FELINE HYPERTHYROIDISM: EFFICACY OF TREATMENT USING VOLUMETRIC ANALYSIS FOR RADIOIODINE DOSE CALCULATION

Hyperthyroidism was diagnosed in 80 cats with thyroid scintigraphy using technetium pertechnetate. These cats were subsequently treated with radioiodine using a modified fixed dose method based on the volume of hyperfunctioning thyroid tissue calculated from the pertechnetate scans. The medical records and thyroid scintigrams were evaluated retrospectively. Follow-up was obtained on the cats to evaluate treatment success. Several parameters were evaluated in an attempt to identify a difference between treatment success and failure. Cats that failed to become euthyroid after one dose of radioiodine had a significantly higher pretreatment serum thyroxine level, had a significantly larger volume of hyperfunctioning thyroid tissue on scintigrams, and cats receiving oral versus intravenous radioiodine were over represented. Based on our results we conclude: 1) the administration of a dose of radioiodine based solely on the volume of hyperfunctioning thyroid tissue as estimated from the pertechnetate scan may be inadequate for those patients with extremely elevated serum thyroxine levels or large thyroid glands, and 2) oral administration of radioiodine is not recommended for the treatment of feline hyperthyroidism.     

Association of Iatrogenic Hypothyroidism with Azotemia and Reduced Survival Time in Cats Treated for Hyperthyroidism

Background: Iatrogenic hypothyroidism can occur after treatment of hyperthyroidism, and is correlated with a reduced glomerular filtration rate in humans and dogs. Hypothesis: Cats with iatrogenic hypothyroidism after treatment for hyperthyroidism will have a greater incidence of azotemia than euthyroid cats. Animals: Eighty client owned cats with hyperthyroidism. Methods: Two retrospective studies. (1) Longitudinal study of 12 hyperthyroid cats treated with radioiodine (documented as euthyroid after treatment), to assess changes in plasma thyroid stimulating hormone (TSH) concentration over a 6‐month follow‐up period, (2) Cross‐sectional study of 75 hyperthyroid cats (documented as euthyroid) 6 months after commencement of treatment for hyperthyroidism to identify the relationship between thyroid status and the development of azotemia. Kaplan‐Meier survival analysis was performed to identify relationships between thyroid and renal status and survival. Results: Plasma TSH concentrations were not suppressed in 7 of 8 cats with hypothyroidism 3 months after radioiodine treatment. The proportion of cats with azotemia was significantly (P= .028) greater in the hypothyroid (16 of 28) than the euthyroid group (14 of 47). Twenty‐eight of 41 cats (68%) with plasma TT4 concentration below the laboratory reference range had an increased plasma TSH concentration. Hypothyroid cats that developed azotemia within the follow‐up period had significantly (P= .018) shorter survival times (median survival time 456 days, range 231–1589 days) than those that remained nonazotemic (median survival time 905 days, range 316–1869 days). Conclusions and Clinical Importance: Iatrogenic hypothyroidism appears to contribute to the development of azotemia after treatment of hyperthyroidism, and reduced survival time in azotemic cats.     

Recombinant human thyrotropin in veterinary medicine: current use and future perspectives

Recombinant human thyrotropin (rhTSH) was developed after bovine thyrotropin (bTSH) was no longer commercially available. It was approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) as an aid to diagnostic follow-up of differentiated thyroid carcinoma in humans and for thyroid remnant ablation with radioiodine. In addition, rhTSH is used in human medicine to evaluate thyroid reserve capacity and to enhance radioiodine uptake in patients with metastatic thyroid cancer and multinodular goiter. Likewise, rhTSH has been used in veterinary medicine over the last decade. The most important veterinary use of rhTSH is thyroidal functional reserve testing for the diagnosis of canine hypothyroidism. Recent pilot studies performed at Ghent University in Belgium have investigated the use of rhTSH to optimize radioiodine treatment of canine thyroid carcinoma and feline hyperthyroidism. Radioiodine treatment optimization may allow a decreased therapeutic dosage of radioiodine and thus may improve radioprotection. This review outlines the current uses of rhTSH in human and veterinary medicine, emphasizing research performed in dogs and cats, as well as potential future applications.     

