A 7-year-old castrated male Havanese with a 3-week history of excessive panting, hyperactivity, and aggression was evaluated by its primary care veterinarian. Eight weeks prior to that evaluation, a serum sample was obtained and submitted to a remote laboratorya for routine monitoring of thyroid function. Results indicated that the dog's serum T4 (7.7 nmol/L; reference range, 13 to 51 nmol/L) and fT4 (< 3.9 pmol/L; reference range, 7.7 to 47.6 pmol/L) concentrations were decreased from the respective reference ranges; however, because the dog did not have any clinical signs of disease at that time, no treatment was initiated. The dog had a history of environmental allergies, which were treated with diphenhydramine and chlorpheniramine maleate (dosages unavailable). The dog was not receiving any medications or supplements at the time of the initial evaluation. Its diet consisted of a commercial beef-based canned food. According to the owner, there was 1 other dog in the household, which was fed a different diet and was healthy. Results of the physical examination performed during the initial evaluation by the primary care veterinarian were unremarkable, and the dog weighed 7.5 kg (16.5 lb) and was assigned a BCS of 6/9. Thoracic radiography was performed, which revealed a diffuse, mild bronchial pattern in the lungs.
The dog was suspected to have bronchitis, and it was administered a tapered dosage regimen of prednisone that began at 5 mg, PO, daily and was gradually decreased over 12 days. No improvement in the panting, aggression, and hyperactivity was noted. During the last 4 days of prednisone tapering, while the dog was receiving a dose of 2.5 mg of prednisone every other day, serum T4 (< 0.6 nmol/L; reference range, 10 to 45 nmol/L) and fT4 (14 pmol/L; reference range, 8 to 40 pmol/L) concentrations measured by a different diagnostic laboratoryb were still below or near the lower limit of the respective reference ranges. A serum sample was obtained from the dog 9 days later and submitted to a third laboratoryc for thyroid function testing. Results revealed that the T4 concentration (8.37 nmol/L; reference range, 10 to 49 nmol/L) was still decreased from the reference range, fT4 concentration (7.9 pmol/L; reference range, 7.1 to 29.9 pmol/L) was within the reference range, and T3 (5.8 nmol/L; reference range, 0.46 to 1.07 nmol/L) and fT3 (16.7 pmol/L; reference range, 2.5 to 5.4 pmol/L) concentrations were markedly increased from the respective reference ranges; test results were negative for autoantibodies against thyroglobulin (< 1%; reference range, < 10%).
Three weeks after the initial evaluation by the primary care veterinarian, the dog was evaluated at Dogs and Cats Veterinary Referral and Emergency. At that time, the dog weighed 7.2 kg (15.8 lb) and had a BCS of 6/9. Abnormal physical examination findings included persistent panting and tachycardia (HR, 160 bpm; reference range, 70 to 140 bpm). Results of thyroid function tests performed by a fourth laboratoryd revealed serum T4 (11 nmol/L; reference range, 11 to 60 nmol/L), fT4 (13 pmol/L; reference range, 6 to 42 pmol/L), and TSH (0.07 ng/mL; reference range, 0 to 0.48 ng/mL) concentrations were at or near the lower limit of the respective reference ranges, whereas serum T3 (5.0 nmol/L; reference range, 0.8 to 2.1 nmol/L) and fT3 (24.6 pmol/L; reference range, 1.2 to 8.2 pmol/L) concentrations were markedly increased from the respective reference ranges (Figure 1). Test results for thyroglobulin, T3-binding and T4-binding autoantibodies were negative. No treatment was prescribed.
Serum T4 (dashed line) and T3 (solid line) concentrations for a 7-year-old castrated male Havanese at 6, 8, and 12 weeks after developing clinical signs of excessive panting, hyperactivity, and aggression and 1, 10, and 60 days after a diet change. Notice the serum T3 and T4 concentrations returned to within the respective reference ranges after the diet change. All thyroid function tests were performed by the same laboratory.d The reference range for T4 concentration was 11 to 60 nmol/L, and the reference range for T3 concentration was 0.8 to 2.1 nmol/L.
