proliferative thyroid lesions and hyperthyroidism in

Journal of Zoo and Wildlife Medicine 41(2): 296–308, 2010 Copyright 2010 by American Association of Zoo Veterinarians

PROLIFERATIVE THYROID LESIONS AND HYPERTHYROIDISM IN CAPTIVE FISHERS (MARTES PENNANTI) Elizabeth M. Bunting, V.M.D., Michael M. Garner, D.V.M., Dipl. A.C.V.P., Noha Abou-Madi, D.V.M., M.Sc., Dipl. A.C.Z.M., Robert E. Schmidt, D.V.M., Dipl. A.C.V.P., and George V. Kollias, D.V.M., Ph.D., Dipl. A.C.Z.M.

Abstract: Diseases of the thyroid gland are common in many zoo species, but there are few descriptions of thyroid dysfunction in Mustelidae. A 7-yr-old, captive-bred female fisher (Martes pennanti) with progressive alopecia was diagnosed with clinical hyperthyroidism based on persistent elevation of both total and free serum thyroxine and triiodothyronine, ultrasound examination, and histologic evidence of adenomatous hyperplasia. Four additional geriatric adult fishers (two male and two female) were identified with thyroid adenomatous hyperplasia in a review of 23 postmortem records. Banked sera were available for thyroid hormone testing from three of the four necropsy cases. Total and free thyroxine were elevated in four of four animals tested, and triiodothyronine was elevated in two of three animals tested. Necropsy findings in four cases identified cardiac hypertrophy, congestive heart failure, and vascular lesions consistent with hypertension; complete tissues were not available from the remaining case. Clinical and subclinical hyperthyroidism may be a common but overlooked condition of captive fishers. Key words: cardiac hypertrophy, fisher, hyperthyroidism, Martes pennanti, mustelid, thyroid adenomatous hyperplasia.

INTRODUCTION Thyroid lesions are a common postmortem finding in zoo and wildlife species. A review of over 1,000 pathology reports in zoo and circus animals found that thyroid masses accounted for 55.2% of all tumors recorded, by far the most common tissue affected.16 Cases of benign thyroid disease have been described in numerous captive species, including blue and gold macaws (Ara ararauna),45 cynomolgus monkey (Macaca fascicularis),18 llama (Lama glama),14 white rhinoceros (Ceratotherium simum simum),41 hippopotamus (Hippopotamus amphibius),55 bongo antelope (Tragelaphus eurycerus),44 red lechwe (Kobus leche),56 black bear (Ursus americanus),47 wild beluga whales (Delphinapterus leucas),28 wild and captive elasmobranchs,7 and wild and captive bottlenose dolphins (Tursiops truncatus).6,13 Hyperthyroidism in geriatric domestic cats is one of the most well-documented clinical syndromes of thyroid disease in the veterinary literature. Excess levels of thyroid hormone are produced by From the Department of Clinical Sciences, Section of Wildlife Health, College of Veterinary Medicine, Cornell University, Tower Road, Ithaca, New York 14853, USA (Bunting, Abou-Madi, Kollias); Northwest ZooPath, 654 West Main, Monroe, Washington 98272, USA (Garner); and Zoo/Exotic Pathology Service, 2825 Kovr Drive, West Sacramento, California 95605, USA (Schmidt). Correspondence should be directed to Dr. Bunting ([email protected]).

hyperplastic nodules of thyroid tissue independent of the influence of thyroid stimulating hormone (TSH). Treatment options include medical management with the thyroid hormone inhibitor methimazole (AAI Pharma, Wilmington, North Carolina 28405, USA), surgical resection, or radiotherapy. Genetic, environmental, and age-related causes have been examined in the cat; current investigations38,53 have focused on apparent down-regulation of inhibitory G proteins in the TSH receptor and TSH receptor mutations. Despite the frequency of thyroid lesions in other species, the disease appears to be rare in the well-studied domestic mustelids, with only two cases of thyroid abnormalities described in the pet ferret (Mustela putorius furo) and none in the mink (Mustela lutreola, Mustela vison).10,54 There is one necropsy finding4 of thyroid adenoma in a fisher (Martes pennanti), an 11-yr-old, captive female. In general, there are few other publications regarding diseases of fishers, and those few publications8,39 consist primarily of incidental descriptions of parasites and serosurveys indicating exposure to a range of viruses and bacteria. In 2004, a captive, 7-yr-old female fisher at the Rosamond Gifford Zoo (RGZ, Syracuse New York) was diagnosed with clinical hyperthyroidism based upon thyroid hormone elevation and the presence of adenomatous hyperplasia in bilateral thyroid gland biopsies. A review of 23 postmortem records from fishers housed at RGZ

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Table 1. Prethyroidectomy (Nos. 1, 2) and postthyroidectomy (Nos. 3–7) serum thyroid hormone and sex hormone values from case 1, a 7-yr-old, intact female fisher. All testing was by radioimmunoassay.