Echocardiographic findings in 103 cats with hyperthyroidism

Using M-mode echocardiography, cardiac abnormalities were studied in 103 cats with untreated hyperthyroidism. In addition, follow-up echocardiography was performed on 24 of these cats to assess the long-term (4 to 21 months) effect of treatment (thyroidectomy or radioiodine) on thyrotoxic cardiac disease. The most common echocardiographic abnormality in the 103 untreated hyperthyroid cats was hypertrophy of the left ventricular caudal wall (71.9%). Hypertrophy of the interventricular septum also was documented in 39.8% of the 103 cats. Other abnormalities included high values for left atrial diameter (70.0%), aortic root diameter (18.5%), and left ventricular diameter at end diastole (45.6%). In some of these cats, indices of contractility were enhanced; in 21.4% and 14.6% of the cats, values for shortening fraction and velocity of circumferential fiber shortening, respectively, were greater than those values measured in clinically normal cats. After treatment of the hyperthyroidism, left ventricular hypertrophy resolved or improved in many of the cats, as indicated by decreases in left ventricular caudal wall and interventricular septum thicknesses. Hyperdynamic wall motion resolved in all cats after treatment, as evidenced by consistent decreases in shortening fraction and velocity of circumferential fiber shortening. Despite these improvements, some cats had one or more persistently abnormal echocardiographic values after treatment. These results suggested that in cats, hyperthyroidism commonly is associated with largely reversible cardiomyopathy. In those cats in which cardiomyopathy persists or worsens after treatment, underlying primary cardiomyopathy or thyroid hormone-induced cardiac structural damage may exist.     

Thyroid scintigraphy in hyperthyroidism

Thyroid scintigraphy is a nuclear medicine procedure that produces a visual display of functional thyroid tissue based on the selective uptake of various radionuclides by thyroid tissue. Thyroid scintigraphy provides valuable information regarding both thyroid anatomy and physiology and can play an integral role in the diagnosis and management of cats with hyperthyroidism. Thyroid scintigraphy allows the direct visualization of the functional adenomatous thyroid tissue responsible for the development of hyperthyroidism. For this reason, thyroid scintigraphy will allow the diagnosis of hyperthyroidism before laboratory tests are consistently abnormal. Thyroid scintigraphy can also exclude a diagnosis of hyperthyroidism in cats with thyroid hormone elevations of nonthyroidal origin. Thyroid scintigraphy provides an additional method for determining the relative severity of thyroid disease that is less affected by the presence of concurrent nonthyroidal illness than laboratory evaluations. When treating hyperthyroid cats with radioiodine, the lowest effective dose should be administered. In an effort to administer the lowest radioiodine dose possible, the volume of adenomatous thyroid tissue present in the individual hyperthyroid cat should be considered. Thyroid scintigraphy provides an excellent method for evaluating the size of hyperfunctional thyroid tissue that is not limited by the presence of ectopic or intrathoracic thyroid tissue. Thyroid scintigraphy also provides valuable information in the diagnosis and evaluation of hyperthyroid cats with thyroid carcinoma.     

