Injeção percutânea de etanol no tratamento de nódulos tiroidianos sólidos, císticos e autônomos

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Percutaneous ethanol injection for treatment of unilateral hyperplastic thyroid nodules in cats Richard E. Goldstein, DVM, DACVIM; Craig Long, DVM, DACVR; Nigel C. Swift, BvetMed; William J. Hornof, DVM, DACVR; Richard W. Nelson, DVM, DACVIM; Thomas G. Nyland, DVM, DACVR; Edward C. Feldman, DVM, DACVIM

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yperthyroidism is a commonly diagnosed endocrine disease in cats. Current treatment options include longterm use of antithyroid medications, thyroidectomy, and administration of radioactive iodine (131I).1 All 3 of these treatment modalities are commonly used and effective. Each also has disadvantages. The most commonly used antithyroid medication, methimazole, usually requires daily administration; may cause anorexia, vomiting, and self-excoriation; and less commonly has been associated with hematologic abnormalities, hepatopathies, and bleeding disorders.1-3 Thyroidectomy and treatment with 131I can provide permanent resolution of hyperthyroidism. Treatment with 131I, however, may be limited by availability, hospitalization time, and expense. Surgery may be limited by anesthetic risk and concern of iatrogenic hypoparathyroidism.1 Treatment with ultrasound-guided per- Figure 1—Longitudinal ultrasonographic images of a normal thyroid gland (A), cutaneous ethanol injection (PEI) has hyperplastic thyroid gland (B), and cystic thyroid gland (C) in a cat. Notice the been successfully used in recent years in carotid artery (C) and thyroid gland (T). humans with hyperparathyroidism or roidism (ie, polyuria, polydipsia, polyphagia, weight hyperthyroidism.4-7 We recently reported the use of PEI loss). Further, each cat must have had persistent increasfor the treatment of primary hyperparathyroidism in es in serum thyroxine (T4) concentration. Serum total dogs.8,a Treatment with PEI in 1 cat with hyperthyT4 concentration must have been evaluated at least 3 roidism has been reported.9 Ultrasound guidance was times during a period of at least 4 weeks to confirm the not used, and that cat required several ethanol injecdiagnosis. A thyroid nodule must have been palpable tions for which manual palpation was used to guide and findings on technetium 99mTc 99m albumin (99mTc) placement of the needle. After the final ethanol injecthyroid scans must have been consistent with a solitary tion, the cat developed bilateral laryngeal paralysis that nodule, causing the hyperthyroidism.1 The affected thymay have been caused by leakage of ethanol around the roid gland also must have been visible ultrasonographithyroid area. In our report, use of ultrasound-guided cally, using a 10-MHz phased array transducer probe,b as PEI for the treatment of hyperthyroidism in 4 cats with described elsewhere (Fig 1).10 a solitary thyroid nodule was evaluated. A thorough history, physical examination, CBC, urinalysis, serum biochemical analysis, and serum total Procedure T411,c and an analog free T4 assay, previously validated Cats—Cats brought to the Veterinary Medical (2 cats),12,d were performed prior to inclusion. All cats Teaching Hospital at the University of California, Davis, had been treated with methimazole.e Methimazole was for treatment of hyperthyroidism were assessed for withheld for 5 days prior to PEI treatment to allow for inclusion in this report. For inclusion, each cat must a natural increase in serum T4 and free T4 concentrahave had typical clinical signs associated with hyperthytions above reference ranges. These variables were From the Veterinary Medical Teaching Hospital (Goldstein, Long, assessed immediately prior to the injection procedure. Swift) and the Departments of Medicine and Epidemiology (Feldman, Nelson) and Surgery and Radiology (Hornof, Nyland), School of Veterinary Medicine, University of California, Davis, CA, 95616. Dr. Goldstein’s present address is the Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot 76100 Israel. Supported by a grant from the Center for Companion Animal Health, Davis, Calif. Address correspondence to Dr. Feldman. 1298 Scientific Reports: Descriptive Report

Injection procedure—Volume of the affected thyroid nodule was estimated by use of ultrasonography, using the product of maximum length, height, and width. The dose of 96% ethanol to be injected was determined, in part, by an arbitrary target dose (one-half of the calculated thyroid gland volume) and, more importantly, by observed ethanol dissemination within the thyroid JAVMA, Vol 218, No. 8, April 15, 2001

