed in cats ha - ving or suspected of having renal disease. The dosage can be increased as described earlier with special attention to renal parameters such as serum creatinine and phosphor concentration, and urinalysis. When the renal function is not decreased after euthyroidism is achieved, medication can be continued with monitoring for occurrence of possi ble side ef fects, or a de fi ni te tre at ment such as I can be considered. However, when the renal function decreases to the point whe re re nal fail ure be co mes clear, it can be beneficial to continue MMI administration at a lower dose. In this situation mild hyperthyroidism is maintained, which fa vors the re nal func ti on (Feld man and Nel - son, 2004). Long-term tre at ment Once hyperthyroidism is controlled, a long-term dosing regimen can be designed, which involves monitoring the cats eve ry 3 to 6 months. After the ini ti al 3 month pe ri od, side ef fects are un com mon, but can still oc cur. Because thiourylenes only control the disease up to a cert ain point and tu mor cell growth con ti nu es, dose ad - justments are likely to be necessary. Another important issue during long-term therapy is owner compliance. Poor ow ner com pli an ce can be due to im prac ti cal time sche du les for the ow ner, a cat that is dif fi cult to pill or sim ply an un wil ling ow ner. A so lu ti on for this can be to reduce the frequency of administration but to maintain the same to tal dai ly dose of MMI. In this case it is im por - tant for the ow ners to clo se ly ob ser ve their cats for the possible gradual return of clinical signs. Be cau se cats can be dif fi cult to pill, se ver al ot her me - thods for MMI administration have been investigated. Trans der mal MMI ad mi nis te red in a to pi cal gel is one op - tion (Hoffmann et al., 2003; Sar tor et al., 2004). Ther a - peu tic res pon se is seen af ter 4 weeks, which is long er than with the use of oral MMI, and may not even oc cur in every cat. The hepatic and hematologic side effects and pru ri tus are equal to that with oral MMI, but cats can ex - pe rien ce crus ting and eryt he ma of the pin nae of the ear whe re the drug is ap plied. Just as with the oral MMI, a low dose tri al the ra py is ad vi sed with a star ting dose of gel equal to 2.5 mg MMI ap plied twi ce dai ly (Sar tor et al., 2004). The ow ner must wear glo ves when rub bing the gel in on al ter na ting ears, with any ex cess re mo ved af - ter 30 to 120 mi nu tes. The dis ad van ta ges of this form of tre at ment are the re la ti ve ly high cost and the tri al sta ge this form of tre at ment is still in. In one stu dy, the use of transdermal MMI led to significantly fewer gastrointestinal side effects compared to oral administration. There was, however, no difference in the incidence of hematological abnormalities, hepatopathy or facial excoriations. Veterinarians must be warned about the variable types of creams and methimazole used by the compounding pharmacies, with implications for its use. Another option, although not thoroughly investigated, is the parenteral way for administration of MMI (Sassnau, 1999). The administra ti on of MMI, in the same dose as ad vi sed when ad mi nis - tered orally, was in some cases experienced as a beneficial route with advantages compared to oral administration. Over all, when a cat is dif fi cult to pill, the best tre at ment option is administration of I. TREATMENT WITH RADIOACTIVE IODINE (RA - DIOIODINE, ISOTOPE I) Prin ci ple of the ra py Administration of I can be in tra ve nous (IV), sub cu - ta ne ous (SC) or oral (Beh rend, 1999; Moon ey, 2001). Thyroid cells actively take up stable or radioactive iodine and incorporate it into tyrosyl groups during thyroid hormone synthesis. Hyperplastic or tumoral thyrocytes are hy per ac ti ve and will take up more I as op po sed to he al - thy cells. Upta ke of I by nor mal cells is sup pres sed due to the negative feedback system on the hypothalamic-pituitary-thyroid axis. Radioiodine undergoes β de cay and emits β-particles and γ-radiation. The β-particles travel a maximum distance of approximately 2 mm, during which they cause local destruction of the surrounding follicle