Citation: Journal of the American Veterinary Medical Association 250, 12; 10.2460/javma.250.12.1427
Serum T4 (dashed line) and T3 (solid line) concentrations for a 7-year-old castrated male Havanese at 6, 8, and 12 weeks after developing clinical signs of excessive panting, hyperactivity, and aggression and 1, 10, and 60 days after a diet change. Notice the serum T3 and T4 concentrations returned to within the respective reference ranges after the diet change. All thyroid function tests were performed by the same laboratory.d The reference range for T4 concentration was 11 to 60 nmol/L, and the reference range for T3 concentration was 0.8 to 2.1 nmol/L.
Citation: Journal of the American Veterinary Medical Association 250, 12; 10.2460/javma.250.12.1427
Serum T4 (dashed line) and T3 (solid line) concentrations for a 7-year-old castrated male Havanese at 6, 8, and 12 weeks after developing clinical signs of excessive panting, hyperactivity, and aggression and 1, 10, and 60 days after a diet change. Notice the serum T3 and T4 concentrations returned to within the respective reference ranges after the diet change. All thyroid function tests were performed by the same laboratory.d The reference range for T4 concentration was 11 to 60 nmol/L, and the reference range for T3 concentration was 0.8 to 2.1 nmol/L.
Citation: Journal of the American Veterinary Medical Association 250, 12; 10.2460/javma.250.12.1427
The dog was reevaluated 2 weeks later. At that time, its body weight and BCS had decreased to 6.7 kg (14.7 lb) and 5/9, respectively, despite the fact that the owner reported no change in the amount or type of food that it was eating. The only remarkable abnormality noted during physical examination was tachycardia (HR, 200 bpm). Results of follow-up thyroid function tests performed by the fourth laboratoryd revealed that serum T3 (4.3 nmol/L) and fT3 (16.6 pmol/L) concentrations were still increased from the respective reference ranges, whereas serum T4 (5 nmol/L), fT4 (6 pmol/L), and TSH (0 ng/mL) concentrations were at or decreased from the lower limits of the respective reference ranges (Figure 1). No treatment was initiated.
The dog developed polyuria, polydipsia, and mild diarrhea over the next 2 weeks and was evaluated for a third time at Dogs and Cats Veterinary Referral and Emergency. Abnormal physical examination findings included tachycardia (HR, 192 bpm) and a grade 3/6 systolic heart murmur for which the point of maximum intensity was detected over the tricuspid valve. Systolic blood pressure (120 mm Hg) was within the reference range (110 to 150 mm Hg). No remarkable abnormalities were observed during ultrasonographic evaluation of the cervical region, which included assessment of both lobes of the thyroid gland. The dog was prescribed atenolol (6.25 mg, PO, q 12 h) and reevaluated 4 days later. At that time, the dog's body weight and BCS were 6.6 kg (14.5 lb) and 5/9, respectively, and it was still tachycardic (HR, 176 to 200 bpm). The dose of atenolol was increased to 12.5 mg every 12 hours, and the dog was referred to the Virginia-Maryland College of Veterinary Medicine Veterinary Teaching Hospital for thyroid scintigraphy.
The dog was examined at the teaching hospital 9 weeks after the initial evaluation by the primary care veterinarian, at which time it continued to have clinical signs of hyperactivity and aggression. The dog was still consuming the same commercial beef-based canned food, but the amount being fed had been increased in an attempt to resolve the weight loss. During the initial physical examination at the teaching hospital, the dog weighed 6.1 kg (13.4 lb) and had a BCS of 4/9. Abnormalities detected included a grade 4/6 holosystolic murmur with the point of maximum intensity over the left apex of the heart and tachycardia (HR, 160 bpm). No abnormalities of the thyroid gland (ie, goiter) were palpated. Echocardiographic examination revealed the presence of a bileaflet mitral valve with severe mitral valve regurgitation and prolapse of the tricuspid valve with mild tricuspid valve regurgitation. A serum sample was obtained and submitted to the fourth laboratoryd for thyroid function testing. Serum T4 (6 nmol/L) and fT4 (5 pmol/L) concentrations were decreased from the respective reference ranges, TSH concentration (0.10 ng/mL) was within the reference range, and T3 (4.1 nmol/L) and fT3 (19.7 pmol/L) concentrations were still markedly increased from the respective reference ranges. Results for thyroglobulin, T3-binding and T4-binding autoantibodies were negative.