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Monitoring—All cats were monitored in the hospital for 5 days after the procedure for adverse effects to the injection. Serum was obtained for measurement of total T4 concentration (4 cats) and free T4 concentration (2) immediately prior to the alcohol injection (day 0) and then every 12 hours after the injection for 5 days. Complete blood counts and serum biochemical analyses were performed on days 1 and 5 after the injection. Serum total T4 and free T4 concentrations were then assessed once a week for 4 weeks, every 2 weeks for 4 weeks, once monthly for 6 months, and again at 9 and 12 months. Repeat thyroid scintigraphy scans were performed at 3, 6, and 12 months. Repeat ultrasonographic

Figure 2—Ultrasonographic images of injection of ethanol into the thyroid gland of a cat. A—Notice the needle (arrow) in the gland prior to injection. B and C—A test volume of ethanol was injected (arrows). D—Ethanol was disseminated throughout the gland (between the solid arrows).

gland. All cats were anesthetized with infusions of propofolf (1.4 to 2.3 mg/lb [3 to 5 mg/kg] of body weight, IV) to ensure complete immobilization during the injection process. Hair over the affected thyroid gland was shaved, skin was cleansed with povidone iodine solution, and sterile gel was used as an acoustic coupler. With ultrasonic guidance, a 27-gauge 0.58-cm needle was inserted into the thyroid gland (Fig 2). The needle was attached to a 0.28-cm diameter extension tube to prevent exces-

Figure 3—Serum thyroxine (T4; µg/dl) and free T4 (ng/dl) concentrations before and over time (days 1, 2, and 3; weeks 2, 3, and 6; and months 2, 4, 6, and 9) after percutaneous ethanol injection (PEI; each graph represents data from 1 cat). JAVMA, Vol 218, No. 8, April 15, 2001

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sive movement of the needle during the injection. The extension tube was attached to a 1-ml tuberculin syringe. When the needle tip echo was observed to be within the thyroid nodule, a test injection of < 0.05 ml of ethanol was administered to confirm needle placement (the injected alcohol causes a hyperechoic wave within the nodule). After placement of the needle was definitively established, ethanol was injected slowly while being monitored ultrasonographically. The injection was terminated and the needle removed either after the target dose had been administered or the nodule appeared to be completely infiltrated with ethanol. Cats were recovered from anesthesia immediately after the injection procedure.

