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Thyroid Diseases in Rodent Species
T h y ro i d D i s e a s e s in R o d e n t S p ec ie s Lindsay Thorson,
DVM*
KEYWORDS Thyroid disease Hyperthyroidism Hypothyroidism Thyroid neoplasia KEY POINTS There are abundant studies of thyroid disease in rodents in a laboratory setting; however, research is limited in pet rodent populations. Validated reference intervals for thyroid testing are scarce, making interpretation of blood work difficult. Hyperthyroidism and hypothyroidism has been reported in multiple rodent species, with the most data available for guinea pigs. Thyroid neoplasia has been reported in the most common rodent species although often as an incidental finding at necropsy. Further research is needed to determine frequencies of disease, methods of diagnosing, and treatment options with the best efficacy.
INTRODUCTION
Information available on naturally occurring thyroid disease in small mammals is extremely limited. Although there is an abundance of research with experimentally induced thyroid disease in laboratory rodents, this does not follow the pattern of naturally occurring diseases in these species and often has limited value when evaluating pet rodents. Overall, naturally occurring thyroid gland dysfunction is poorly documented in rodents, and more research is needed to explore these diseases. The expense associated with diagnostics is a limiting factor for many exotic pet owners, often preventing clinicians from being able to diagnose thyroid diseases definitively. Furthermore, due to the small size of most rodents, it may difficult to obtain sufficient blood volume to run multiple diagnostics. Even if enough blood is collected, it is also quite challenging to interpret the results because the assays have not been validated in most rodent species.
Central Animal Hospital, 317 Ardsley Road, Scarsdale, NY 10583, USA * 77 Lake Avenue, Tuckahoe, NY 10707. E-mail address: [email protected] Vet Clin Exot Anim 17 (2014) 51–67 http://dx.doi.org/10.1016/j.cvex.2013.09.002 vetexotic.theclinics.com 1094-9194/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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ANATOMY
The thyroid gland, located at the cranial-ventral aspect of the trachea, is bilobed and connected by an isthmus.1 It is closely associated with the parathyroid glands, which are responsible for secretion of parathyroid hormone. Based on embryologic development, it is possible to have ectopic thyroid tissue in other locations, ranging from the larynx to the diaphragm2; this becomes important if the ectopic tissue begins secreting excess thyroid hormones. Histologically, the thyroid gland is composed of 2 cell types: follicular cells, which predominate, and C cells, which are also known as parafollicular cells.2 The main functional units of the thyroid gland are the numerous follicles, which are lined by low cuboidal epithelium (follicular cells).1,2 C cells are found in small groups of 10 cells or fewer scattered throughout the gland, either in connective tissue between follicles or at the base of the follicular cells. These cells account for 0.1% of thyroid epithelial cells.1 PHYSIOLOGY
Thyroid hormones are essential for normal body function including growth and the development of neurologic and skeletal systems.2 They increase normal metabolism in most tissues and have catabolic effects on muscle and fat. They also increase the number and affinity of b-adrenergic receptors, which have inotropic and chronotropic effects on the heart. The hormones are also responsible for erythropoiesis and cholesterol synthesis and breakdown.3 In rodents, thyroid hormones, along with catecholamines, play an important role in thermogenesis of brown fat, allowing them to adapt to cold temperatures.4 As stated previously, the thyroid gland consists of 2 primary cell types. Follicular cells produce thyroglobulin and are responsible for the uptake and oxidation of iodine. Once oxidized, the iodine is released into the follicular lumen and interacts with thyroglobulin, producing mostly thyroxine (T4) and a small amount of triiodothyronine (T3). T4 is the main product of the thyroid gland and is solely produced there. In contrast, only a small portion of T3 is made in the thyroid gland; the remainder is produced from deiodination of T4 to T3 within target cells.3 When signaled to be released, the iodinated thyroglobulin undergoes hydrolysis, releasing T3 and T4 into the bloodstream.2 The vast majority (>99%) of serum thyroid hormones are stored in the biologically inactive, protein-bound state.3 It is the unbound, free T4 (fT4) and T3 (fT3) that are biologically active and able to enter cells and stimulate negative feedback on the pituitary gland and hypothalamus. Circulating fT3 enters cells more rapidly and has a faster onset of action than T4.3 Once in cells, T3 is able to act directly, and T4 is deiodinated to the more bioactive T3, which acts on the cell to exert its effects. Thyroid hormone production and release are controlled by the hypothalamicpituitary-thyroid axis. The hypothalamus detects decreased circulating levels of thyroid hormones and releases thyrotropin-releasing hormone (TRH). TRH acts on the anterior pituitary gland to release thyrotropin-stimulating hormone (TSH), which stimulates T3 and T4 release from the thyroid gland. Rising levels of thyroid hormones in the blood initiates a negative feedback loop, which inhibits additional release of TSH.3 The thyroid also contains C cells, which are responsible for the production of calcitonin. Calcitonin is responsible for controlling calcium deposition in bone by inhibiting bone resorption by osteoclasts, leading to decreased serum calcium levels. Calcitonin acts in opposition to parathyroid hormone.2
Thyroid Diseases in Rodent Species
LABORATORY TESTS
Thyroid function can be assessed by measuring blood levels of total T4 (TT4), fT4, total T3 (TT4), fT3, and TSH. In addition, T3 suppression and TSH stimulation tests can be performed.5,6 Due to the small size of most rodents, it can be difficult to obtain adequate blood samples to perform these tests. In addition, validated reference ranges are limited in exotic species; therefore, the results can be difficult to interpret. As with dogs and cats, TT4 is generally the initial screening test. Determining fT4 values is beneficial because it is less likely to be affected by medications or euthyroid sick syndrome.2,7 Total T3 and fT3 values are not used as frequently because they are generally considered less reliable in veterinary medicine.3 TSH assays are used in thyroid testing of humans and dogs; however, this method has yet to be validated in rodents. T3 suppression tests have recently been increasing in use for diagnosing feline hyperthyroidism. Last, a TSH response test can be performed, although the adequate dose and response need further validation.6 It is also worth noting that several medications are known to decrease serum thyroxine levels including glucocorticoids, sulfonamides, phenobarbital, and nonsteroidal anti-inflammatory drugs.2,8 For this reason, evaluating thyroid levels in patients on these medications can be difficult. GUINEA PIGS (CAVIA PORCELLUS) Thyroid Testing
There have been several reports of reference intervals in both laboratory and pet guinea pigs.5–12 Although there are multiple reference ranges reported, interpretation is somewhat difficult based on differences in testing modalities used (chemiluminescent competitive assays, Radioimmunoassay [RIA], Enzyme Immunoassay [EIA]), sample sizes, age ranges, and sources of animals (some pet, other laboratory).10 Further evaluation of these testing methods is needed to determine the validity of these tests. Table 1 shows the various reference ranges that have been reported.