No.

Date

Body weight (kg)

TT4a (mg/dl)

FT4b (ng/dl)

TT3c (ng/ml)

Androstenedione (nmol/L)

Estradiol (pmol/L)

17-Hydroxyprogesterone (nmol/L)

1 2 3 4 5 6 7

27 May 2004 6 Jun 2004 2 Aug 2004 29 Sep 2004 15 Nov 2004 19 Jan 2005 3 Oct 2005

3.50 3.18 3.72 4.00 4.18 4.50 3.70

5.73 6.63 0.51 1.38 2.86 2.57 3.80

6.03 7.56 0.34 0.66 1.32 1.10 3.06

3.22 3.69 0.84 1.11 1.18 1.26 1.86

284.4 346.4 NDd 78.5 47.0 ND ND

196.0 161.0 ND 179.2 252.0 ND ND

4.12 3.60 ND 1.40 1.18 ND ND

a

TT4, total thyroxine. FT4, free thyroxine. c TT3, total triiodothyronine. d ND, not done. b

or submitted to Northwest ZooPath (Monroe, Washington 98272, USA) from 1992 through 2008 produced four additional cases of thyroid adenoma or thyroid adenomatous hyperplasia. CASE REPORTS History Case 1: An intact, captive-bred female fisher (7 yr, 2 mo of age) was examined in late May 2004 at RGZ for progressive alopecia of 5-mo duration. The fisher was housed outdoors in a wire-mesh enclosure adjacent to two intact adult male fishers. Initial hair loss, first observed in January 2004, involved a thinning of the guard hairs along a 15-cm length of the dorsum of the tail. Over the subsequent 4 mo, the hair loss extended to complete circumferential alopecia of the tail, caudo-dorsal lumbar region, and flanks. The fisher was not pruritic, no abnormalities were visually noted in the underlying skin, and the animal maintained normal appetite and activity levels. The fisher was anesthetized by hand injection with ketamine (KetasetH, Fort Dodge Animal Health, Fort Dodge, Iowa 50501, USA; 17 mg/kg i.m.) and midazolam (VersedH, Bedford Laboratories, Bedford, Ohio 44146, USA; 0.3 mg/kg i.m.) for examination. Other than hair loss, no abnormalities were discovered on physical exam. Skin scrapings were negative for ectoparasites and fungi; fungal culture was negative for dermatophytes. Blood was collected for hematologic (complete blood count, CBC) and serum biochemistry panels and thyroid hormone radioimmunoassays, including free thyroxine (FT4) with equilibrium dialysis, total triiodothyronine (TT3), and total thyroxine (TT4) (Endocrinology Section, New York State Animal Health Diag-

nostic Laboratory [AHDL], Cornell University, College of Veterinary Medicine, Ithaca, New York 14853, USA). Serum was also submitted for adrenal hormone testing, including estradiol, androstenedione, and 17-hydroxyprogesterone (Clinical Endocrinology Service, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA). The hematologic parameters were within normal limits. The serum biochemistry panel showed a mild increase in alanine aminotransferase (ALT) at 218 IU/L (reference range, 77 6 34 IU/L).15 Results from the thyroid and adrenal hormone panels appear in Table 1. No reference values for these tests are established for fishers; references from other species are listed in Table 2. Thyroid values appeared to be markedly elevated compared to available reference ranges for mink, wild and domestic ferrets, and the AHDL references for domestic ferrets and cats. Androstenedione elevation was reported by the laboratory as consistent with the form of adrenal cortical hyperplasia documented in domestic ferrets. Three weeks later the fisher was immobilized, as previously described, intubated, and maintained on isoflurane (AErrane, Baxter, Deerfield, Illinois 60015, USA, 0.5–1.0%) and oxygen for ultrasonography and repeat clinical laboratory testing. CBC and chemistry results were similar to those of the previous exam, while thyroid and androstenedione hormone levels had increased (Table 1). The right adrenal gland measured 6.1 mm 3 3.8 mm, the left adrenal gland measured 5.8 mm 3 2.8 mm, with no distinct nodules, and the size appeared to be within normal limits compared to other species.20,58 The left thyroid gland measured 16.0 mm 3 5.0 mm, with two hypoechoic nodules (3.3 mm 3 2.6 mm and 2.9 mm 3 2.7 mm); the right gland measured