Interference of iohexol with radioiodine thyroid uptake in the hyperthyroid cat

Absorbed thyroid dose and effective half-life were determined in 46 hyperthyroid cats after treatment with a low dose (mean 111MBq) of radioiodine intravenously. Thirteen of these cats had received iohexol for glomerular filtration rate (GFR) measurement within 24h before treatment with radioiodine in view of another ongoing study at our institution. Pre-therapy values were obtained for total thyroxine (TT(4)) and for the thyroid to salivary gland ratio with sodium pertechnetate gamma-camera imaging. All cats underwent post-therapy scans at 24, 48 and 120 h for evaluation of radioactive iodine uptake (RAIU) and the effective half-life of radioiodine. The absorbed dose was calculated from the cumulative activity with Olinda software. Both groups were comparable in age, TT(4) and the ratio of thyroid activity to salivary gland activity. Statistical analysis revealed a significant decreased absorbed dose in the thyroid in the iohexol group. This decreased uptake was not accompanied by an decreased effective half-life of the radioiodine. The variation of inter-individual RAIU decreased in this group and more homogenous absorbed doses were obtained. No significant difference in outcome could be demonstrated. However, a tendency towards a higher number of residual hyperthyroidism in the iohexol group was noted (15 versus 6% in control group). This study demonstrates that iohexol interferes with the uptake of radioiodine in the hyperthyroid cat but does not provoke increased turnover. In this study, albeit including a small number of cats, outcome did not seem to be significantly affected.     

Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment

This study reports the scintigraphy, histopathology, sole treatment with high-dose radioactive iodine and outcome of eight cases of feline thyroid carcinoma. Scintigraphic findings were variable and in 7/8 cases scintigraphic features could not reliably distinguish whether the thyroid tissue was malignant. Histopathology revealed typical criteria of malignancy in all cases, with mitotic activity described most frequently (7/8 cases), followed by infiltration of local tissues (4/8 cases). Cellular pleomorphism was infrequently observed. Single high-dose (1100MBq I(131)) radioiodine therapy was successful in 6/8 cases, with complete resolution of hyperthyroidism, and was associated with prolonged survival times (181-2381 days). Sole treatment with high-dose radioiodine is a safe and effective treatment for functional thyroid carcinoma. The prognosis for feline thyroid carcinoma successfully treated with radioiodine is good, with extended survival times commonly achieved.     

Radio-iodine treatment of hyperthyroid cats

Thirty-two elderly domestic shorthaired cats (mean age 12.9 years) were treated with radioiodine (131I). The dose of 131I administered ranged from 39 mBq to 134 mBq. Twenty-eight cats became euthyroid after treatment, one became hypothyroid and three remained hyperthyroxaemic. Two of the hyperthyroxaemic cats were successfully re-treated with 131I. Five cats died from concurrent diseases within one year of treatment. The administration of a dose of 131I selected by assessing the severity of the clinical signs, the size of the thyroid gland(s) and the serum level of thyroxine was an effective treatment for hyperthyroidism.     

Radio-iodine treatment of hyperthyroid cats

Thirty-two elderly domestic shdrthaired cats (mean age 12.9 years) were treated with radioiodine (¹³¹I). The dose of ¹³¹I administered ranged from 39 mBq to 134 mBq. Twenty-eight cats became euthyroid after treatment, one became hypothyroid and three remained hyperthyrox-aemic. Two of the hyperthyroxaemic cats were successfully re-treated with ¹³¹I. Five cats died from concurrent diseases within one year of treatment. The administration of a dose of ¹³¹I selected by assessing the severity of the clinical signs, the size of the thyroid gland(s) and the serum level of thyroxine was an effective treatment for hyperthyroidism.     

Association of the risk of development of hypothyroidism after iodine 131 treatment with the pretreatment pattern of sodium pertechnetate Tc 99m uptake in the thyroid gland in cats with hyperthyroidism: 165 cases (1990-2002)