Table 1 Thyroid hormone levels that have been reported for groups of guinea pigs Thyroid Hormone
Reference Ranges
TT4 (mg/dL)
1.1–5.2 (2.1) 2.26–5.82 (4.04) 2.3–3.5 2.9 0.6 (male) 3.2 0.7 (female) 0.56–1.33 (0.7)
fT4 (ng/dL)
1.26 1.33 0.67 1.17
TT3 (ng/dL)
22–56 39 17 (male) 44 10 (female
fT3 (pg/dL)
257 35 (male) 260 59 (female)
Data from Refs.5–12
0.41 (male) 0.25 (female) 0.57 0.09
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Age and sex both affect thyroid levels in several other species,11,13 raising the question of whether this also holds true for guinea pigs. One study11 found a statistically significant difference in thyroid levels between females and neutered males, while others have not seen a significant difference.10 Although age has yet to be reported as a significant factor in the guinea pig, this observation is limited in its implications because many studies used juvenile to mid adult animals. Further research is needed to determine if age and sex play a role in thyroid levels. Hyperthyroidism
Hyperthyroidism is not well-documented in guinea pigs in the United States, although reports recently have been increasing.7,10 Interestingly, it is a fairly common syndrome in German literature7 and may be due to genetic differences between German and American guinea pigs or could be an indication that hyperthyroidism is underdiagnosed in the United States. The neoplasia section reports on the incidence of thyroid pathologic abnormality. The percentage of thyroid neoplasms that secrete excess hormones is unknown. Cause/physiology
Excess thyroid hormone leads to increased metabolic rate and calorie utilization and can affect the sympathetic nervous system, leading to clinical signs of hyperthyroidism.14,15 Hyperthyroidism is thought to be secondary to functional thyroid tumors, including thyroid hyperplasia, adenoma, and adenocarcinoma. The tumors may be unilateral or bilateral and in some cases can also be the result of excess secretion by ectopic thyroid tissue.2,6 Further research is needed to determine what type of tumor most commonly leads to hyperthyroidism. Signalment
Hyperthyroidism can affect guinea pigs of any age; however, most reported cases occur in pigs older than 3 years of age. There is no known sex predilection, although there is speculation that females may be more prone to thyroid hypertrophy, and therefore, hyperthyroidism.12 More research is needed to determine if this is the case. Clinical signs
Clinical signs of hyperthyroidism vary considerably. The most consistent signs include weight loss despite an increased appetite, hyperactivity, nervousness, and hyperesthesia.10–12 Clinical signs that occur more sporadically include polyuria, polydipsia, soft stools, and progressive alopecia. In addition to a decreased body condition, physical examination may reveal a palpable thyroid nodule, tachycardia, arrhythmia, or heart murmur. Anorexia can also occur at later stages of hyperthyroidism.10–12 Differential diagnoses
Table 2 describes the differentials of hyperthyroidism. The various clinical signs of hyperthyroidism include a cervical neck mass, weight loss, alopecia, PU/PD, soft stool, and cardiac abnormalities. As a result, the differential diagnoses are quite varied based on the clinical signs seen in an individual patient. Diagnostic testing
Table 3 provides an overview of treatment options to diagnose hyperthyroidism, as well as the advantages and disadvantages of each. Diagnostics include bloodwork, which can include a CBC, serum chemistry, TT4, fT4, and TSH test. Additional diagnostics include thoracic radiographs, ultrasound, FNA and cytology of the mass, and biopsy. Advanced diagnostics include CT, MRI, and nuclear scintigraphy. In
Thyroid Diseases in Rodent Species
Table 2 Differentials of hyperthyroidism Clinical Sign/ Finding Cervical neck mass
Weight loss
Possible Differential Diagnosis Thyroid hyperplasia/neoplasia Cervical lymphadenitis or other abscess Lymphadenopathy Mandibular salivary gland neoplasia Granuloma
T4, cytology, biopsy FNA
Dental disease Endoparasites Renal disease Ovarian cysts
Skull rads/oral examination Fecal CBC/Chem/UA History, abdominal palpation, ultrasound T4 History
Late-stage hypothyroidism Food competition/deprivation/poor nutrition Alopecia
Diagnostics that May Aid in Differentiation
Ovarian cysts Barbarism (self/cagemate) Late-stage hypothyroidism Ectoparasites/Dermatophytosis Adrenal tumor
FNA/biopsy FNA/biopsy FNA/biopsy
History, palpation abdomen, ultrasound Evaluate for broken hair shafts, history T4 Skin scrape, determine if pruritic Ultrasound
PU/PD
Renal disease Diabetes
CBC/chem/UA Blood and urine glucose, fructosamine
Soft stool/diarrhea
Endoparasites Recent antibiotic use Bacterial infection
Fecal Owner history History/physical examination
Cardiac abnormalities
Primary cardiac disease
Echocardiogram, ECG, thoracic radiographs
Data from Refs.5,10,12,15,16
cases where diagnostics cannot be performed, a methimazole trial can be initiated. Further information about each diagnostic is described below. Blood work Initial blood work should consist of a complete blood count (CBC) and
serum chemistry to determine the overall health status of the patient. A TT4 is the initial thyroid screening test; it is important to keep in mind that hyperthyroid animals can have thyroxine levels within the normal reference interval.14 Additional thyroid testing may be necessary because diagnosing hyperthyroidism based on one elevated T4 is not ideal.5 Euthyroid sick syndrome, which is well documented in dogs and cats, may also occur in guinea pigs and could result in a hyperthyroid animal having a TT4 level within the normal range.7 Obtaining a fT4 may be helpful because it is less likely to be affected by concurrent illnesses, although reference intervals are not complete. As with hyperthyroid cats, it is possible to encounter hyperthyroid guinea pigs that do not have significant elevations of T3 and T4, making diagnosis more challenging. A T3 suppression test may also be helpful.6 Ultrasound/Fine-Needle Aspiration/Cytology A palpable thyroid nodule supports the