The dog was administered sodium pertechnetate Tc 99m (3.4 mCi, IV) and underwent nuclear scintigraphy 20 minutes later. Scintigraphic results indicated normal blood pool distribution of sodium pertechnetate in the thorax and abdomen. There was low-intensity uptake of pertechnetate within the left thyroid lobe (percentage dose uptake, 0.05%; thyroid-to-salivary ratio, 0.6). The right thyroid lobe was not visible, which was indicative of a hypofunctioning thyroid gland or suppressed activity of the thyroid sodium iodide symporter (Figure 2). Collectively, the nuclear scintigraphy and thyroid function testing results were consistent with thyrotoxicosis induced by an exogenous source of T3.
Nuclear scintigraphic images of the cervical region of the dog of Figure 1 with the dog positioned in ventral and right and left lateral recumbencies. The images were obtained 20 minutes after the dog was administered sodium pertechnetate Tc 99m (3.4 mCi, IV). Notice there was only low-intensity uptake of sodium pertechnetate in the left lobe of the thyroid gland and no uptake of sodium pertechnetate in the right lobe of the thyroid gland. There was also no evidence of ectopic thyroid tissue. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 250, 12; 10.2460/javma.250.12.1427
Nuclear scintigraphic images of the cervical region of the dog of Figure 1 with the dog positioned in ventral and right and left lateral recumbencies. The images were obtained 20 minutes after the dog was administered sodium pertechnetate Tc 99m (3.4 mCi, IV). Notice there was only low-intensity uptake of sodium pertechnetate in the left lobe of the thyroid gland and no uptake of sodium pertechnetate in the right lobe of the thyroid gland. There was also no evidence of ectopic thyroid tissue. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 250, 12; 10.2460/javma.250.12.1427
Nuclear scintigraphic images of the cervical region of the dog of Figure 1 with the dog positioned in ventral and right and left lateral recumbencies. The images were obtained 20 minutes after the dog was administered sodium pertechnetate Tc 99m (3.4 mCi, IV). Notice there was only low-intensity uptake of sodium pertechnetate in the left lobe of the thyroid gland and no uptake of sodium pertechnetate in the right lobe of the thyroid gland. There was also no evidence of ectopic thyroid tissue. See Figure 1 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 250, 12; 10.2460/javma.250.12.1427
The dog was hospitalized for 24 hours and fed a different diet, after which thyroid function testsd were repeated. Results revealed that serum T4 (1 nmol/L), fT4 (2 pmol/L), T3 (0.1 nmol/L), and fT3 (0.7 pmol/L) concentrations were decreased from the respective reference ranges (Figure 1), and TSH concentration (0.07 ng/mL) was near the lower limit of the reference range. The dog was discharged from the hospital with instructions to feed it the same commercial diet that the other dog in the household was being fed.
Thyroid function testsd were repeated 10 days later, and the serum T4 (2 nmol/L), fT4 (2 pmol/L), and T3 (0.1 nmol/L) concentrations remained decreased from the respective reference ranges, whereas the fT3 (1.2 pmol/L) and TSH (0.06 ng/mL) concentrations were within the respective reference ranges. The dog was slowly weaned off the atenolol during the next 2 weeks. Within 1 month after the diet change, the clinical signs of hyperactivity and aggression had subsided. Results of thyroid function testsd performed 2 months after the dog was discharged from the teaching hospital indicated that serum T4 (25 nmol/L), fT4 (30 pmol/L), T3 (1.0 nmol/L), fT3 (4.4 pmol/L), and TSH (0.29 ng/mL) concentrations were all within the respective reference ranges. Also, all clinical signs of thyrotoxicosis, including tachycardia, had resolved.
The dog's clinical history and results of the thyroid function tests and nuclear scintigraphy, along with the rapid resolution of clinical signs of hyperthyroidism during and after hospitalization at the teaching hospital, were consistent with a diagnosis of thyrotoxicosis induced by an exogenous source of T3. However, thorough questioning of the owner failed to reveal an obvious source of the exogenous T3.