OBJECTIVE: To assess whether the risk of development of hypothyroidism after treatment with iodine 131 (131I) was associated with the pattern of sodium pertechnetate Tc 99m activity in the thyroid gland detected via scintigraphy before treatment in cats with hyperthyroidism. DESIGN: Retrospective study. ANIMALS: 165 cats. PROCEDURE: Medical records of cats with hyperthyroidism that had been treated with 131I (from 1990 to 2002) and had undergone scintigraphy of the thyroid gland before treatment were reviewed; data regarding signalment, scintigraphic findings (classified as unilateral, bilateral-asymmetric, bilateral-symmetric, or multifocal patterns), serum total thyroxine (T4) concentrations before treatment and prior to hospital discharge, and 131I treatment were collected. A questionnaire was sent to each referring veterinarian to obtain additional data including whether the cats subsequently developed hypothyroidism (defined as serum total T4 concentration less than the lower reference limit > or = 3 months after treatment). RESULTS: 50 of 165 (30.3%) 131I-treated cats developed hypothyroidism. Hypothyroidism developed in 39 of 109 cats with bilateral, 10 of 50 cats with unilateral, and 1 of 6 cats with multifocal scintigraphic patterns of their thyroid glands. Cats with a bilateral scintigraphic pattern were approximately 2 times as likely to develop hypothyroidism after 131I treatment than were cats with a unilateral scintigraphic pattern (hazard ratio, 2.1; 95% confidence interval, 1.04 to 4.2). CONCLUSIONS AND CLINICAL RELEVANCE: Cats with hyperthyroidism that have a bilateral scintigraphic pattern in the thyroid gland before 131I treatment appear to have a significantly higher risk of subsequently developing hypothyroidism, compared with cats with a unilateral scintigraphic pattern.     

Overexpression of c-Ras in hyperplasia and adenomas of the feline thyroid gland: an immunohistochemical analysis of 34 cases

Formalin-fixed, paraffin-embedded thyroid glands from 18 cats diagnosed with hyperthyroidism were evaluated immunohistochemically for overexpression of the products of oncogenes c-ras and bcl2 and the tumor suppressor gene p53. Fourteen thyroid glands from euthyroid cats without histologically detectable thyroid lesions were examined similarly as controls. Results from these investigations showed that all cases of nodular follicular hyperplasia/adenomas stained positively for overexpression of c-Ras protein using a mouse monoclonal anti-human pan-Ras antibody. The most intensely positively staining regions were in luminal cells surrounding abortive follicles. Subjacent thyroid and parathyroid glands from euthyroid cats did not stain immunohistochemically for pan-Ras. There was no detectable staining for either Bc12 or p53 in any of the cats. These results indicated that overexpression of c-ras was highly associated with areas of nodular follicular hyperplasia/adenomas of feline thyroid glands, and mutations in this oncogene may play a role in the etiopathogenesis of hyperthyroidism in cats.     

Thyroid tumors in dogs and cats.

The clinical presentation and biologic behavior of thyroid tumors vary widely among dogs, cats, and human beings. Although thyroid tumors in dogs are rare, they are most likely to be malignant. Clinical signs are usually the result of impingement on surrounding structures, and clinical hyperthyroidism is rare. In contrast, hyperthyroidism resulting from benign thyroid proliferation is relatively common among older cats. Malignant tumors are extremely uncommon but have high metastatic potential. Irrespective of the tumor's ability to produce functional thyroid hormone, scintigraphy is often helpful in the diagnosis and staging of thyroid tumors in all three species. Treatment with surgery is a reasonable treatment option for noninvasive tumors. Iodine 131 is a well-established treatment for thyroid nodules in cats, but its effectiveness in dogs is controversial. In dogs, external beam radiation therapy has produced more consistent results in affording local tumor control when surgery is not possible.     

Diagnostic tests for hyperthyroidism in cats

The diagnosis of hyperthyroidism, one of the most common disorders affecting elderly cats, is usually straightforward and considered routine by most practitioners. Nowadays, however, most cats suffering from hyperthyroidism tend to be diagnosed earlier and at a milder stage of the disease than those cats diagnosed 10 to 25 years ago. There are, in fact, a growing number of cats with clinical signs of hyperthyroidism and palpably large thyroid glands whose baseline serum total thyroid hormone concentrations are within the normal or borderline range, making diagnosis problematic. This paper reviews the available tests used to confirm a diagnosis of hyperthyroidism in cats and discusses their overall usefulness.     