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13.0 mm 3 2.5 mm. The thyroid gland was not palpable. Based on the results of the ultrasound examination and thyroid hormone assays, clinical hyperthyroidism was diagnosed. One week later, the fisher was anesthetized as described previously for surgical resection of the thyroid glands. The cranial 10.0 mm of the left thyroid and 7.4 mm of the right thyroid gland were enlarged, nodular, and dark purple. The remaining caudal poles of both glands appeared to be grossly normal. To preserve the parathyroid glands that were not identified, a modified bilateral partial thyroidectomy was performed. Bilateral thyroid adenomatous hyperplasia was identified histologically in the submitted tissues. Twenty-seven days after surgery, there was complete hair regrowth and the body weight was increased; however, the fisher was lethargic and inappetant. Blood collected under anesthesia revealed that calcium levels were within normal limits, while thyroid hormone levels were below the reference range (Tables 1, 2). The fisher was diagnosed with hypothyroidism secondary to the partial thyroidectomy, and corrective treatment was initiated with levothyroxine (SoloxineH, Virbac Animal Health, Inc., Fort Worth, Texas 76137, USA; 15 mg/kg p.o., s.i.d.). Thyroid hormone levels were maintained within normal limits, and repeat ultrasonography showed no change in the size or appearance of either the adrenal glands or the remaining thyroid tissue during immobilizations at 3, 5, 7, and 15 mo postoperatively. Androstenedione levels declined within 3 mo postsurgery, although estradiol increased moderately (Table 1). As a result of increasing thyroid hormone levels, levothyroxine treatment was reduced and then discontinued in August 2007, while treatment with methimazole (2.5 mg p.o., s.i.d.), a thyroxine synthesis inhibitor, was initiated in December 2007. Despite ongoing medical management the TT4 levels remained persistently high (range from 6.3 to 10.6 mg/dl, n 5 9 samples). The fisher was diagnosed with congestive heart failure in August 2008 and was euthanized in September 2008, when it was in severe respiratory distress despite treatment with diuretics. A necropsy was performed and representative tissues were submitted for histologic examination. Case 2: An intact, captive-bred, 13-yr-old male fisher died unexpectedly in February 2002 at RGZ. Housing was similar to that described for Case 1. At the time of death appetite and activity were reported to be within normal limits. Banked serum from 2002 was submitted for

thyroid hormone analysis in June 2004 (Table 3). The TT4 and FT4 levels were elevated compared to seven of nine and one of one mustelid references, respectively, but these values were within the normal range for domestic cats (Table 2). The intact carcass was submitted for necropsy. Case 3: An intact, wild-caught, captive female fisher estimated to be 16 yr of age died in December 1996 at the RGZ. The fisher was housed outdoors, and the carcass froze prior to discovery. From 1993 to the time of death the fisher’s body condition was considered poor. No banked serum was available for thyroid hormone assays. At the time of death the thyroid glands were found to be abnormally enlarged, and formalin-fixed thyroid glands and a cervical lymph node were submitted for histologic examination. Case 4: An intact, captive-bred female fisher was 12 yr, 7 mo of age at the time of death in November 2002. The fisher was housed in an indoor–outdoor exhibit at the Woodland Park Zoo (Seattle, Washington 98103, USA); the fisher shared the exhibit with a single male sibling. Activity and appetite were reported to be normal up to the time of death. Banked sera from April 1997, April 1998, March 2000, and March 2002 were submitted, as described, for thyroid hormone testing. Testing also included FT4 by the two-step method, TSH (ImmuliteH, Diagnostic Products Corporation, Los Angeles, California 90045, USA), thyroglobulin autoantibody (Canine Immunoassay Kit, Oxford Laboratories, Inc., Oxford, Michigan 48371, USA), and androstenedione assays (DSL Beckman, Webster, Texas 77598, USA). Thyroid hormones TT4, FT4, and TT3 were markedly elevated compared to all references at the last examination in 2002, while TSH appeared depressed in 2000 and 2002. Androstenedione levels were within or below range for other mustelids (Tables 2, 3). Clinical laboratory testing from four dates between 2000 and 2002 showed that hematologic parameters were within normal limits or had variable and mild alterations. Abnormal biochemistry values included an elevated total bilirubin of 1.1 mg/dl (reference range: 0.3 6 0.2 mg/dl, one of four dates), elevated ALT ranging from 159 to 413 IU/L (three of four dates), and high alkaline phosphatase (ALKP), at 253 IU/L (reference range: 78 6 73 IU/L, one of four dates).15 At the final health exam in March 2002, 8 mo prior to death, alanine amino transferase (AST) was increased, at 240 IU/L

Pooled, farmed Female, farmed Male, farmed Pooled, farmed Male, European, farmed Female, European, farmed Female, commercial breeder Male, commercial breeder Pooled, petf Pooled, pet Female, wild caught Female Male Female, wild caught and captive bred Female, laboratory animal

Sex, origin

e

0.97 6 0.25 0.54 6 0.12 0.61 6 0.09

0.3–0.9

2.39 6 0.30 1.93 6 0.88 4.42 6 1.64 1.5–3.0 1.5–4.0 1.4–4.0

0.80 6 0.25

0.93–1.22 1.15–1.41 0.84 6 0.08

TT3b (ng/ml)

3.52–4.05 2.65–3.12 1.90 6 0.09 2.57 6 0.13 2.16 6 0.21

1.77–2.14

FT4 (ng/dl)