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evaluations were performed on day 5 and at 1, 3, 6, and 12 months after the injection. Results Four neutered domestic shorthair cats were included in the study (2 male, 2 female) and ranged from 11 to 15 years of age. Mean serum total T4 concentrations at the initial time of diagnosis in each cat were 7.8, 9.8, 12.7, and 24.3 µg/dl, respectively (reference range, 1.1 to 3.9 µg/dl). Each cat had been treated with methimazole successfully for 60 to 90 days. Complete resolution of signs were reported by each owner. Administration of methimazole was discontinued in each cat 5 days prior to ethanol injection. Two cats were mildly polydipsic and polyuric, 1 cat had an increase in appetite, and 1 cat had an increase in appetite and diarrhea by the fifth day after discontinuation of methimazole. Serum T4 concentrations immediately before PEI treatment were 4.0, 5.2, 7.0, and 8.4 µg/dl, respectively. Free T4 concentrations were assessed in 2 cats before PEI treatment, and were 5.9 and 4.3 ng/dl (reference range, 1.1 to 3.9 ng/dl), respectively. Three cats had affected thyroid nodules that appeared homogeneous, and 1 had a thyroid nodule that appeared cystic ultrasonographically (Fig 1). Volume of the affected thyroid nodules were calculated to be 0.20, 0.3, 0.74, and 0.84 cm3. Each cat received 1 injection of ethanol. Complete dissemination of the ethanol was evident in 3 cats. In 1 cat, cystic fluid within the thyroid mass was removed Figure 4—Pertechnetate scans of a healthy cat and 2 cats with hyperthyroidism. prior to injection to facilitate ethanol dis- A—Healthy cat. B—Scan of a cat with hyperthyroidism caused by 2 thyroid nodules semination, and only partial dissemination (arrow). C—Scan of a cat with hyperthyroidism caused by a solitary right-sided thywas observed. Two cats received the calcu- roid nodule (arrowhead; notice the left thyroid lobe is not visible). D—Scan of the cat in C 3 months after PEI; there is no visible thyroid lobe on the right side, and lated injection volume (50% of the calculat- the left lobe is normal. E—Scan of a cat with hyperthyroidism caused by a solitary ed nodule volume), and 2 cats received thyroid nodule on the right side (arrowhead). F—Scan of the cat in E; there is residbetween 50 and 100% of the calculated nod- ual abnormal pertechnetate uptake in the right thyroid nodule 3 months after PEI . ule volume. Duration of the procedure was the 4 weeks after injection. Clinical signs of hyperthyapproximately 10 minutes for each cat. roidism did not recur within the 12-month period after No local, systemic, or biochemical adverse affects injection. No cat had clinical signs of hypothyroidism were detected during the 5 days following injection at any time during the 12-month observation period. with ethanol. After the cats were returned to their ownAll affected thyroid nodules appeared smaller and ers, 2 had mild dysphonia (a higher pitch than before mottled on ultrasonographic examinations performed 5 the procedure). Dysphonia in 1 cat normalized within days and 1 month after injection. At 3, 6, and 12 months 6 weeks. The other cat continued to have dysphonia 1 after PEI treatment, the injected thyroid lobe was undeyear after the injection. tectable ultrasonographically in 2 cats. The injected thySerum total T4 concentrations decreased to within roid lobe remained visible, but considerably smaller or below reference range values in 3 cats within 24 than before treatment (< 25% of pretreatment size) in 2 hours of injection and in the fourth cat within 48 hours cats. One of the 2 cats with a thyroid lobe that remained of injection. Serum free T4 concentrations decreased small but visible after injection had the cystic mass. into the reference range within 24 hours in the 2 cats The injected thyroid lobe was not detectable on that had free T4 evaluated before the injection. Serum 99m Tc scans performed on 3 cats 3, 6, and 12 months total and free T4 concentrations remained within or after PEI treatment. In 1 cat (the cat that had the cysbelow reference range values for 12 months following tic mass), 99mTc uptake in the injected thyroid lobe was PEI treatment (Fig 3). The mild clinical signs of hyperslightly increased at 3, 6, and 12 months, although it thyroidism began to resolve in all cats within 1 week of had diminished considerably in size, compared with release from the hospital, as assessed by the owners. the scan obtained before injection (Fig 4). The noninEach cat was considered healthy by its owner within 1300 Scientific Reports: Descriptive Report

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Discussion In humans, PEI has been used extensively for the treatment of toxic (functional) and nontoxic (nonfunctional) thyroid adenomas. Reported success rates for ablation vary from 50 to 100%.5-7 Success of PEI treatment has been reported to be inversely related to the size of the nodule injected.5 Multiple injections are usually necessary, in part, because of the pain people feel during the injection (sedation is not routinely used) and, in part, because of the large size of the thyroid nodules in some patients.5-7 Success with a single ethanol injection in the 4 cats treated in our report may be related to the relatively small size of their thyroid nodules, although the calculated volume of each thyroid mass was typical for cats with hyperthyroidism with solitary thyroid nodules or 2 thyroid nodules.10 Relatively large volumes of ethanol, compared with the size of the nodule, were administered (50 to 100% of estimated thyroid volume). Injection of this large volume may have been possible because the cats were anesthetized. The mild abnormalities in serum T4 concentration prior to injection were related to the methimazole treatment each cat had received until 5 days prior to inclusion in this report. Their rapid improvement following ethanol injection was also likely related to successful management with methimazole and mild clinical signs at the time of ethanol administration. Each cat became euthyroid, none developed hypothyroidism or had recurrence of hyperthyroidism, and no adverse effects were evident in 2 cats. Adverse effects were mild in the other 2 cats (dysphonia). That adverse effect was transient in 1 of the 2 cats and may have been a result of ethanol directly affecting the laryngeal fold or, indirectly, via an effect on the recurrent laryngeal nerve. Cats with hyperthyroidism caused by a solitary thyroid nodule were chosen because of similarities between the nature of this condition (solitary mass) and that seen in dogs with primary hyperparathyroidism. Dogs with primary hyperparathyroidism usually have a solitary adenoma. Thus, there were anatomic similarities in comparing cats with a solitary thyroid nodule to dogs in which we have had success using PEI treatment.8 Localized pain and transient dysphonia are the most common adverse effects in people treated with PEI for hyperthyroidism. Laryngeal swelling as well as rare transient unilateral laryngeal paralysis have also been documented.5,6,13 Two of 8 dogs treated with PEI for primary hyperthyroidism had transient changes in the tone of their bark.8 In a recent report,9 a fourth ethanol injection in a cat resulted in severe respiratory distress and apparent bilateral laryngeal paralysis that required emergency surgical intervention. No cat in our report appeared to have signs of pain, vocalized, scratched at the injection site, or had signs of respiratory distress. It appears likely that the 2 cats in this report that developed mild dysphonia JAVMA, Vol 218, No. 8, April 15, 2001