diagnosis of hyperthyroidism but is not diagnostic. If present, an ultrasound of the mass using a high-frequency probe of 10 mHz or higher will give information about
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Table 3 Diagnostics available to diagnose hyperthyroidism Diagnostic
Advantages
Disadvantages
CBC/chem
Can help rule out other diseases for clinical signs, tell about overall status of the animal
Does not evaluate thyroid function directly
T4 fT4 TSH test
Will give information on thyroid
Fully validated reference intervals not established Euthyroid sick syndrome possible
Ultrasound
Will detect anatomic changes of gland Will give information of vascular supply Can use ultrasound to assist FNA
Will not reveal if tumor is functional Gas in trachea can interfere with evaluation
FNA, cytology, T4
If mass is exfoliative, cytology may yield diagnosis Thyroxine level of aspirated fluid may reveal increased T4
May be nondiagnostic
Radiographs
Can rule out some other causes of clinical signs, such as dental disease Can evaluate for pulmonary metastases Will be able to detect osseous metaplasia of the mass, making thyroid neoplasia higher on the differential list
Will not give information if tumor is functional
CT
Will give information of the structure of the mass Will be able to evaluate for pulmonary metastases, more sensitive than thoracic radiographs
Will not give information if tumor is functional
Magnetic resonance imaging
Can help define local tissue invasion, as has a higher contrast resolution than ultrasound Will be able to evaluate tissue dorsal to the trachea as is not affected by gas
Will not give information if the tumor is functional
Nuclear scintigraphy
Appears to be one of the most precise methods of diagnosis in guinea pigs Will detect local and distant metastases, ectopic thyroid tissue Can have false negatives if not hypersecreting
Limited availability of facilities
Data from Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509–23; and Reese S. Cervical soft tissues. In: Krautwald-Junghanns ME, Pees M, Reese S, editors. Diagnostic imaging of exotic pets: birds, small mammals, reptiles. Germany: Schluetersche; p. 247, 255.
morphology and blood supply to the mass. A fine-needle aspirate (FNA) and cytology may diagnose the type of tumor but would not reveal if the mass is functional.16 Performing a T4 on any fluid aspirated from the thyroid mass may reveal elevated thyroxine, which correlates with elevated serum levels.12 If the cytology is not diagnostic or is unable to be performed, a biopsy with histopathology is needed for definitive diagnosis of the type of tumor present.5 Advanced Diagnostics Computed tomography (CT) and magnetic resonance imaging will also give information about the architecture of the mass. CT and thoracic
Thyroid Diseases in Rodent Species
radiographs may be beneficial to reveal pulmonary metastases. Radiographs of the mass may reveal osseous metaplasia, which is present in some benign and malignant thyroid neoplasias.17 Nuclear scintigraphy is currently considered the gold standard for diagnosing hyperthyroidism in guinea pigs. One benefit of this test in neoplasia is that it may be able to detect metastases, both local and distant, as well as ectopic thyroid tissue.7 Methimazole Trial Although it is ideal to have full diagnostics to support hyperthyroidism, as an alternative, a methimazole trial can be performed. Hyperthyroid guinea pigs should show a rapid improvement in weight gain and behavioral changes when placed on methimazole. Clinical signs will quickly return when taken off of the medication.12 Other If any cardiac abnormalities are detected on physical examination, cardiac
diagnostics, such as an echocardiogram, should be performed. Treatment
Treatment of hyperthyroidism is aimed at reducing the levels of circulating thyroid hormones. Options are extrapolated from treating feline hyperthyroidism and include daily oral medication, radioactive iodine (131I), and surgery.12 Table 4 overviews the treatment options. Oral Medications The goal of medication is to suppress production of thyroid hormones directly. The most common options include methimazole and carbimazole.5 The advantages of this approach include the relatively low cost, noninvasive nature
Table 4 Treatment options for guinea pig hyperthyroidism Treatment
Advantage
Disadvantage
Oral medication
Inexpensive Rapid response Can be used before 131I or surgery to stabilize Can be used as a therapeutic trial when diagnostics not possible No reported side effects in the literature currently
Not addressing underlying cause Therapy will be lifelong Stopping medication will result in rapid return of clinical signs
131
May be curative Able to target ectopic thyroid tissue Less invasive than surgery No risk of affecting parathyroid glands
Expense Limited availability Treatment doses not fully determined Recurrence is possible
Thyroidectomy
May be curative If tumors is malignant, may prevent metastasis
I
Technically difficult surgery Can potentially recur May miss ectopic thyroid tissue Risk of complications: recurrent laryngeal nerve damage, parathyroid gland removal, hemorrhage
Data from Brandao K, Vergneau-Grosset C, Mayer J. Hyperthyroidism and hyperparathyroidism in guinea pigs (cavia porcellus). Vet Clin North Am Exot Anim Pract 2013;16:407–20; and Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509–23.