8 Vlaams Dier ge nees kun dig Tijd schrift, 2007, cells. Surrounding structures, such as the parathyroid and healthy suppressed thyroid cells, are spared (Mooney, 2001; Feld man and Nel son, 2004). The γ-radiation penetra tes the tis sue, is less ra di o toxic than the β-particles, and per mits ima ging with the γ camera. Iodine not taken up by the thy roid is ex cre ted in sa li va and uri ne, and through the gastrointestinal system. Follow-up after I the ra py is very im por tant. It is re - commended to measure serum TT4, creatinine and BUN after I the ra py. An exam ple of a fol low-up sche du le is mo ni to ring 1, 3 and 6 months af ter I the ra py. When cats have a low se rum TT4 con cen tra ti on 1 month af ter tre at - ment, it is pos si ble that he al thy re ac ti va ted cells are not yet producing enough thyroid hormones. This production usually increases hereafter and euthyroidism is achieved 3 to 6 months af ter I. Before treatment, a scintigraphic scan of the thyroid using pertechnetate ( 99m TcO4) should be per for med to in - vestigate whether there is uni- or bilateral involvement of the thy roid lo bes, and whe ther the re is a pre sen ce of ec to - pic thyroid tissue or signs of malignancy. Pertechnetate is trap ped by the thy roid gland in the same way as io di de but is not or ga ni fied by the thy roid gland. It de cays with γ radiation, enabling visualization with a γ camera. In rare ca ses the thy roid pa tho lo gy can be ma lig nant (adenocarcinoma). Adenocarcinoma gives non-homogenous uptake on the pertechnetate scan, however it can only be confirmed by histology. Adenocarcinoma is treated with a hig her dose of I of 10 tot 30 mci (Pe ter son, 2000). Dose as ses sment The ultimate goal of the treatment of adenomatous hy - per pla sia is to res to re the eu thy roid sta te with a sing le dose of I, without developing hypothyroidism or recurrence of hyperthyroidism. A variety of methods to assess the op ti mal dose of I have been investigated. These methods can be di vi ded into three groups, being a tra cer stu - dy combined with 99m TcO4, a sco ring sy stem, or ad mi ni - stra ti on of a fixed dose. Tra cer stu dy com bi ned with 99m TcO 4 This dose as ses sment uses the ki ne tic pa ra me ters and vo lu me of the thy roid gland (Tur rel et al., 1984; Me ric et al., 1986; The on et al., 1994). A tra cer stu dy using a low dose of µci I is per for med. Du ring 3 to 5 con - secutive days after injection, a scintigraphy is performed from which the up ta ke and the re si den cy time of I in the thyroid (biological half life) are calculated. To estimate the vo lu me of the thy roid gland, the cat is in jec ted with 99m TcO4 and a scin ti grap hy is per for med af ter 1 hour. Spe - ci fic al go rithms are used to quan ti fy the vo lu me of the af - fec ted thy roid. The goal of this dose as ses sment is the cal - cu la ti on of the amount of I activity (mci I) to be injected IV to achieve a radiation dosage of 150 Gray (Gy) in the thy roid. This as ses sment of do sa ge has the disadvantage of the need for repeated sedations, which is not advisable in a geriatric population such as hyperthyroid cats. Sco ring sy stem A sco ring sy stem ba sed on the se ve ri ty of the cli ni cal symp toms, size of the thy roid and se rum TT4 con cen tra - ti on is des cri bed in Jo nes et al., 1991; Moon ey, 1994; and Nykamp et al., Ba sed on this sco ring sy stem, 3 dose rate re gi mes can be used: a low dose of I of mci IV, a mo de ra te dose of mci IV and fi nal ly a high dose of mci IV (Pe ter son and Bec ker, 1995). The ad van ta ges of this me thod are that less time is re qui - red be cau se no tra cer stu dies are per for med, and that no sedations are necessary. Fixed dose of I For administration of a fixed dose, a difference is made be tween a mo de ra te dose of 4 mci and a very high dose of mci. A dose of 10 to 30 mci will not only destroy the adenomatous tissue, but the healthy tissue as well. This will lead to an unac cep ta bly high num ber of hy po thy roid cats af ter tre at ment with a high cost pri ce, as well as high exposure to radiation for the environment. A fixed dose of 4 mci can be ad mi nis te red with (Chun et al., 2002) or wit hout (Me ric and Ru bin, 1990) per for ming a 99m TcO4 scan pre vi ous to I. When a 99m TcO4 scan is per for - med and the fixed-dose of I is cho sen wit hin a range ac - cor ding to the out co me of the scan, the me thod is cal led the modified fixed-dose me thod (For rest et al., 1996). Rou te of ad mi ni stra ti on There is no difference between IV or SC administration for efficacy of treatment, hospitalization period, I uptake by the thy roid or I excretion (Theon et al., 1994). Sub - cutaneous administration gives a risk for radiation induced dermatitis. For the oral administration route, a higher dose is nee ded com pa red to the IV or SC rou te, with in cre a sed risk du ring tre at ment for the en vi ron ment cau sed by vomi ting or bi ting the cap su le (Ma lik et al., 1993; For rest et al., 1996). The re fo re, the oral rou te is not ad vi sed in cats.