CALCULATION AND USAGE OF THE THYROID TO BACKGROUND RATIO ON THE PERTECHNETATE THYROID SCAN

Feline hyperthyroidism is a common endocrine disorder. A single dose of 148 MBq (4 mCi) ¹³¹I is 95–98% effective for the treatment of hyperthyroidism in cats; however, the cause for treatment failures has not been determined. In a series of 113 hyperthyroid cats having pertechnetate thyroid scintigraphy before treatment using a standard 148 MBq (4 mCi) ¹³¹I dose, the thyroid to salivary gland (T:S) ratio and the thyroid to background (T:B) ratio were calculated. Results in 107 (95%) cats successfully treated were compared with results in six (5%) cats that remained hyperthyroid after treatment. T:B ratio was significantly higher for cats that had treatment failure (median 13.0, range 3.6–73.0) than for cats successfully treated (median 4.4, range 1.2–69.0) (P=0.02), whereas there was no significant difference in their T:S ratios (P=0.2). The T:B ratio is a new approach to evaluating the thyroid pertechnetate scan with the intent of identifying which hyperthyroid cats may fail treatment using a standard 148 MBq (4 mCi) ¹³¹I dose and which, therefore, require a higher dose.     

PREDICTORS OF RESPONSE TO RADIOIODINE THERAPY IN HYPERTHYROID CATS

The objective of this retrospective study was to evaluate hyperthyroid cats for pretreatment factors that would predict response to radioiodine therapy. Hyperthyroidism was diagnosed in 193 cats based on elevated serum thyroxine levels and/or elevated thyroid to salivary gland ratios on thyroid scintigraphy. All cats were treated with an intravenous bolus of 4 mCi of radioiodine and follow-up serum thyroxine levels were evaluated at 1 week and 1, 3, 6, and 12 months post-therapy. There was a significant relationship between pretreatment thyroxine values and post-treatment thyroxine values at all of the follow-up time points (p < 0.001). There was also a relationship between thyroid to salivary gland technetium scan ratio results and serum thyroxine values at pretreatment and at 1 week post-treatment (p = 0.02, 0.005, respectively). A greater scan ratio was associated with higher thyroxine levels at these time points, but not at 1, 3, 6 or 12 months post-therapy. Ninety-eight cats pretreated with methimazole were analyzed for the effect of this drug on response to therapy. Methimazole was discontinued > or = 5 days before radioiodine therapy in 58 cats and < 5 days in 31 cats, in 9 cats the number of days off methimazole was unknown. There was no difference in response to radioiodine based upon when methimazole was discontinued (p = 0.70).     

Medical management of hyperthyroidism

Radioiodine is considered the treatment of choice for hyperthyroidism, but in some situations, methimazole therapy is preferred, such as in cats with pre-existing renal insufficiency. Methimazole blocks thyroid hormone synthesis, and controls hyperthyroidism in more than 90% of cats that tolerate the drug. Unfavorable outcomes are usually due to side effects such as gastrointestinal (GI) upset, facial excoriation, thrombocytopenia, neutropenia, or liver enzyme elevations; warfarin-like coagulopathy or myasthenia gravis have been reported but are rare. Because restoration of euthyroidism can lead to a drop in glomerular filtration rate, all cats treated with methimazole should be monitored with BUN and creatinine, in addition to serum T4, complete blood count, and liver enzymes. Transdermal methimazole is associated with fewer GI side effects, and can be used in cats with simple vomiting or inappetance from oral methimazole. Hypertension may not resolve immediately when serum T4 is normalized, and moderate to severe hypertension should be treated concurrently with-atenolol, amlodipine, or an ACE inhibitor. Alternatives to methimazole include carbimazole, propylthiouracil, or iodinated contrast agents.     

Radioactive Iodine Treatment of a Functional Thyroid Carcinoma Producing Hyperthyroidism in a Dog