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of treatment, and rapid improvement once medications are started. Most guinea pigs only need once-a-day dosing so owner compliance is fairly high. Because the medication is generally well tolerated, it can be used as a trial therapy when diagnostics are not possible. The main disadvantage of these medications is that the guinea pig will require lifelong therapy because the underlying cause of overproduction is not being addressed. In addition, when medications are stopped, clinical signs return very quickly, typically within a couple days.12 Methimazole is generally started at 0.5 mg/kg orally every 12 to 24 hours and anecdotally can be increased to 2.0 mg/kg every 12 to 24 hours if needed. Many cases respond to once-a-day dosing.12 Compounding is often required because of the large tablet size relative to the dose needed. One author12 found some success with transdermal methimazole, although noted that the treatment depigmented brown guinea pig skin. Possible side effects are extrapolated from felines and include anorexia and depression. There are currently no confirmed side effects in guinea pigs. Carbimazole is another option and is used at a dose of 1 to 2 mg/kg orally every 24 hours. Side effects are similar to methimazole.12 Although a link between hyperthyroidism and renal disease has not been firmly established in guinea pigs, as it has in cats, it is certainly possible. Therefore monitoring renal values before and during treatment is recommended. Response to therapy is based largely on clinical signs. It is recommended to recheck the physical examination, including weight and T4 levels, every 2 weeks until clinical signs have improved and levels are within normal range. Subsequently, the examination and thyroid levels should be rechecked every 3 to 6 months based on how the patient is doing at home.12 131
I Radioactive iodine is possibly curative and helps with longterm control of hyperthyroidism. It is less invasive than surgery and is able to target ectopic thyroid tissue.5 Disadvantages include a high expense, limited number of facilities, and a possibility of recurrence. Although there are currently no studies regarding the best dose to use, 2 guinea pigs in the literature were successfully treated with radioactive iodine.12 Placing the patient on methimazole for several weeks before 131 I is recommended to stabilize the patient and to observe for possible unmasking of renal disease. Radioactive iodine:
Thyroidectomy Thyroidectomy may be an option to remove either a portion of or the entire gland, depending on the extent of involvement of the tumor.18 This procedure is performed in laboratory settings but is relatively uncommon in clinical practice. Surgery is potentially curative if the tumor is not invading surrounding tissue and has not metastasized.5 The procedure is technically difficult, and there is a risk of missing ectopic thyroid tissue. For this reason, before surgery it is recommended to perform an ultrasound to determine morphology and blood supply to the mass and a nuclear scintigraphy to determine if there is ectopic thyroid tissue present. In addition, as with any potential neoplasia, preoperative thoracic radiographs (or CT) can be helpful to rule out pulmonary metastases. If the tumor is functional, it is recommended to have the patient on methimazole before surgery for stabilization.5 Caution must be used to avoid contact with the recurrent laryngeal nerves and to prevent removing the parathyroid glands. If the entire gland must be removed, the patient will need thyroxine and oral calcium supplementation. Ionized calcium should be checked immediately after surgery and the animal should be supplemented with oral calcium daily for at least 7 to 10 days before attempting to wean off of the calcium. Ionized calcium should be rechecked 2 weeks after surgery.12 In one study, 42% of guinea pigs had regrowth of thyroid tissue, indicating a high risk of recurrence.18
Thyroid Diseases in Rodent Species
Additional therapies Radiation Radiation therapy has not been reported in guinea pigs but has been used
in both humans and dogs with thyroid gland tumors.5 Radiation may prove useful for incompletely excised tumors or in cases in which surgery is not in the best interest of the patient. Percutaneous ethanol ablation Percutaneous ethanol ablation has been described in
the literature but is currently not recommended.12 Hypothyroidism Cause
Hypothyroidism is an uncommon condition in guinea pigs. As with other animals, the disease can be congenital, acquired, or iatrogenic. Although neoplastic lesions in the thyroid gland can be functional and result in hyperthyroidism, they can also destroy the normal architecture of the gland, leading to reduced synthesis of thyroid hormones.3,14 In dogs, most cases of hypothyroidism are due to lymphocytic thyroiditis.3 Other mechanisms include primary or metastatic neoplasia, and in rare cases, a deficiency of TSH or congenital causes. It is unknown if these same mechanisms occur in guinea pigs. Iatrogenic causes include 131I iodine treatment, oversupplementation of antithyroid medications, and thyroidectomy.3 Clinical signs
Clinical signs are variable and often include decreased activity and weight gain. As seen with canine hypothyroidism, the onset of clinical signs is often subtle and gradual, which may make it difficult for owners to recognize. Clinical signs of chronic cases can coincide with signs of hyperthyroidism including weight loss and bilateral alopecia, often on the dorsum and thighs. Bradycardia may also occur.12 Differential diagnosis
Late-stage hypothyroidism can be confused with hyperthyroidism. A TT4 should help differentiate. Diagnostics
Appropriate clinical signs, paired with a TT4 less than 1 mg/dL, should make the clinician suspicious of hypothyroidism. A CBC and serum chemistry, as well as any other appropriate diagnostics based on history and physical examination, should be performed to rule out euthyroid sick syndrome. If no other illness can be found that would cause a decrease in T4, a TSH stimulation test is recommended if it is not cost prohibitive for the client.6 Although more research is needed to validate testing protocols and references, it is currently thought that the thyroxine level should at least double 3 to 4 hours after recombinant human thyroid-stimulating hormone (rhTSH) injection.6 Treatment