.0.030

0.038 6 0.018

0.038 6 0.018

TSHc (ng/ml)

5.35–22.5

0.2–76.8 20–96 0.63–9.32

Androstenedioneb (nmol/L)

31.2–60.9 122–210 109–278 55.1–183.5

Estradiolb (pmol/L)

9.9–84.0

2.3–13.1 0.24–1.54 3.2–143.1

17-Hydroxyprogesteroneb (nmol/L)

b

TT4, total thyroxine; FT4, free thyroxine; TT3, total triiodothyronine; TSH, thyroid stimulating hormone. Values were standardized by the following method: thyroxine: nmol/L 4 12.87 5 mg/dl; triiodothyronine: nmol/L 4 1.54 5 ng/ml; androstenedione: ng/ml 3 3.49 5 nmol/L; estradiol: pg/ml 3 3.67 5 pmol/L; progesterone: ng/ml 3 3.18 5 nmol/L. c Immunoradiometry. d Endocrinology Section, New York State Animal Health Diagnostic Laboratory at the College of Veterinary Medicine, Cornell University, Ithaca, New York 14850, USA. e Pooled 5 combined male and female. f Neutered. g Clinical Endocrinology Service, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, USA.

a

Mustela vison48 (n 5 13)

Mustela vison (n 5 40) Mustela vison17 (n 5 90) Mustela vison31 (n 5 10) Martes americana34 (n 5 7) Mustela putorius furo33 (n 5 16) Mustela putorius furo33 (n 5 16) Mustela putorius furo12 (n 5 10) Mustela putorius furo12 (n 5 27) Mustela putorius furod Domestic catd Meles meles29 (n 5 8) Mustela putorius furog Mustela putorius furog Martes pennanti5 (n 5 14)

21

Species

TT4b (mg/dl)

Table 2. Summary of reference values for serum thyroid and sex hormones used to evaluate testing in fishers with thyroid adenomatous hyperplasia. Testing by radioimmunoassay in intact mustelids 6 mo and older, unless otherwise noted.a


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Table 3. Thyroid and androstenedione hormone assay results from banked sera for cases 2, 4, and 5, adult fishers with thyroid adenomatous hyperplasia. Testing by radioimmunoassay.

Case

Date

Body weight (kg)

TT4a (mg/dl)

FT4b (ng/dl)

FT4c (ng/dl)

TT3d (ng/ml)

TSHe (ng/ml)

TgAf (positive/ negative)

Androstenedione (nmol/L)

2 4 4 4 4 5 5 5

12 Feb 2002 10 Apr 1997 22 Apr 1998 30 Mar 2000 19 Mar 2002 01 May 1996 10 Apr 1997 9 May 1997

5.00 5.08 4.71 5.83 4.17 5.35 6.17 6.16

3.41 2.18 1.62 2.51 11.14 4.04 5.16 4.67

2.76 ND ND ND 8.90 0.95 2.94 ND

NDg 1.09 ND 2.08 5.63 1.73 3.74 1.92

ND 1.04 0.42 1.05 3.22 0.89 1.13 0.90

ND 0.033 0.029 ,0.010 ,0.010 0.015 0.012 0.017

ND Negative Negative Negative Negative Negative Negative Negative

ND ND ND 3.49 6.74 ND 12.22 ND

a

TT4, total thyroxine. FT4, free thyroxine, equilibrium dialysis. c FT4, free thyroxine, two-step method. d TT3, total triiodothyronine. e TSH, thyroid stimulating hormone, ImmuliteH assay. f TgA, thyroglobulin autoantibody, canine immunoassay. g ND, not done. b

(reference range: 107 6 51 IU/L), and there was a marked hyperphosphatemia of 9.1 mg/dl (reference range: 5.2 6 1.1 mg/dl).15 The fisher was found dead, a necropsy was performed, and representative tissues were collected and submitted for histologic examination. Case 5: This fisher was an intact, wild-caught male, estimated at 11 yr of age. Housing consisted of a shared indoor–outdoor exhibit at the Woodland Park Zoo. Cardiac enlargement was first noted during a routine annual exam in April 1997. One month later the fisher decompensated rapidly, demonstrated severe respiratory distress, and was euthanized. A necropsy was performed and tissues were submitted for histologic examination. Banked sera were available from examinations in May 1996 and in April and May 1997 for thyroid and androstenedione assays (Table 3). Levels of TT4 were elevated in all samples, compared to seven of nine mustelid references (Table 2). Values for two of three of the TT3 samples were within normal limits or low, compared to five of seven mustelid references and the domestic cat reference. Only one of three FT4 values was elevated compared to the available mustelid reference, and none was elevated compared to domestic cat values. TSH was depressed in all three samples using the cat and mustelid references. Androstenedione levels were mildly elevated compared to those of intact male ferrets (Tables 2, 3). Hematologic parameters were within normal limits or had mild and variable changes. There were no persistent serum biochemical abnormalities. Significant changes at