Radioactive iodine (131I) was used in the treatment of a 12-year-old female dog with hyperthyroidism resulting from a large, unresectable (and metastatic) thyroid carcinoma associated with signs of severe inspiratory stridor and dyspnea. Hyperthyroidism was diagnosed on the basis of clinical signs (polyuria, polydipsia, polyphagia, weight loss, nervousness) and high basal serum thyroxine (T4) concentrations, as well as thyroid radioiodine kinetic studies that showed a high radioiodine uptake into the thyroid (% thyroid uptake) and markedly increased serum concentrations of protein-bound iodine-131 (PB131I) after 131I tracer injection. Thyroid imaging revealed diffuse radionuclide accumulation by the tumor, which involved both thyroid lobes. The dog was treated with three large doses of radioiodine (131I), ranging from 60 to 75 mCi, given at intervals of 5 to 7 months. The dog became euthyroid, and the size of the tumor decreased by approximately 25% after each 131I treatment, improving the severe inspiratory stridor and dyspnea, but both the hyperthyroid state and breathing difficulty recurred within a few months of each treatment. The dog was euthanatized 5 months after the last treatment because of progressive tracheal compression and pulmonary metastasis.     

Lack of circulating thyroid stimulating immunoglobulins in cats with hyperthyroidism

Although feline hyperthyroidism has become a commonly diagnosed disorder of older cats, the underlying etiology remains unknown. Pathological findings of adenomatous hyperplasia involving both thyroid lobes in most hyperthyroid cats suggests the possibility that feline hyperthyroidism may be similar to human Graves' disease, which results from high circulating levels of thyroid stimulating immunoglobulins (TSIs). To exclude high circulating levels of TSIs as the cause of feline hyperthyroidism, we measured intracellular concentrations of cyclic adenosine monophosphate (cAMP) in functioning rat thyroid cells (FRTL-5) incubated with IgG extracted from hyperthyroid cat serum. Since TSIs stimulate thyroid hormone secretion through activation of cAMP, their presence can be evidenced in vitro by generation of high cAMP concentrations in cultured thyroid cells. No significant difference was found in intracellular cAMP concentrations in FRTL-5 cells incubated with IgG from normal versus hyperthyroid cats. In contrast, IgG from a human patient with Graves' disease caused substantially more cAMP generation than either normal human IgG or IgG from the cats of this study. These results indicate that feline hyperthyroidism does not result from high circulating concentrations of TSI and, in that respect, is not analogous to Graves' disease.     

INVESTIGATION OF TWO METHODS FOR ASSESSING THYROID-LOBE ASYMMETRY DURING PERTECHNETATE SCINTIGRAPHY IN SUSPECTED HYPERTHYROID CATS

Our aim was to investigate thyroid:thyroid (T:T) ratio and visual inspection for assessing thyroid-lobe asymmetry in suspected hyperthyroid cats. Although thyroid-salivary asymmetry is a preferred test, inherent thyroid symmetry may assist image interpretation. Association was determined using a scatter plot and Spearman's rank correlation. Agreement was assessed using the kappa (K) statistic. Accuracy was assessed by sensitivity and specificity. Hyperthyroidism was diagnosed in 33/48 (69%) cats based on elevated serum total thyroxine level. Using two Wilcoxan rank-sum tests, a significant difference (P < 0.0001) was detected between cats with and without hyperthyroidism for both methods of assessing thyroid symmetry. For the 18 cats with T:T ratios < or = 1.5, there was poor correlation between the two methods (r(s) = 0.39). Using a cut-point of 1.5 for the T:T ratio, the test accurately predicted hyperthyroidism in 28/33 cats (sensitivity, 85%; 95% confidence interval (CI), 71-99%) and correctly predicted that hyperthyroidism was absent in 14/15 cats (specificity, 93%; CI, 77-100%). For visual inspection, agreement for diagnosing hyperthyroidism was excellent between methods (kappa = 0.82), within the same examiner (weighted kappa = 0.85) and between examiners (weighted kappa = 0.89). Considering cats with only definitely asymmetric thyroid lobes as positive, visual inspection accurately predicted hyperthyroidism in 28/33 cats (sensitivity, 85%; CI, 71-99%) and correctly predicted that hyperthyroidism was absent in 11/15 cats (specificity, 73%; CI, 48-99%). Thyroid-lobe asymmetry occurs more frequently in hyperthyroid than in euthyroid cats but caution should be exercised because some euthyroid cats have asymmetric thyroid glands.