Therapy for hypothyroidism is thyroxine supplementation. L-thyroxine has been used at a dosage of 10 mg/kg orally every 24 hours.12 TT4 should be rechecked at 2 weeks and again at 2 months. Response is also based improvement of clinical signs. Neoplasia Cause
Although thyroid neoplasias are not well documented in guinea pigs, recent reports suggest that they are underdiagnosed. For example, a recent study found that 3.6% of guinea pigs at a pathology service had thyroid tumors. Adenomas comprised 63% of the tumors and adenocarcinomas comprised the remaining 37%.17 Many of
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these findings were incidental, with the guinea pigs not reported to show overt signs of hyperthyroidism. Another pathology facility found thyroid tumors in 4.6% of guinea pig submissions, second only to lymphoma.7,12 There have been various other reports in the literature of thyroid gland neoplasia.18,19–23 In some groups of guinea pigs, thyroid pathologic abnormality can reach up to 30% of the population.12 It is not known what percentage of thyroid tumors alter thyroid hormone synthesis. It is possible for the tumors to increase, decrease, or have no effect on hormone production.23 In one pathology laboratory, adenomas were thought to be nonfunctional and were often unilateral but adenocarcinomas/carcinomas were thought to have variable behavior with respect to their effect on hormone synthesis.23 Further research is needed to determine the percentage of tumors that lead to a hyperthyroid or hypothyroid state. Signalment
Neoplasia is uncommon in guinea pigs less than 1 year of age and increases in likelihood after 3 years of age.12 In one study, the average age of affected guinea pigs was 4.3 years, with the ages ranging from 2.5 to 6 years of age.17 In another study the age ranged from 3.5 to 7 years.23 A sex distribution has not been determined. In one report, 10 guinea pigs were female, 7 were male, and the sex of 2 were not reported.17 In another study, there was an even representation of sexes between adenomas and adenocarcinomas.23 Clinical signs
Often a palpable thyroid mass is detectable on physical examination, although this is not always the case. The guinea pig may be completely asymptomatic or signs may be nonspecific, such as weight loss or decreased appetite. The animal may show signs of hyperthyroidism if the tumor is functional, or hypothyroidism if the tumor inhibits normal thyroid hormone production.3,14 If metastases occur, clinical signs may develop based on the location that the tumor spreads. Differential diagnoses
Table 2 provides differentials of cervical neck masses. Diagnostics
Diagnostics are aimed at determining the identity of the tumor, its structure, and invasiveness, if there is any evidence of metastasis, and if the tumor is functional. The guinea pig hyperthyroidism section and Table 3 can be referred to for more information. Treatment
The need for treatment is determined by the type of tumor and clinical signs present. If the tumor has resulted in alterations of thyroid hormone production, then the animal will need to be treated accordingly. The tumors can be removed via thyroidectomy,18 although this is a difficult procedure. The treatment section of guinea pig hyperthyroidism can be referred to for more information. Concurrent disease
In one study, the most common concurrent findings included lesions consistent with congestive heart disease, myocardial degeneration, atrophy of fat, and nephrosclerosis. Many other concurrent findings were found in lesser proportions.17 In cats, hyperthyroidism is linked to cardiac disease and renal disease14; however, it is unknown if animals in this study had hyperthyroidism. Therefore, it is difficult to draw conclusions about whether there is a similar link in guinea pigs.
Thyroid Diseases in Rodent Species
RAT (RATTUS RATTUS)
A reported reference interval for TT4 in rats is 3 - 7 mg/dL and TT3 is 25 - 100 ng/dL.7,8 Although there is abundant research on experimentally induced thyroid disease in laboratory rats, there is very little published information on thyroid function and disease in pet rats. As a result, most of the information available is extrapolated from laboratory medicine. Different lines of rats have very different genetics and disease susceptibility; therefore, data can be difficult to interpret as the genetics of pet rats are usually unknown. Unique Features
The rat thyroid gland lies ventrolateral to the first 4 to 5 tracheal rings, just caudal to the larynx.24 In laboratory studies, male rats have higher circulating levels of throxine11 and TSH than female rats. Castration has been found to decrease TSH and response to TRH injection.2 T3 and T4 levels in rats decline with advancing age.13 Rats have been found to have euthyroid sick syndrome11; therefore, concurrent disease will affect thyroid hormone interpretation. Neoplasia
Spontaneously occurring thyroid gland tumors, usually benign, are commonly found during necropsies of large colonies of laboratory rats. Clinical signs from these tumors are uncommon.25–27 The incidence of these tumors varies greatly with genetics. One study found that most follicular adenomas were unilateral, with distinct foci of neoplastic tissue.28 Parafollicular C-cell adenomas and C-cell hyperplasia are also common in rats.26,27,29–31 Malignant tumors (follicular adenocarcinomas and C-cell carcinomas) have also been discussed in rats.25,26,31 Dietary goitrogens or prolonged iodine deficiency may promote thyroid tumors30; therefore, a diet history is important when a thyroid enlargement is suspected. Clinical signs
Thyroid tumors in rats are usually asymptomatic and not detectable on physical examination.30 Differential diagnoses
Other possible diagnoses for a palpable cervical swelling include insufficient iodine intake, enlarged lymph nodes, mandibular salivary gland neoplasia, abscess, and mammary gland neoplasia.16 Hypothyroidism
Naturally occurring hypothyroidism is uncommon in rats. Hypothyroidism has been found to cause polyuria as a result of impaired renal concentrating abilities, as well as decreased serum sodium concentrations.32 In addition, although nonregenerative anemia can be seen with hypothyroidism in other species, there is not a clear link seen in rats.33 In a study of experimentally induced hypothyroidism, rats were found to develop decreased appetite, weight loss, lethargy, and piloerection. Decreases in heart rate, blood pressure, and body temperature were also noted.34 On histopathology, myocardial segmental degeneration was found, showing a rapid alteration in cardiac function with hypothyroidism. Although hypothyroidism is traditionally thought to cause weight gain, the authors theorized that the weight loss may be related to the sudden decrease in thyroid hormones due to the hypothyroidism being experimentally induced. However, the authors did note that decreased appetite and failure to gain weight rapidly
