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All work was performed at the Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Nuclear Medicine Division, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium. Results of this study were partially presented at the annual ACVIM forum in San Antonio, 2008.
Corresponding author: Ingrid van Hoek, DVM, Department of Medicine & Clinical Biology of Small Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Ghent, Belgium; e-mail: email@example.com.
Background: Hyperthyroidism is the most diagnosed endocrine disorder in cats and radioiodine (131I) is the treatment of choice. The dose emission rate and radioactivity in urine, saliva, and on hair and paws are determined by the dose of administered 131I. A dose reduction of therapeutic 131I could possibly be achieved after recombinant human thyrotropin (rhTSH) administration as in humans with nodular goiter.
Hypothesis: rhTSH will increase radioiodine uptake in hyperthyroid cats.
Animals: Five hyperthyroid cats.
Methods: Twenty-five micrograms rhTSH (day 1) or 2 mL 0.9% sodium chloride (NaCl) (day 9) was injected IV. One hour later, 11.4 ± 4.1 (mean ± SD) MBq 123I was injected IV. Radioactive iodine uptake (RAIU) was measured 6, 12, and 24 hours after rhTSH (RAIU-rhTSH) or NaCl (RAIU-blanco) injection. Blood samples for measurement of TT4 were taken before injection of rhTSH or NaCl (TT40) and at the time of imaging.
Results: Percentages of RAIU-rhTSH (and RAIU-blanco) at 6, 12, and 24 hours after administration of rhTSH were 34 ± 18 (31 ± 21), 46 ± 20 (38 ± 18), and 47 ± 15 (36 ± 14). There was a statistically significant effect of rhTSH administration on RAIU (P= .043) but not on serum TT4 concentration. Baseline serum TT40 concentration influenced RAIU-rhTSH significantly at 6 hours (P= .037).
Conclusion and Clinical Importance: The increased RAIU observed after rhTSH administration in hyperthyroid cats could lead to a lower therapeutic dose of 131I after rhTSH administration in hyperthyroid cats and decreased risk of environmental and owner contamination during and after hospitalization.
Hyperthyroidism in cats is comparable to toxic nodular goiter in humans and is the most common endocrine disorder in cats, with a reported increased incidence over the past 10 years.1–4 Treatment with radioiodine (131I) is considered the treatment of choice.4 The procedure is only minimally stressful to cats, requires no anesthesia, has a very low complication rate, leads to a rapid cure of the disease, and 1 treatment is sufficient in the majority of cases.5,6 Radiation exposure should be kept “as low as reasonably achievable” (ALARA principle) to minimize risks for human health.7 The same problems that occur in the treatment of hyperthyroid humans arise in the treatment of hyperthyroidism in cats using radioiodine. This issue was addressed earlier in human medicine when the hazards caused by the excreta and direct radiation from the cat were emphasized.8 A lower efficacious dose will reduce the surface dose emission rate, radioactivity found in urine and on the hair and paws, and duration of isolation for cats treated with 131I, thereby conforming to the ALARA principle.9–11
In humans with nodular goiter, the administration of recombinant human thyroid-stimulating hormone (rhTSH) has been adopted because administration of rhTSH increases radioactive iodine uptake (RAIU) in the thyroid and changes the regional distribution of 131I in humans with nodular goiter or subclinical hyperthyroidism.12–15 This results in lower therapeutic doses needed and less irradiation to extrathyroidal tissue.16–18
Thyroid glands from hyperthyroid cats consist of multiple hyperplastic nodules of active thyroid tissue surrounded by inactive paranodular tissue. A recent study showed that thyroid cells from hyperthyroid cats in monolayer culture exhibit growth and a functional response to TSH in a concentration-dependent manner. This suggests that these cells have a high level of unstimulated activity and require higher TSH concentrations than normal cells to stimulate DNA synthesis and thyroglobulin expression.19 Administration of rhTSH is safe and triples the serum thyroxine (total T4, TT4) concentration in euthyroid healthy cats.20 We hypothesized that there could be a similar application of rhTSH in hyperthyroid cats as in humans. The objectives of this study were to evaluate the effect of administration of 25 μg rhTSH on RAIU in hyperthyroid cats.
Materials and Methods
Five client-owned hyperthyroid cats aged 13 ± 2 years and with body weight (BW) of 3.3 ± 0.4 kg were included in the study. Informed consent was obtained from the owners before inclusion. Diagnosis of hyperthyroidism was based on clinical signs compatible with hyperthyroidism and increased serum TT4 concentration. To assess the clinical condition of the cats, the initial screening included physical and routine laboratory examinations (CBC, biochemistry). Cats were maintained on their original diet throughout the study period. Treatment with antithyroid medication was terminated at least 2 weeks before the study.