9 77 Vlaams Diergeneeskundig Tijdschrift, 2007, 76 Ta ble 3. Re sults of tre at ment with I using dif fe rent ty pes of dose as ses sment in hy pert hy roid cats. Me thod of dose as ses sment Dose I ad mi nis te red (mci) N (num ber of cats) Fol low-up (months) % hy pert hy roid (n) % hy po thy roid (n) Tra cer stu dy (Tur rel et al., 1984) (3) 18 (2) (Me ric et al., 1986) (3) 7 (2) (The on et al., 1994) (5) 6 (7) Sco ring sy stem (Jo nes et al., 1991) (3) 3 (1*) (Moon ey, 1994) (5) 56 (28) af ter 1 month 14 (7) af ter 15 months (Pe ter son and Bec ker, 1995) eve ry 3-6 months 2.5 (13) af ter 3 months 1.6 (8) af ter 16 (84) af ter 3 months 11 (57) af ter 6 months 2.1 (11*) af ter 1.6 ye ars 6 months (Ny kamp et al., 2005) Not re por ted 30 (50) (23*) Fixed dose (Me ric and Ru bin, 1990) (5) 8 (5) (For rest et al., 1996) 2-5** (11) Not re por ted (Chun et al., 2002) (2) 9 (19*) n: num ber of cats *supplemented with thyroxine because of clinical signs of hypothyroidism. **according to scintigraphic 99m TcO 4 scan Ra di opro tec ti on After the administration of I, the cat must be con si - dered a source of radioactive radiation and radioprotective precautions must be taken. The advised period of hospitalization depends on national legislation and shows some variation from country to country. In Belgium, the re le a se li mit is pa tient emis si on of less than 20 µsv/hour at a dis tan ce of 1 me ter. No cli ni cal pa ra me ters al low pre dic - tion of the hospitalization period required (Weichselbaum et al., 2003). With the in jec ted dose used in our set tings, the cat is al re a dy be low this li mit at 24 h af ter in jec ti on. Ne ver - the less, the cats are hos pi ta li zed for a long er time be cau se du ring the first 72 hours the hig hest ra di a ti on bur den is achie ved in uri ne and fe ces due to the eli mi na ti on of free radioiodine. After an average hospitalization period of 5 days, by which time the dose tem po is usu al ly less than 20 µsv at a dis tan ce of 1 me ter from the cat, the pa tient can go home with sa fe ty pre cau ti ons. For a pe ri od of two weeks, the re must be no con tact be tween the cat and litt le chil dren or preg nant wo men, though li mi ted con tact with the rest of the hou se hold is al lo wed. All ma te ri al that was in con tact with the cat or its ex cre ments, in clu ding lit ter box fil ling, must be kept se pa ra te for a time pe ri od of three months (this is 10 ti mes the phy si cal half-life of I, af ter this time <0,1% of the ini ti al ra di o ac ti vi ty is left) un - til it can be dis po sed as nor mal was te. Out co me of I tre at ment The out co me de pends on the me thod of dose as ses s - ment, age at time of di ag no sis and sex (Sla ter et al., 2001). Possible factors influencing prognosis are the administration of MMI previous to I (Chun et al., 2002; Niec karz and Da niel, 2001) and bi- or uni la te ral in vol ve - ment of thy roid lo bes (Ny kamp et al., 2005). The suc cess