may have had some degree of laryngeal compromise or swelling. These changes were mild in both cats and transient in 1. Laryngeal examinations were not performed. None of the 4 cats in our report became clinically hypothyroid or required thyroid supplementation. Hypothyroidism, including transient disease, is an uncommon sequela after PEI treatment in humans and is seen less commonly after PEI treatment than the incidence of hypothyroidism seen following thyroidectomy or treatment with 131I.13 Clinical hypothyroidism has been documented as an uncommon sequela of thyroidectomy or treatment with 131I in cats.1,14 Ultrasonography is becoming well-established in small animal veterinary medicine, and ultrasonography of the cervical region has been useful.10,15 Guidance by ultrasound and chemical immobilization were used to improve accuracy of injection and help in determination of the volume administered. Full dissemination appeared to be achieved in the 3 cats with a solid mass. This was more difficult in the cat with the cystic thyroid mass. Cystic masses have been documented in some cats with hyperthyroidism.16 This cat did respond fully to the treatment, although it required 24 hours longer than the other cats for serum T4 concentration to decrease into the reference range. The injected thyroid lobe in this cat continued to concentrate some 99m Tc 3, 6, and 12 months after injection. The importance of the abnormal 99mTc scans in this cat after PEI treatment is questionable, because abnormalities were not detected clinically or hematologically. Pertechnetate scans in human and veterinary medicine have been used primarily as a method of localizing active thyroid tissue and not as a thyroid function test.1 Comparison of 99mTc uptake in thyroid lobes and salivary glands has been used to aid in the diagnosis of hyperthyroidism in cats.17 Continued monitoring will be necessary to determine whether an abnormal 99mTc scan has value in predicting the recurrence of hyperthyroidism years after PEI treatment. The cat in our report has not had a recurrence of hyperthyroidism 1 year after treatment, despite the abnormal 99mTc scans. One cat developed abnormal 99mTc concentration in the noninjected thyroid lobe. This cat was not hyperthyroid clinically or biochemically at the time of the scan and has not developed hyperthyroidism in the 9 months since the final scan was performed. Ultrasonography of the cervical region, completed 5 days after ethanol injection, revealed decreases in lobe size of the thyroid gland in all 4 cats. The 2 cats that still had a visible thyroid lobe at 3, 6, and 12 months after injection include the cat with the cystic mass and a cat without uptake on 99mTc scans at those same times. Therefore, it is difficult to speculate on the importance of these ultrasonographic findings. Within the 1-year period in which we studied the cats, ultrasonography performed after injection did not appear to have an important role for assessment of the success of PEI treatment. To perform PEI treatment with the methods we used, a 99mTc scan must be performed prior to treatment to localize the affected thyroid nodule and to rule out ectopic abnormal thyroid tissue. Somewhat specialized Scientific Reports: Descriptive Report

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jected thyroid lobe was visible in all 4 cats and considered to be of normal size in 3 cats; size and density were similar to that of the salivary glands. The noninjected thyroid lobe in 1 cat had slightly increased size and density on 99mTc scan.