The T3 concentration was measured in an unopened can of the commercial canned food that the dog was being fed at the onset of clinical signs of thyrotoxicosis (diet 1; provided by the owner), as well as an unopened can of the same food from a different manufacturing lot (diet 2), and 4 other canned foods with beef as the main protein source (diets 3 to 6). The T3 in each diet was extracted by use of a previously described1 ethanol extraction method with some modifications. Briefly, 20 g of each diet was homogenized in 10 mL of 70% ethanol and shaken for 30 minutes. The sample was then centrifuged at 4,400 × g for 20 minutes. The T3 concentration in the resulting supernatant was measured with a commercial radioimmunoassay kite designed to measure T3 concentration in serum. Serial dilutions (1:2, 1:4, 1:8, and 1:16) of the supernatant for each diet were created with 70% ethanol and assayed. Kit standards were used to calculate a standard curve, and the highest standard was serially diluted with 70% ethanol and assayed to assess linearity.
The T3 concentration was highest in diet 1 (1.39 μg/g) followed by diets 2 and 3 (0.85 μg/g each), diet 5 (0.55 μg/g), and diet 4 (0.37 μg/g). The T3 concentration in diet 6 was less than the lower detection limit of the assay, which was not determined.
Following diagnosis of thyrotoxicosis, serum samples left over from other diagnostic testing at various times before and after the diet change as well as samples of each diet were submitted to the same laboratoryd that performed the thyroid function testing for the referral and teaching hospitals for determination of serum total iodine concentration. The total iodine concentration (reference range, < 100 ng/mL) in serum samples obtained 6, 8, and 12 weeks after onset of clinical signs and prior to the diet change was 1,625, 2,265, and 2,557 ng/mL, respectively, whereas that in serum samples obtained 1, 10, and 60 days after the diet change was 1,387, 71, and 122 ng/mL, respectively. The total iodine concentration was 82.44 μg/g in diet 1, 50.50 μg/g in diet 2, 63.05 μg/g in diet 3, 17.48 μg/g in diet 4, 43.61 μg/g in diet 5, and 2.11 μg/g in diet 6. The current Association of American Feed Control Official standards2 for iodine concentration in commercial dog foods are a minimum of 1.5 μg/g and maximum of 50 μg/g.
Discussion
The dog described in the present report represented an unusual case of thyrotoxicosis induced by excessive T3 without a concurrent abnormal increase in serum T4 concentration. The source of T3 was believed to be exogenous on the basis of the consistently high serum T3 and fT3 concentrations, consistently low T4 and fT4 concentrations, and TSH concentrations near the lower limit of the reference range as well as evidence of suppressed sodium pertechnetate Tc 99m uptake by the thyroid gland during nuclear scintigraphy. The rapid resolution of clinical signs of hyperthyroidism and decrease in serum T3 concentration after hospitalization and a diet change also suggested the presence of an exogenous source of T3 in the dog's environment. Exogenous sources of thyroid hormone include food contaminated with thyroid gland, natural supplements, and pharmaceutical liothyronine.3–8
Autoimmune thyroiditis can be associated with the production of autoantibodies against thyroid hormones including T3, which can interfere with measurement of thyroid hormones by immunoassays. Although the presence of autoantibodies against T3 can artificially increase the T3 concentration measured by many assays, the assay used to measure the T3 concentration in most serum samples for the dog of this report involved a charcoal separation step that generally results in underestimation of the T3 concentration. Also, test results for antibodies against thyroglobulin, T4, and T3 were negative for multiple serum samples. Malignant neoplasia can cause an abnormal increase in serum T3 and fT3 concentrations in human patients,9,10 but no evidence of neoplasia or functional ectopic thyroid tissue was identified in the dog of this report during physical examination or thyroid scintigraphy.
Because the thyrotoxicosis resolved after the diet was changed, it was considered a likely source of exogenous T3. According to the owner, the dog was not fed anything other than the canned diet. The T3 and iodine concentrations varied dramatically among the diet that was fed to the dog of this report (diet 1) and the 5 other diets (diets 2 through 6) with similar compositions that were evaluated. The relevance of the T3 and iodine concentrations in the diet with regard to the clinical signs observed in the dog of this report is unclear. Although diet 1 had the highest concentration of both T3 and iodine among the diets evaluated, the T3 and iodine concentrations for the other 5 diets were not that much lower than those for diet 1. Given the amount of diet 1 consumed by the dog of this report, it was estimated that it was ingesting 65 to 98 μg of T3/d. That exceeds the dose of T3 (4 to 6 μg/kg, q 8 h) recommended for the treatment of dogs with hypothyroidism.11 If the measured T3 concentration in diet 1 was accurate and the bioavailability of that T3 was similar to that in T3 tablets, thyrotoxicosis would be expected in any dog fed that diet. However, the T3 concentration in diets 2, 3, 4, and 5 also exceeded the recommended dose of T3 for dogs with hypothyroidism. Thus, the role of diet in the pathogenesis of thyrotoxicosis for the dog of this report is unclear because, if excessive T3 in the diet was the singular cause of the condition, it seems like thyrotoxicosis would be commonly observed in dogs that were fed any of the evaluated diets except diet 6.