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have been seen in other hypothyroid rats. Experimental hypothyroidism in rats is reversible with L-thyroxine supplementation.34,35 Although the clinical signs and changes in parameters were seen rapidly in this study (within 2 weeks), they are likely to have a slower onset in natural hypothyroidism as the decrease in thyroid hormones is likely slower. The information above may mimic the more acute drop in thyroid hormones that can occur with oversupplementation of methimazole, too high a dose of 131I, or if the entire thyroid gland needs to be removed due to neoplasia. Hyperthyroidism
Experimentally induced hyperthyroidism in rats has been found to cause weight loss, despite increased food intake,35 and to increase spontaneous physical activity.36 Euthyroid status has been successfully restored in laboratory rats using methimazole.37 MICE (MUS MUSCULUS)
A reported reference interval for TT4 in mice is 4 - 7 mg/dL and TT3 is 65 - 140 ng/dL.8 The thyroid gland in mice generally extends from the larynx along the first 3 to 4 tracheal rings. In adult mice, the gland is approximately 2 mm long, 1 mm wide, and 0.5 mm deep. Due to its small size, a significant enlargement would have to occur before it could be detected on palpation.1 Aging Changes
When evaluating aging changes in mice, it has been found that elderly mice are prone to immune dysfunction leading to amyloid deposition in multiple organs, including the thyroid gland. Long-term corticosteroid use can decrease this deposition.38 In addition, elderly mice have a decreased ability to bind iodine, causing the gland to increase in size and weight via hyperplasia. Decreased levels of circulating T3 and T4 and thyroid hyperplasia have also been reported in aging mice.38 Neoplasia
Spontaneously occurring follicular cell adenomas have been reported.25,29,30,39 HAMSTER (MESOCREICETIS AURATUS)
The thyroid gland in the hamster sits at the level of the first tracheal cartilage.40 A reported reference interval for TT4 in hamsters is 3 - 7 mg/dL and for TT3 is 30 - 80 ng/dL.8 Thyroid hormone production in hamsters is affected by age, pregnancy, as well as several external factors, including hibernation status and temperature.9 Chronic exposure to decreased photoperiods and temperatures, consistent with hibernation or the shortened length of days in winter, leads to a decrease in levels of TSH, T3, and T4. This change has been found when hamsters are exposed to less than 12.5 hours of daylight, as well as in blind animals. Aging leads to decreased levels of T3 and T4 and TSH response.41–44 Pregnancy may also alter thyroid metabolism due to decreased protein-bound iodine.9 These factors should be taken into account when interpreting thyroid hormone results. Neoplasia
Thyroid gland tumors in hamsters are one of the most commonly seen tumors in this species.45 Most of these tumors are benign and are usually not found on gross examination. One study of laboratory hamsters reported an incidence between 1.5% and
Thyroid Diseases in Rodent Species
2.6%.45 Another study of spontaneous endocrine tumors in 2 groups of laboratory hamsters found carcinomas in approximately 1% of each group, and adenomas in approximately 7% of one group and 5.5% of the other.46 Most of these neoplasms were not visible grossly. As with rats, iodine deficiency may contribute to the development of benign follicular thyroid adenomas.47 Thyroidectomy has been described but has a poor postsurgical survival rate.48 Hypothyroidism
Hypothyroidism has been anecdotally reported in hamsters.27,30 Clinical signs include alopecia, hyperpigmentation of the skin, lethargy, cold intolerance, and skin thickening. Hamsters treated with thyroxine showed an improvement in clinical signs. A differential for the alopecia is Cushing disease, which occurs more frequently in hamsters than hypothyroidism.30 Perifollicular Amyloidosis
One report cited 64% of perifollicular amyloidosis in aging hamsters. Other changes include cysts and reduced colloid.41 GERBIL (MERIONES UNGUICULATUS)
Information on thyroid disease in gerbils is extremely limited. There is one case report of a thyroid follicular adenoma in a laboratory gerbil, although the animal was not noted to show clinical signs as a result of the tumor.49 CHINCHILLA (CHINCHILLA LANIGERA)
A reported reference interval for TT4 in chinchillas is 3.4–6.4 mg/dL.50 Hyperthyroidism
A single case of hyperthyroidism has been reported in the chinchilla.51 The chinchilla presented with a history of weight loss. On physical examination the patient was underweight and had focal, scaly alopecia on one forelimb. Elevated TT4 was repeatable. Other abnormalities found were hyperglycemia and glucosuria, despite a low fructosamine, and elevated aspartate aminotransferase. These abnormalities were ultimately attributed to the hyperthyroidism. The animal was treated with methimazole and showed improvement in clinical signs. A thyroid nodule was not able to be detected on physical examination or ultrasonic evaluation. As with guinea pigs, there are no studies on treatment of hyperthyroidism in chinchillas. Therefore, treatment is extrapolated from feline medicine. Treatment options are similar to guinea pigs and include oral medications, 131I, and thyroidectomy.50,51 A possible sequela to hyperthyroidism is cardiomyopathy.23 A study in 1973 comparing fur-chewing chinchillas to normal chinchillas revealed that the fur-chewing group had increased thyroid activity than the normal group.52 The animals did not show weight loss or any other clinical signs of hyperthyroidism. Further studies are needed to determine if elevated thyroid levels led to the furchewing, or if fur-chewing led to the elevated thyroid levels. One theory is that fur-chewing chinchillas have less insulation and need increased thermogenesis to maintain body temperature, leading to an increase in thyroid hormones.52,53 Thyroidectomy
Thyroidectomy is difficult in chinchillas due to the size and location of the gland. In addition, the parathyroid glands are challenging to separate from the thyroid gland.