On day 1, a blood sample for measurement of TT4 (serum TT40) was taken by jugular venipuncture and 25 μg rhTSHa was injected IV. The rhTSH had been dissolved in sterile water, divided in aliquots containing 25 μg rhTSH and frozen at −20 °C for a maximum of 8 weeks.21 Aliquots were allowed to thaw at room temperature shortly before administration. One hour later, a dose of 11.4 ± 4.1 (mean ± SD) MBq 123I was injected IV via a catheter, preceded and followed by 1 mL of 0.9% sodium chloride (NaCl) solution.b The injected dose of 123I was measured in a dose calibrator. Blood samples for TT4 measurement were taken and RAIU was measured 6, 12, and 24 hours after rhTSH injection (RAIU-rhTSH). Blood was centrifuged and stored for 3 days (−20 °C) to reach sufficient decay of radioactivity and analyzed for serum TT4 concentration. For RAIU measurement, a static planar ventrodorsal image of 200,000 counts was made with a γ-camerac using a low-energy high-resolution collimator with the cat in sternal recumbency under general anesthesia.d A syringe with a known amount of radioactivity (2.5 ± 1.6 MBq) was placed next to the animal and used as the standard activity necessary to calculate RAIU. Regions of interest were manually drawn in the image obtained with the γ-camera over uptake regions in the thyroid and uptake from the standard activity by the same co-author (Peremans) to measure the counts per minute (cpm). RAIU was calculated as a percentage of the administered dose of 123I corrected for physical decay using the following formula: ([(cpmthyroid− cpmbackground) / (cpmstandard− cpmroom)] × (MBqstandard/ MBqdose)) × 100. On day 9, the same study as day 1 was repeated using the same cats, with an injection of 2 mL 0.9% NaCl solutionb instead of rhTSH. Blood samples were taken and stored, and RAIU was measured (RAIU-blanco) according to the same protocol as used on day 1.
Data were analyzed with SAS version 9.1.e The effect of rhTSH administration on RAIU was analyzed by a mixed model with cat as random effect and intervention (rhTSH administration versus NaCl), time and the interaction as categorical fixed effects. The effect of baseline serum TT40 concentration on RAIU and serum TT4 concentration was analyzed separately in the rhTSH administration and NaCl group by a mixed model with cat as random effect, and TT40, time and the interaction as fixed effects. The effect of rhTSH administration on serum TT4 concentration was analyzed by the stratified Wilcoxon rank sum test because data were not normally distributed. All analyses are carried out at the 5% significance level. Results are expressed as mean ± SD.
Cats received a dose of 25 μg, which corresponded to 8 ± 1 μg/kg BW rhTSH. Percentages of RAIU-rhTSH, RAIU-blanco and ratios between RAIU-rhTSH and RAIU-blanco at 6, 12, and 24 hours after administration of rhTSH (5, 11, and 23 hours after 123I administration, respectively) are presented in Table 1. There was an overall significant effect of rhTSH administration on RAIU (P= .043) with an overall mean difference of 7.33% between RAIU-rhTSH and RAIU-blanco. There was no significant difference in effect among the time points after rhTSH administration (P= .070). Peaks in RAIU-blanco and RAIU-rhTSH were observed at 12 hours (n = 2) or 24 hours (n = 2) after 123I administration. All cats had unilateral thyroid uptake of 123I on all scans regardless of previous rhTSH administration. Differences in RAIU-rhTSH and RAIU-blanco 6, 12, and 24 hours after administration are presented in Figure 1.
Table 1. Mean ± SD (range) of RAIU-rhTSH (%), RAIU-blanco (%), and ratio between RAIU-rhTSH and RAIU-blanco in 5 hyperthyroid cats.
34 ± 18
46 ± 20
47 ± 15
31 ± 21
38 ± 18
36 ± 14
Ratio RAIU-rhTSH/ RAIU-blanco
1.2 ± 0.3
1.3 ± 0.3
1.4 ± 0.3
There was no statistically significant effect of rhTSH on the serum TT4 concentration 6 (P= .250), 12 (P= .313) or 24 hours (P= .313) after administration. Serum TT4 concentration after rhTSH (serum TT4-rhTSH) or after 0.9% NaCl, as well as ratios between post- and preserum TT4 concentration-rhTSH and serum TT4 concentration-blanco 6, 12, and 24 hours after administration are presented in Table 2. Baseline serum TT40 concentration positively influenced RAIU-rhTSH significantly at 6 hours (P= .037) but neither at 12 hours (P= .074) nor at 24 hours (P= .522) after administration of rhTSH. No significant effect of baseline serum TT40 was found on RAIU-blanco at 6 (P= .052), 12 (P= .079) or 24 hours (P= .464) after administration of 0.9% NaCl solution.