the time of death included hypercholesterolemia of 451 mg/dl (reference range: 283 6 78 mg/dl) and hypoproteinemia of 5.3 g/dl (reference range: 6.2 6 0.4 g/dl).15 Pathology Gross abnormalities were recorded by attending veterinarians who performed the necropsies for cases 1 and cases 3–5. Gross findings for case 2 were recorded by attending pathology residents and pathologists in the Section of Anatomic Pathology at the College of Veterinary Medicine, Cornell University. All formalin-fixed tissues were processed routinely, sectioned at 5 mm, mounted on frosted-glass slides, and stained with hematoxylin and eosin. All histologic slides were reviewed by one pathologist (MMG) for standardization of lesion severity and morphologic terminology. Gross and histologic findings are summarized for each case in Table 4. Necropsy findings Thyroids were reported as bilaterally enlarged for three fishers (cases 1, 3, and 4). A 1-cm cystic mass was noted in the left thyroid of one fisher (case 4), and nodules were reported in the right thyroid gland of one fisher (case 2) and in both glands of one fisher (case 1) (Fig. 1). Gross thyroid abnormalities were not reported for one fisher (case 5). Additional recorded gross abnormalities included pulmonary congestion in four fishers (cases 1, 2, 4, and 5); pitting or scarring of the kidneys in three fishers (cases 2, 4, and 5); cardiomegaly in three fishers (cases 1, 2, and 4); spondylosis; degenerative arthritis; nodules in the


Table 4. Case

Gross and histologic lesions in fishers with proliferative thyroid disease. Gross lesions

Thyroid histologic lesions

1

Intra-abdominal, intrathoracic effusions Pulmonary congestion Globoid, flabby heart Biventricular dilatation Atrophied ventricular walls

Bilateral adenomatous hyperplasia Unilateral cystadenoma

2

Nodules in right thyroid Left ventricular hypertrophy+ Bilateral renal scarring Nodules in pancreas Spondylosis, degenerative arthritis

Adenomatous hyperplasia, right thyroid

3

Bilateral thyroid enlargement Congested lungs Left ventricular hypertrophy Hepatosplenomegaly+ Bilateral thyroid enlargement++ 1-cm cystic mass in left thyroid Bilateral firm, pale kidneys

Bilateral thyroid follicular hyperplasia Bilateral follicular hyperplasia, Cystadenoma, left thyroid

Bilateral pulmonary congestion Bilaterally pitted and slightly shrunken kidneys, gritty on cut surface

Bilateral follicular hyperplasia Unilateral cystadenoma

4

5

301

Additional histologic lesions a

LV myocardial fibrosis++b LAVc endocardiosis+++b Arteriosclerosis in great vessels++ CPCd lung++ APCe liver+b Nephrosclerosis++ Hypertension renal arterioles+++ Pancreatitis+++ Nodular acinar cell hyperplasia++ Bacterial cholangitis+ Cholestasis+ EMHf liver and spleen++ LV myocardial hypertrophy+ RAVg endocardiosis+ Arteriosclerosis lung+, heart++ Nephrosclerosis++ Pancreatic nodular hyperplasia+ Hemosiderosis liver+ Tissues other than thyroid and lymph node were not examined Myocardial fibrosis++ Arteriosclerosis heart, liver, and kidneys++ CPC lung++ Nephrosclerosis++ Bilateral adrenal cortical nodular hyperplasia+ Cystitis+ Hemosiderosis liver+ EMH spleen++ Myocardial fibrosis++ Arteriosclerosis spleen, heart, lung, mesentery, kidney, liver, great vessels++ CPC lung++ APC liver, spleen+ Nephrosclerosis++

a

LV, left ventricle. +, mild; ++, moderate; +++, severe. c LAV, left atrioventricular valve. d CPC, chronic passive congestion. e APC, acute passive congestion. f EMH, extramedullary hematopoiesis. g RAV, right atrioventricular valve. b

pancreas (case 2); and splenomegaly (case 4). Cardiac measurements were available for three fishers (cases 1, 2, and 4). For case 1, the heart was globoid and flabby and both ventricular chambers were markedly dilated. The right: septal:left ventricular wall thickness ratio was 2.5:5:4 mm. For case 2, the left ventricle was judged by the prosector to be mildly hypertrophied, but no luminal observations were recorded. For case 2, the ratio was 3:9:10 mm. For case

4, the left ventricle was judged by the prosector to be thickened. The right ventricle thickness was 2 mm, and the left ventricle thickness was 10 mm; septal thickness and luminal observations were not recorded for this fisher. Histopathologic findings Proliferative follicular lesions were noted in all examined thyroid glands (five of five animals). All fishers had one or more foci of adenomatous