Because T3 and iodine concentrations in food may vary among manufactured lots, we analyzed a can of food presumably from the same manufacturing lot as that fed to the dog of this report (diet 1; provided by the owner) as well as a can of the same brand of food from a different lot (diet 2). Interestingly, the T3 concentration of diet 1 (1.39 μg/g) was 1.6 times that of diet 2 (0.85 μg/g). It is possible that clinical signs of thyrotoxicosis may not develop unless a dog is fed a diet containing excessive T3 for an extended period. It is also possible that the assay used to measure the T3 concentration in the various diets detected something other than T3 that was not bioactive, thus rendering the T3 concentrations measured in the diets invalid. Regardless, the effect of diet on thyroid function test results in dogs merits further investigation.
Thyrotoxicosis induced by excessive T3 has been described in humans ingesting dietary supplements.7,12 In 1 report,8 9 of 10 over-the-counter thyroid health and weight loss supplements contained substantial quantities of both T4 and T3. Tiratricol (3,5,3′-triiodothyroacetic acid), a bioactive metabolite of T3, was considered a possible source of exogenous T3 because it has been available as a dietary supplement for years and cross-reacts with T3 on most radioimmunoassays.13 Thyrotoxicosis induced by excessive T4 was described in a dog following ingestion of feces from another dog in the household that was being treated with levothyroxine.14 Thorough questioning of the owner of the dog of this report revealed that no dietary supplements or medications were being intentionally provided to the patient or the other dog in the household. The patient's controlled environment and lack of supplements being administered to either dog in the household made it unlikely that the thyrotoxicosis was the result of ingestion of a T3 supplement. However, in human medicine, abnormally increased serum T3 concentrations are occasionally the result of factitious thyrotoxicosis owing to surreptitious hormone supplementation. A similar phenomenon, Munchausen syndrome by proxy, has been described in dogs15 and could not be entirely excluded as the cause of thyrotoxicosis for the dog of this report.
The present report described a unique case of a dog with clinical signs of hyperthyroidism in conjunction with serum T3 and fT3 concentrations that were markedly increased and T4, fT4, and TSH concentrations that were at or decreased from the respective reference ranges. Because results of initial routine thyroid function tests indicated serum T4 and fT4 concentrations that were most consistent with hypothyroidism despite the dog having clinical signs of hyperthyroidism, serum T3 concentration was subsequently measured. This highlights the importance of measuring serum T3 and TSH concentrations in addition to T4 and fT4 concentrations when there is incongruity between clinical findings and thyroid function test results. For the dog of this report, the rapid resolution of clinical signs and return of serum T3 concentrations to within the reference range following hospitalization and a change in diet suggested that the thyrotoxicosis was the result of an exogenous source of T3 in the dog's environment, even though that source was not definitively identified.
Acknowledgments
The authors thank Justin Zyskowski, Cheryl Engfehr, and Dr. Thomas Herdt for technical assistance.
ABBREVIATIONS
| BCS | Body condition score |
| bpm | Beats per minute |
| fT3 | Free 3,5,3′-triiodothyronine |
| fT4 | Free thyroxine |
| HR | Heart rate |
| T3 | 3,5,3′-Triiodothyronine |
| T4 | Thyroxine |
| TSH | Thyroid-stimulating hormone |
Footnotes
Idexx Laboratories Inc, Westbrook, Me.
Antech Diagnostics, Irvine, Calif.
Hemopet Diagnostics, Garden Grove, Calif.
Diagnostic Center for Population and Animal Health, Michigan State University, Lansing, Mich.
T3 Solid Phase Component System, MP Biomedicals, Santa Ana, Calif.
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