Table 2. Mean ± SD (range) of serum TT4-rhTSH, serum TT4-blanco, post/pre-TT4 ratio-rhTSH, and post/pre-TT4 ratio-blanco in 5 hyperthyroid cats.
112 ± 61
105 ± 59
87 ± 56
114 ± 55
128 ± 62
90 ± 59
96 ± 63
105 ± 69
Post/pre-TT4 ratio- rhTSH
1.1 ± 0.1
1.0 ± 0.1
0.8 ± 0.1
Post/pre-TT4 ratio- blanco
1.0 ± 0.1
1.0 ± 0.1
1.0 ± 0.2
Over the past few years, there has been an increase in the number of hyperthyroid cats treated successfully with radioiodine in different regions of the world, with special treatment centers committed to radioiodine treatment in hyperthyroid cats.4,22 The use of radioactive material requires hospitalization, specialized facilities and personnel, and most importantly can be a danger for the environment when radioprotective safety precautions are not taken. Hospitalization after radioiodine treatment is required until the radiation dose rate has decreased to a safe level. These levels differ among countries, states, and institutions. The most commonly used are the Nuclear Regulatory Commission guidelines, which state that the emission rate must be <0.02 mSv/h.23 This is usually the case at a distance of 1 m, 1 week after treatment in cats, depending on the injected activity. Nonetheless, radioactivity is still found in urine until 21 days after treatment in amounts that require labeling as radioactive material,9,11,23 and removable radioactivity that can even exceed the maximum acceptable activity for a noncontrolled area is present on the cat during the 1st week after treatment.11,24,25 The amount of radioiodine administered is the only factor determining the remaining radioactivity and duration of isolation; therefore, administration of the lowest possible activity is beneficial.10
Our study is comparable to the study by Huysmans et al12 performed in humans, where a dose of 10 μg rhTSH was followed by 123I injection 2 hours later. Ratios between RAIU-TSH and RAIU-blanco at 5, 8, and 26 hours after administration were 1.3 ± 0.5, 1.1 ± 0.4, and 1.5 ± 0.5, respectively, and the ratio ranged from 1.0 to 2.4 at 26 hours after administration. This result means that response to rhTSH administration can be absent, which could also be the case for the cat that showed a negative difference between RAIU-rhTSH and RAIU-blanco (Fig 1). This finding could be an expression of not responding to rhTSH combined with physiologic variation in 123I uptake. However, in this same study in humans, a dose of 10 μg rhTSH followed by 123I injection 24 hours later caused an RAIU-TSH more than double the RAIU-blanco at 5, 8, and 26 hours after rhTSH administration. This shows the critical influence of time between rhTSH administration and RAIU measurement.
Early uptake measurements are presumed to reflect iodide trapping followed by organic binding, whereas RAIU at 24 hours or after is influenced by secretion of iodine compounds. In healthy cats, a difference between 8 and 24 hours RAIU at baseline and after withdrawal of methimazole treatment has been described, although these results were not analyzed statistically.26 Studies investigating RAIU in hyperthyroid cats advise measurement of RAIU between 4 and 24 hours after radioiodine injection, because the maximal uptake peak probably occurs between 4 and 24 hours.27,28 This recommendation is in accordance with the results of this study, because peaks in RAIU-blanco and RAIU-rhTSH were seen at 12 or 24 hours after 123I injection, although there was no significant difference between the time points after injection of 123I.
Another factor is the dose of rhTSH administered. There is a dose-response effect on thyroid hormones, and this effect can reach a plateau in euthyroid humans29 and patients with nodular goiter,12,18 and also a dose-response effect on RAIU that can reach a plateau in patients with nontoxic or toxic nodular goiter.14,16,18 In vitro studies proved that feline hyperactive thyroid cells require higher TSH concentrations than do normal cells to stimulate DNA synthesis and thyroglobulin expression; therefore the dosage used in this study could have been too low.19 The dosage used in our study is 8 μg/kg BW rhTSH. This dosage is in the range of effective doses of 10–900 μg, which correspond to 0.01–12.9 μg/kg BW (with an arbitrary BW of 70 kg) in humans and are even higher than effective doses in dogs.12,14,18,30,31 Moreover, rhTSH in humans is administered IM, whereas in our study it was given IV, which should accelerate the effect of rhTSH. Nonetheless, a study in euthyroid dogs comparing different administration routes found an equal increase in serum TT4 concentration after 75 μg rhTSH administered IV or IM,32 and another study showed an increase in serum TT4 concentration, although not statistically significant, after IM or SC administration of 50 μg rhTSH.30 Because 25 μg is proven to increase serum TT4 concentration in euthyroid cats and because of the high cost of rhTSH, we first evaluated the effect of this dose in hyperthyroid cats.