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Figure 1. Thyroid gland, fisher, case 1. Note nodular focus representing a. adenoma at one pole of the thyroid (top). On cut surface, note adenoma (a) surrounded by a capsule (arrowheads) and numerous foci of nodular hyperplasia (h) in the adjacent parenchyma (bottom image). Bar 5 3.0 mm.

hyperplasia in each examined gland. These foci were characterized by nodular accumulations of follicles that had considerable variation in luminal diameter and colloid content, hypertrophied follicular epithelium, and occasional papillary infoldings of the follicular epithelium that extended into the follicular lumen and were supported by delicate fibrous stroma. These nodules were juxtaposed with areas of slightly compressed or displaced but otherwise histologically normal thyroid follicles. Thyroid follicular adenomas with similar morphology but larger cystic follicles and partial fibrous capsules were noted in the left thyroid in one fisher (case 4) and in one thyroid each of two fishers (cases 1 and 5) (Fig. 2). Full histologic examination of tissues was available for four of five fishers. Cardiovascular lesions included myocardial fibrosis, primarily in the left ventricle and ventricular septum of three fishers (cases 1, 4, and 5), and hypertrophy of left ventricular myofibers with mild myofiber disarray in one fisher (case 2). Arteriosclerosis characterized by intimomedial hypertrophy and hyaline degeneration of the vessel wall was noted in all fishers, and sites included great vessels (cases 1, 4, and 5), kidney (cases 1, 4, and 5), lung (cases 2 and 5), liver (cases 4 and 5), and mesentery (case 5). Hypertensive change characterized by intimomedial hypertrophy, hyaline degeneration, and laminated ‘‘onion skin’’ appearance of the adventitial tunics was noted in the periglomerular arterioles of one fisher (case 1).

For the four fishers in which kidney was available, parenchymal histologic lesions were consistent with moderate nephrosclerosis. This lesion was characterized by moderate sclerotic change in the glomeruli and interstitium, with varying degrees of tubular dilatation, protein casts or mineralization, and mild interstitial lymphocytic inflammation. Chronic passive congestion was noted in the lungs of four fishers (cases 1, 2, 4, and 5). This condition was characterized by diffuse vascular congestion, edema in the alveoli, and a varying increase in numbers of alveolar macrophages. The interstitium was mildly fibrotic and was sometimes infiltrated by low numbers of lymphocytes and histiocytes. Pneumocytes were mildly hypertrophied, and histiocytes occasionally contained phagocytized erythrocytes or yellow pigment interpreted as iron. Additional histologic lesions interpreted as incidental or unrelated to the thyroid disease included nodular acinar cell hyperplasia in the pancreas of two fishers (cases 1 and 2), mild pigment deposition, interpreted as iron in the hepatocytes, of two fishers (cases 2 and 4), and moderate extramedullary hematopoiesis in the spleen of two fishers (cases 1 and 4) and in liver of one fisher (case 1). One fisher (case 4) had bilateral adrenal nodular cortical hyperplasia and mild chronic urocystitis, and one fisher (case 1) had marked acute neutrophilic pancreatitis. DISCUSSION In this article, the clinical and pathologic findings in five fishers with thyroid adenomatous hyperplasia were summarized. There is some variation in the terminology of proliferative thyroid follicular lesions; however, the multifocal distribution and morphologic features of the fishers’ lesions most closely resembled nodular (adenomatous) hyperplasia, as seen in the domestic cat, although the fisher lesions were more consistently cystic than the lesions in cats.2 Four of the fishers had bilateral disease (similar to 70% of cats),38 and all fishers had nodular adenomatous hyperplasia of the thyroid follicles; two fishers had concurrent thyroid follicular adenomas. Distinction between large nodules of adenomatous hyperplasia and adenoma can be difficult and perhaps academic, since both lesions can be functional and can result in clinical hyperthyroidism. Partial encapsulation of the nodule, with associated displacement and compression of the surrounding follicles, was the


303

Figure 2. Thyroid glands, fishers. a. Case 1. Note multinodular thyroid follicular adenoma (a) with varying degrees of cystic change displacing the normal thyroid follicles (between arrowheads). Hematoxylin and eosin (H&E), bar 5 750 mm. b. Higher magnification of a, showing demarcation of tumor (a) from displaced, slightly compressed follicles (f) by a partial, thin fibrous capsule (arrowheads). H&E, bar 5 350 mm. c. Case 2. Note numerous foci of nodular follicular hyperplasia (h) and cystic change (c). H&E, bar 5 750 mm. d. Higher magnification of c, showing absence of a capsule and minimal displacement or compression of surrounding follicles in areas where hyperplastic follicular tissue (h) merges (arrowheads) with normal follicles (f). H&E, bar 5 440 mm.