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For these reasons, the patient may need lifelong calcium gluconate supplementation. Regrowth of the thyroid tissue has been reported in over half of one group of chinchillas, indicating that recurrence of the hyperthyroidism is highly possible.50 SUMMARY
Although there is limited information on spontaneous thyroid disease in rodent medicine, documented cases indicate that rodents do develop thyroid diseases similar to dogs and cats. Hyperthyroidism has been reported in guinea pigs, and one case of a chinchilla, and many of the same methods used for diagnosing and treating feline hyperthyroidism are also effective in these species. In addition, experimentally induced hyperthyroidism in rats has also proven to have similar clinical signs and successful responsiveness to methimazole. Hypothyroidism has been reported in guinea pigs and hamsters, and although uncommon, the diseases follow patterns similar to canine hypothyroidism. For guinea pigs, hamsters, and laboratory rats, treatment with levothyroxine has been successful at restoring euthyroid status. Although thyroid neoplasia has been reported in many rodent species, it is often an incidental finding. Further research is needed to determine the incidence of thyroid disease in rodents, establish reference intervals for thyroid testing, and determine the best dosing for treatment. REFERENCES
1. DuBray La Perle KM, Jordan CD. Endocrine system. In: Treuting PM, Dintzis SM, Frevert CW, et al, editors. Comparative anatomy and histology: a mouse and human atlas. London: Elsevier/Academic Press; 2012. p. 211–27. 2. Capen CC. Endocrine glands. In: Maxie MG, editor. Jubb, Kennedy & Palmer’s pathology of domestic animals. 5th edition. vol. 3. Edinburgh (United Kingdom): Saunders 2007. p. 325-428. 3. Mooney CT. Hyperthyroidism. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine, vol. 2, 7th edition. St Louis (MO): Saunders Elsevier; 2010. p. 1761–79. 4. Berdanier CD. Gastrointestinal system and metabolism. In: Hedrich HK, Bullock G, editors. The laboratory mouse. Amsterdam (The Netherlands): Elsevier Academic Press; 2004. p. 245–59. 5. Brandao K, Vergneau-Grosset C, Mayer J. Hyperthyroidism and hyperparathyroidism in guinea pigs (cavia porcellus). Vet Clin North Am Exot Anim Pract 2013;16:407–20. 6. Mayer J, Wager R, Mitchell MA, et al. Use of recombinant human thyroidstimulating hormone for evaluation of thyroid function in guinea pigs (Cavia porcellus). J Am Vet Med Assoc 2013;242:346–9. 7. Mayer J, Hunt K, Eshar D, et al. Thyroid scintigraphy in a guinea pig with suspected hyperthyroidism. Exotic DVM 2009;11:25–9. 8. Mayer J, Donnelly T. Laboratory tests: thyroid hormones. In: Mayer J, Donnelly T, editors. Clinical veterinary advisor. Birds and exotic pets. St Louis (MO): Saunders Elsevier; 2012. p. 648–9. 9. Washington IM, Van Hoosier G. Clinical biochemistry and hematology. In: Suckow MA, Stevens KA, Wilson RP, editors. The laboratory rabbit, guinea pig, hamster, and other rodents. Amsterdam (United Kingdom): Elsevier Academic Press; 2012. p. 65. 10. Fredholm DV, Cagle LA, Johnston MS. Evaluation of precision and establishment of reference ranges for plasma thyroxine using a point-of-care analyzer in healthy guinea pigs (cavia porcellus). J Ex Pet Med 2012;21(1):87–93.
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11. Muller K, Muller E, Klein R, et al. Serum thyroxin concentrations in clinically healthy pet guinea pigs (cavia porcellus). Vet Clin Pathol 2009;38: 507–10. 12. Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509–23. 13. Segal J, Troen BR, Ingbar SH. Influence of age and sex on the concentrations of thyroid hormone in serum in the rat. J Endocrinol 1982;93:177–81. 14. Scott Moncrieff JC. Hypothyroidism. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine, vol. 2, 7th edition. St Louis (MO): Saunders Elsevier; 2010. p. 1751–61. 15. Hawkins MG, Bishop CR. Disease problems of guinea pigs. In: Quesenberry KE, Carpenter JW, editors. Ferrets, rabbits, and rodents: clinical medicine and surgery. 3rd edition. St Louis (MO): Saunders; 2012. p. 295–310. 16. Reese S. Cervical soft tissues. In: Krautwald-Junghanns ME, Pees M, Reese S, editors. Diagnostic imaging of exotic pets: birds, small mammals, reptiles. Hannover (Germany): Schluetersche 2010; p. 247, 255. 17. Gibbons PM, Garner MM, Kiupel M. Morphological and immunohistochemical characterization of spontaneous thyroid gland neoplasms in guinea pigs (cavia porcellus). Vet Pathol 2013;50:334–42. 18. Zarrin K. Thyroid carcinoma of a guinea pig: a case report. Lab Anim 1974;8(2): 145–8. 19. Kromka MC, Hoar RM. An improved technic for thyroidectomy in guinea pigs. Lab Anim Sci 1975;25:82–4. 20. Greenacre CB, Newkirk K. Methimazole use in hyperthyroid guinea pigs. Summary style manuscript from 2011 AEMV proceedings (session 2140). Available at: http://www.aemv.org/members_only/proceedings.cfm. Accessed July 3, 2013. 21. Monks D, Cowan M, Raidal S. Thyroid carcinoma in a guinea pig (cavia porcellus). In: AAVAC-UEP proceedings. Available at: http://www.vin.com/members/ proceedings/proceedings.plx?CID5UEP2010&PID563212&O5VIN&id5 4838021. Accessed July 27, 2013. 22. Campbell TW, Grant KR. A 6-year old guinea pig with excessive drinking and urination, soft stools, and weight loss. In: Campbell TW, Grant KR, editors. Clinical cases in avian and exotic animal hematology and cytology. Ames (IA): Wiley-Blackwell; 2010. p. 137–41. 23. Reavill D. The pathology of common diseases in small exotic mammals. In: Western Veterinary Conference Proceedings. 2009. Available at: http://www. vin.com/members/proceedings/proceedings.plx?CID5WVC2009&PID551222 &O5VIN&id53985549. Accessed July 5, 2013. 24. O’Malley B. Rats. In: Clinical anatomy and physiology of exotic species. Structure and function of mammals, birds, reptiles, and amphibians. Edinburgh (United Kingdom): Elsevier Saunders; 2005. p. 209–25. 25. Prejean JD, Peckham JC, Casey AE, et al. Spontaneous tumors in SpragueDawley rats and Swiss mice. Cancer Res 1973;33:2768–73. 26. Nakazawa M, Tawaratani T, Uchimoto H, et al. Spontaneous neoplastic lesions in aged Sprague-Dawley rats. Exp Anim 2001;50(2):99–103. 27. Harkness JE, Turner PV, VandeWoude S, et al. Clinical signs and differential diagnoses. In: Harkness JE, Turner PV, VandeWoude S, et al, editors. Biology and medicine of rabbits and rodents. 5th edition. Ames (IA): Wiley-Blackwell; 2010. p. 195–247.