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ultrasonographic equipment as well as advanced ultrasonographic expertise are necessary. The procedure itself is quick, inexpensive, and requires minimal hospitalization of the animal. After the injection procedure, it appears that monitoring serum thyroid hormone concentrations (total T4 or free T4) and clinical signs are sufficient. The future role of PEI as a definitive treatment for hyperthyroidism in cats has yet to be determined. a

Goldstein RE, Long CD, Feldman EC, et al. Ultrasound guided percutaneous ethanol injection (PEI) for the treatment of primary hyperparathyroidism in 8 dogs (abstr). 17th Annu ACVIM Forum, 1999. b 10 MHz phased array transducer (ATL), Bothel, Wash. c Tetra-Tab radioimmunoassay, Organon Teknika Corp, Durham, NC. d Magic fT4, Ciba Corning Diagnostics, East Walpole, Mass. e Methimazole (Tapazol), Jones Pharma Inc, St Louis, Mo. f Propofol (PropoFlo), Abbott Laboratories, North Chicago, Ill.

References 1. Feldman EC, Nelson RW. Feline hyperthyroidism. In: Feldman EC, Nelson RW, eds. Canine and feline endocrinology and reproduction. 2nd ed. Philadelphia: WB Saunders Co, 1996;118–166. 2. Peterson ME, Kintzer PP, Hurvitz AI. Methimazol treatment of 262 cats with hyperthyroidism. J Vet Intern Med 1988;2:150–157. 3. Murray LAS, Peterson ME. Ipodate treatment of hyperthyroidism in cats. J Am Vet Med Assoc 1997;211:63–67. 4. Livraghi T, Paracchi A, Ferrari C, et al. Treatment of autonomous thyroid nodules with percutaneous ethanol injection: preliminary results. Radiology 1990;175:827–829. 5. Lippi F, Ferrari C, Manetti L, et al. Treatment of solitary autonomous thyroid nodules by percutaneous ethanol injection: results of an Italian multicenter study. J Clin Endocrinol Metab 1996;81:3261–3264.

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6. Monzani F, Caraccio N, Goletti O, et al. Five-year follow up of percutaneous ethanol injection for the treatment of hyperfunctioning thyroid nodules: a study of 117 patients. Clin Endocrinol 1997;46:9–15. 7. Bennedbaek FN, Karstrup S, Hegedüs L. Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol 1997;136:240–250. 8. Long CD, Goldstein RE, Hornof WJ, et al. Percutaneous ultrasound-guided chemical parathyroid ablation for treatment of primary hyperparathyroidism in dogs. J Am Vet Med Assoc 1999;215: 217–221. 9. Walker MC, Schear M. Percutaneous ethanol treatment of hyperthyroidism in a cat. Feline Pract 1998;28(5):10–12. 10. Nyland TG, Wisner ER. Ultrasonography of the neck. In: Nyland TG, Mattoon JS, eds. Veterinary diagnostic ultrasound. Philadelphia: WB Saunders Co, 1995;165–177. 11. Broome MR, Feldman EC, Turrel JM. Serial determination of thyroxine concentrations in hyperthyroid cats. J Am Vet Med Assoc 1988;192:49–51. 12. Refsal KR, Nachreiner RF, Stein BE, et al. Use of the triiodothyronine suppression test for diagnosis of hyperthyroidism in ill cats that have serum concentration of iodothyronines within normal range. J Am Vet Med Assoc 1991;199:1594–1601. 13. Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med 1998;338:1438–1447. 14. Peterson ME, Becker DV. Radioiodine treatment of 524 cats with hyperthyroidism. J Am Vet Med Assoc 1995;207:1422–1428. 15. Wisner ER, Mattoon JS, Nyland TG, et al. Normal ultrasonographic anatomy of the canine neck. Vet Radiol Ultrasound 1991;32:185–190. 16. Wisner ER, Theon AP, Nyland TG, et al. Ultrasonographic examination of the thyroid gland of hyperthyroid cats: comparison 99m to Tc scintigraphy. Vet Radiol Ultrasound 1994;35:53–58. 17. Beck KA, Hornof WJ, Feldman EC. The normal feline thyroid: technetium pertechnetate imaging and determination of thyroid to salivary gland radioactivity ratios in 10 normal cats. Vet Radiol 1985;26:35–38.

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