criterion used to distinguish the adenomas from hyperplastic foci in these fishers.2,49 Clinical signs of thyroid disease in cats include weight loss, polyphagia, polyuria and polydipsia, vomiting and diarrhea. More than 95% of cats are greater than 10 yr of age at the time of onset, and there is no strong sex predilection.9,35,38 For the three female and two male fishers, the age at diagnosis or death ranged from 7 to 16 yr (published life expectancy for either wild or captive fishers is 10 yr).3 However, obvious clinical signs of disease were lacking in the fishers and likely contributed to the absence of an early diagnosis in four of the five cases. Body weight was unchanged in two animals (cases 1 and 5), and in case 2 weight loss was mild (less than 10% of the previous body weight). One animal (case 3) was considered to be in chronically poor body

condition; no serum was available from this case to determine if active thyroid disease was present. In all five cases, keepers did not note vomiting, diarrhea, increased urination, altered water intake, or unusual changes in appetite or behavior. In addition, clinical laboratory testing (available for three fishers) showed mild changes not clearly associated with thyroid disease in two of three animals. Marked hyperphosphatemia and persistent elevation in liver enzymes were seen in case 4. Consistent clinical laboratory abnormalities reported in the cat include mild to moderate hyperphosphatemia; elevations in the liver enzymes ALT, ALKP, and AST; and a stress leukogram.30,36 Reference ranges for thyroid hormone testing in fishers are not known, and the domestic cat values may not be accurate for diagnosis of

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disease in fishers. There are nine references for TT4 available from related mustelid species (Table 2). In seven of nine of these TT4 references the maximum end of the range was 3.12 mg/dl or less, at least 16% lower than that reported37 in the domestic cat. The only available mustelid reference for FT4 has an upper limit of 2.14 ng/dl, slightly more than half the value of 4.0 ng/dl given for cats (Table 2).21 Using the mustelid references, all the TT4 samples (six of six), five of six of the FT4 samples, and four of five of the TT3 samples taken closest to the time of death or diagnosis were elevated (Tables 1–3). Depression of TSH to ,0.03 ng/ml may be a marker of early subclinical thyroid disease in older cats that have thyroid lesions, and references are similar in cats and mustelids (Table 2).52 In cases 4 and 5, the TSH value was depressed 2 yr and 1 yr, respectively, before the elevation in TT4. However, confounding factors include poor sensitivity of the TSH test at the low end of the range, poor cross-reactivity of the canine test with other species, and the tendency of TSH to be suppressed with chronic illness.9 Thyroglobulin auto-antibodies, present in autoimmune thyroiditis, were not found in any fishers using a canine immunoassay kit. The crossreactivity of this assay with fisher antibodies is unknown. The progressive hair loss observed in case 1 was unusual in that alopecia is not associated with hyperthyroidism in cats or humans.19,30 The normal cycle of hair coat shedding and replacement in mustelids and other species is mediated by complex interactions between cyclic reproductive and thyroid hormones under photoperiodic control.1,22–26,32 Progressive hair loss over the back and flanks is a classic clinical sign of adrenal cortical hyperplasia in ferrets, a result of elevated production of 17-hydroxyprogesterone, estradiol, or androstenedione.11,42,43 The androstenedione and estradiol levels in this fisher were considered by the laboratory (Tennessee) to be elevated and consistent with adrenal disease, and they were higher than values seen in similar mustelid species (Tables 1–2). However, the adrenal glands of this fisher were within normal limits on multiple ultrasound examinations, the hair coat re-grew following surgical partial thyroidectomy, and androstenedione levels returned to normal without treatment to address any potential adrenal involvement. Adrenal glands were not collected from case 1 for histologic examination, and skin was not available for histologic examination for any of the fishers.

Abnormal increases in reproductive androstenedione in response to excess thyroid hormone stimulation are documented40,46,57 in some species. Serum sex hormone binding globulin is also increased in hyperthyroid humans, resulting in increased estrogen and testosterone and decreased metabolic clearance of estradiol.40,51,57 The pattern of androstenedione production in case 1 was similar to the reproductive cycle of the European badger (Meles meles), a well-studied mustelid with similar induced ovulation and a 10mo diapause.27 Androstenedione in the badger peaks in May–August and January–February, corresponding to the onset of diapause and implantation, respectively, while levels are lowest in the early fall.29 Rising thyroxine in late summer to autumn, coinciding with a period of low testosterone, is responsible for the onset and progression of molt, which occurs from late summer to fall in badgers and fishers.24 In thyroidectomized badgers and mink, high thyroxine levels produced by artificial oral supplementation induced early molt, while testosterone levels elevated over a critical threshold delayed onset of molt until later fall and completely suppressed hair coat regrowth.24,25 It is possible that either an abnormal rise in thyroxine and/or high levels of androgens induced by thyroid disease could have resulted in an abnormal molt cycle and suppression of hair regrowth in case 1. It is also not clear if thyroid hormone can induce androstenedione production outside of seasonal breeding and reproductive activity. Androstenedione levels measured in March and April for cases 4 and 5 were low or minimally over reference values despite elevated thyroid hormone levels, and no other cases had similar hair loss. The timing of the hormonal interactions is likely critical. Thyroid hormones also have extensive effects on the cardiovascular system. In cats, heart rate, contractility, and stroke volume are increased, resulting in higher left ventricular work load and thickening of the ventricular wall.50 Most pathologic changes in hyperthyroid cats are mild to moderate; few (2–3%) progress to congestive heart failure, and only 9–19% have documented hypertension.50 Clinical cardiac abnormalities in the undiagnosed fishers were not noted on multiple health exams, even when thyroid hormone levels were markedly elevated, but anesthesia and handling stress may make it difficult to assess alterations in heart rate and blood pressure. Four of the fishers had histologic evidence of hypertrophic or fibrotic cardiac changes (cases 1, 2, 4, and 5) and may have had