The reduction in therapeutic 131I dose after RAIU-rhTSH measurement has been investigated by Nieuwlaat et al.16 The therapeutic dose was reduced according to the ratio of post- and pre-rhTSH RAIU measured 24 hours after administration, by dividing the original therapeutic dose by this ratio. If we applied this reasoning to the cats in our study that responded positively to rhTSH administration and used the RAIU ratio measured 24 hours after rhTSH, this would account for a mean dose reduction of 33%. The reduction in cost for therapeutic 131I when decreased by 33% is much higher than the cost of 25 μg rhTSH when 1 vial of rhTSH is aliquoted and stored at −20 °C as in our study. Hence, although the effect of rhTSH on RAIU is small, the effect on the dose reduction is substantial. Moreover, not only the reduction in cost after rhTSH administration is worthwhile, more important is keeping the therapeutic dose as low as reasonably achievable (ALARA principle), and this can possibly be achieved after rhTSH administration.
Decreased uptake or trapping of radioiodine 131I by the thyroid, defined as thyroid stunning, has been described after low doses of diagnostic 131I. This stunning effect however does not happen when 123I is used; therefore this cannot influence repeated RAIU and the study results here.33 Nonetheless, because 123I still represents a dose of iodine, it theoretically can compete for the iodide pump in thyrocytes. This however is the case only when high doses of iodine are administered, which need to exceed 0.1 mg to alter the relative iodine-accumulating function in hyperthyroid humans.34 The concentration and dose of iodine administered in the 123I solution used in this study were much lower (1.3 × 10−6 mg iodine per dose of 250 μCi 123I).
In our study, all 5 cats remained hyperthyroid (unilaterally) after rhTSH stimulation without a difference in distribution of radioiodine uptake in the thyroid, suggesting that healthy thyroid tissue is not stimulated by this low dose of rhTSH. The latter also is important for treatment outcome. The goal of treatment is achievement of euthyroidism after a single dose of radioiodine. If healthy thyroid tissue responds to rhTSH, it will take up radioiodine and will be subject to irradiation, thereby possibly causing iatrogenic hypothyroidism.
Possible explanations for the absence of change in serum TT4 concentration in hyperthyroid cats could be secretion of thyroid hormones independent of TSH control or T4 production at a nearly maximal rate.1 The response to rhTSH with increased RAIU described in this study and the response to rhTSH of feline hyperthyroid cells in vitro makes the 1st explanation less likely. Cats with a higher serum TT4 concentration often are more clinically hyperthyroid and need a higher effective dose of radioiodine for successful treatment.35,36 This study showed that the basal serum TT4 concentration positively influenced RAIU 6 hours after rhTSH. This suggests that these cats will receive more benefit from rhTSH administration before radioiodine treatment because they can receive a lower dose of administered radioiodine.
Limitations of this study were the small number of cats, investigation of only 1 dose of rhTSH, and evaluation of only 1 time interval between rhTSH and 123I administration. However, the results were significant. Ratios between RAIU-TSH and RAIU-blanco were positive at all measured time points in 4/5 cats and the administration of 25 μg rhTSH caused an overall increase in RAIU of 7%. Moreover, there is a wide interindividual variation in the thyroid RAIU response to rhTSH in humans.12,29 This results in the need for a study design in which the subject serves as its own control. The costs of rhTSH and thyroid scanning, the limited number of hyperthyroid cats suitable for repeated anesthesia, and the duration of the study period limited the number of cats included in this study.
The results of this study show that rhTSH may be used in the treatment of hyperthyroid cats with radioiodine to decrease risk of contaminating radioactivity during and after hospitalization. There were no adverse effects noted and healthy euthyroid tissue did not respond to rhTSH stimulation. Further studies optimizing the doses of rhTSH and time intervals between rhTSH and RAIU are needed before effective doses of radioiodine can be decreased in hyperthyroid cats after rhTSH administration.
aThyrogen, Genzyme Corporation, Naarden, the Netherlands