10 Vlaams Dier ge nees kun dig Tijd schrift, 2007, of treatment is not significantly correlated to symptoms be fo re tre at ment such as the pre sen ce of weight loss, po - lyuria, polydipsia, behavioral changes, anorexia, vomiting, cardiac murmur or tachycardia (Chun et al., 2002). The re sults of tre at ment using the dif fe rent ty pes of dose assessment described in the literature are outlined in Table 3. Slater et al. (2001) has shown that each year of hig her age at diagnosis increases the relative risk to die within two years after treatment, since the increasing number of he alth pro blems in the old cat di mi nis hes the sur vi val time strong ly. The se fin dings are not sur pri sing, sin ce hy - pert hy roi dism is a dis e a se of ge ri at ric cats. Also, it is re - por ted that male cats have a poor er sur vi val rate over time with a hig her risk of dy ing wit hin two ye ars af ter di ag no - sis and treatment, compared to female cats diagnosed and tre a ted at the same age. Other im por tant pre dic ti ve fac - tors for sur vi val are re nal fail ure and ne opla sia af ter tre at - ment. The ef fect of an ti thy roid drugs on I therapy remains controversial. Methimazole does not inhibit thyroidal iodine uptake, but the administration of MMI without discontinuation before I therapy is currently not recommended. It lo wers the ef fec ti ve half-life of I by inhibiting incorporation of iodine in tyrosyl groups and lowering the residence time of I in the thy roid. No net he less, the re is a short rebound effect with enhanced iodine uptake after re cent MMI withdra wal in he al thy cats (Niec karz and Daniel, 2001). This re bound ef fect can be potentially beneficial in I therapy of hyperthyroid cats. Despite this, a re cent stu dy has shown that dis con ti nuing MMI for less than or more than five days pri or to I the ra py has no ef - fect on treatment outcome (Chun et al., 2002). It can be reasonably advised to cease MMI administration three days pri or to I treatment. A bi la te ral ly en lar ged thy roid gland may be a hig her risk for developing hypothyroidism after treatment compared to a unilateral enlargement, because both thyroid lo bes in the bi la te ral en lar ged thy roid gland take up I, while in a unilateral enlargement one lobe is suppressed and does not take up I (Ny kamp et al., 2005). Overall, the treatment of feline hyperthyroidism with I should be con si de red the tre at ment of choi ce. In the majority of cases, one treatment is sufficient. This procedu re is only mi ni mal ly stres sful to ol der cats, re qui res no anest he sia, has a very low com pli ca ti on rate and le ads to a ra pid cure of the dis e a se. No net he less, the use of ra di o - active material requires hospitalization, specialized facili ties and per son nel, and can be a me na ce for the en vi ron - ment when radioprotective safety precautions are not ta ken (Kint zer and Pe ter son, 1994; Mee king, 2005). Be - fore initializing an irreversible treatment like I, the re - nal func ti on should be ca re ful ly eva lu a ted. When a cat is presented with hyperthyroidism and suspected of underly ing kid ney fail ure, a tri al pe ri od with anti-thy roid drugs previous to I can give in sight into the de ve lop ment of CRF after therapy. LITERATURE Adams W.H., Da niel G.B., Le gen dre A.M., Gompf R.E., Gro - ve C.A. (1997). Chang es in re nal func ti on in cats fol lo wing treatment of hyperthyroidism using I. Veterinary Radiology and Ultra sound 38, Behrend E.N. (1999). Medical Therapy of Feline Hyperthyroidism. Compendium on Continuing Education for the Practicing Veterinarian 21, Brous sard J.D., Pe ter son M.E., Fox P.R. 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