clinical cardiac insufficiency or congestive heart failure at the time of death, based on clinical and gross necropsy observations, and histologic evidence of chronic passive congestion in the lung. Three of these cases were associated with hypertrophic changes in the left ventricle, and this could be attributed to hyperthyroidism, aging, or both. Case 1 had biventricular dilated cardiomyopathy, a condition more often associated with genetic factors or taurine deficiency. It is likely that the cardiomyopathy in this fisher had a different pathogenesis than in the other cases, although increased volume loading on the heart can exacerbate underlying cardiac abnormalities and lead to heart failure in hyperthyroid cats.50 Marked hypertension is not a hallmark of the disease in cats, primarily as a result of a reduction in systemic vascular resistance mediated by T3.50 In the cases presented here, four fishers had evidence of systemic arteriosclerosis, and the fisher in case 1 had hypertensive changes in the periglomerular arterioles, indicating that hypertension may be a prominent feature of hyperthyroidism in fishers, possibly as a result of the advanced state of disease at the time of death. In addition, four animals had chronic renal lesions, although none of the fishers had elevations in creatinine that would indicate significant renal disease. In older cats, thyroid disease and chronic renal disease are both common findings, and it can be difficult to determine causality. Hyperthyroidism masks poor renal function in cats as a result of an increase in cardiac output and glomerular filtration rate. It is less clear what effect chronic hyperthyroidism and/or hypertension may have on cats without preexisting renal disease, and investigations are ongoing.30,50 Treatments for thyroid disease in cats include medical management with methimazole, surgical resection, or radiotherapy with injectable iodine.1,30,31 As a result of the prolonged need for quarantine in a licensed facility following radiotherapy, this may not be practical for fishers. Bilateral surgical resection in the cat is commonly performed and can be curative, but a modified intracapsular or extracapsular technique is recommended for complete excision of abnormal thyroid tissue with preservation of the associated parathyroid glands.30 In the clinical case presented here, incomplete surgical resection of abnormal thyroid tissue led to a 2-yr period of controlled hypothyroidism, but hyperthyroid disease recurred that was refractory to medical treatment.

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The cause of hyperthyroidism and proliferative thyroid lesions in these fishers is unknown. In addition to autoimmune disease, other potential causes of thyroid disease include iodine deficiency, environmental pollutants, and genetic mutations.21,33,38 The fishers in this report were unrelated and were held at different facilities. Because of the extensive links between the thyroid, photoperiod, and reproductive cycle, it is interesting to speculate what role these factors may have played in the disease. Fishers typically breed on immediate postpartum estrus, and females are almost continuously pregnant in the wild.5 All the affected fishers were exposed to natural daylight conditions, but the females were not successfully bred, and females and males were housed together, a situation that would not occur naturally. Further study is needed to establish normal reference intervals for thyroid hormones in male and female fishers and to assess possible genetic or environmental factors that might influence the development of thyroid disease in this species. CONCLUSIONS Thyroid adenomatous hyperplasia leading to clinical or subclinical hyperthyroidism may be a common but undiagnosed disease of older captive fishers. Left untreated, the disease may lead to cardiac hypertrophy and congestive heart failure. Affected animals may have few clinical signs or clinical laboratory changes, although thyroid disease should be considered in animals presenting with alopecia. As a result of the severity of heart disease in untreated animals, it is advisable to perform screening tests during annual physical exams, starting in early middle age (5–6 yr and older). Because thyroid hormone testing can be altered by concurrent illness (sick euthyroid syndrome) and daily and seasonal fluctuations, ultrasonography of the heart and thyroid glands may be helpful in detecting early changes. Acknowledgments: The authors wish to thank the staff at the Rosamond Gifford Zoo, Woodland Park Zoo, Elmwood Park Zoo, Northwest ZooPath, Cornell University, and Zoo/Exotic Pathology for assistance with case records; in addition, they thank Drs. Linda Homco, Sara Childs, Susie Bartlett, Michele Steffey, Ned Place, Barbara Schanbacher, Darin Collins, Janis Joslin, and Adam Denish for their clinical assistance with surgery, hormone testing, ultrasonography, and care of case animals.

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Received for publication 19 September 2009