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28. Schardein JL, Fitzgerald JE, Kaump DH. Spontaneous tumors in HoltzmanSource rats of various ages. Pathol Vet 1968;5:238–52. 29. Greenacre CB. Spontaneous tumors of small mammals. Vet Clin North Am Exot Anim Pract 2004;7:627–51. 30. Keeble E. Endocrine diseases in small mammals. Practice 2001;23:570–85. 31. Boorman GA, Everitt JI. Neoplastic disease. In: Suckow MA, Weisbroth SH, Franklin CL, editors. The laboratory rat. 2nd edition. Amsterdam (United Kingdom): Elsevier Academic Press; 2006. p. 479–511. 32. Cadnapaphornchai MA, Kim TW, Gurevich AK, et al. Urinary concentrating defect in hypothyroid rats: role of sodium, potassium, 2-chloride cotransporter, and aquaporins. J Am Soc Nephrol 2003;14:566–74. 33. Car BD, Eng VM, Everds NE, et al. Clinical pathology of the rat. In: Suckow MA, Weisbroth SH, Franklin CL, editors. The laboratory rat. 2nd edition. Amsterdam (United Kingdom): Elsevier Academic Press; 2006. p. 127–46. 34. Patel M, Mishra V, Pawar V, et al. Evaluation of acute physiological and molecular alterations in surgically developed hypothyroid Wistar rats. J Pharmacol Pharmacother 2013;4(2):110–5. 35. Lopez M, Varela L, Vazquez MJ, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010;16(9): 1001–8. 36. Levine JA, Nygren J, Short KR, et al. Effect of hyperthyroidism on spontaneous physical activity and energy expenditure in rats. J Appl Physiol 2003;94:165–70. 37. Khorshidi-Behzadi M, Alimoradi H, Haghioo-Javanmard S, et al. The effect of chronic hyperthyroidism and restored euthyroid state by methimazole in rat small mesenteric arteries. Eur J Pharmacol 2013;701:1–3. 38. Anver MR, Haines DC. Gerontology. In: Hedrich HK, Bullock G, editors. The laboratory mouse. Amsterdam (United Kingdom): Elsevier Academic Press; 2004. p. 327–43. 39. Mikaelian I, Ichiki T, Ward JM, et al. Diversity of Spontaneous neoplasms in commonly used inbred strains and stocks of laboratory mice. In: Hedrich HK, Bullock G, editors. The laboratory mouse. Amsterdam (United Kingdom): Elsevier Academic Press; 2004. p. 345–54. 40. O’Malley B. Hamsters. In: O’Malley B, editor. Clinical anatomy and physiology of exotic species. Structure and function of mammals, birds, reptiles, and amphibians. Edinburgh (United Kingdom): Elsevier Saunders; 2005. p. 227–36. 41. Vaughan MK, Richardson BA, Craft CM, et al. Interaction of ageing, photoperiod, and melatonin on plasma thyroid hormones and cholesterol levels in females Syrian hamsters (mesocricetus auratus). Gerontology 1982;28: 345–53. 42. Vaughan MK, Braindard GC, Reiter RJ. Photoperiodic and light spectral conditions which inhibit circulating concentrations of thyroxine in the male hamster. Life Sci 1985;36:2183–8. 43. Petterborg LJ, Vaughan MK, Johnston LY, et al. Modification of testicular and thyroid function by chronic exposure to short photoperiod: a comparison in four rodent species. Comp Biochem Physiol 1984;78:31–4. 44. Vaughan MK, Powanda MC, Richardson BA, et al. Chronic exposure to short photoperiod inhibits free thyroxine index and plasma levels of TSH, T4, triiodothyronine (T3) and cholesterol in female hamsters. Comp Biochem Physiol 1982; 71(4):615–8. 45. Collins BR. Endocrine diseases of rodents. Vet Clin North Am Exot Anim Pract 2008;11(1):153–62.
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46. Pour P, Mohr U, Althoff J, et al. Spontaneous tumors and common disease in two colonies of Syrian hamsters. III. Urogenital system and endocrine glands. J Natl Cancer Inst 1976;56:949–61. 47. Harkness JE, Turner PV, VandeWoude S, et al. Specific diseases and conditions. In: Harkness JE, Turner PV, VandeWoude S, et al, editors. Biology and medicine of rabbits and rodents. 5th edition. Ames (IA): Wiley-Blackwell; 2010. p. 249–396. 48. Johnson-Delaney CA. Endocrine system and diseases of exotic companion mammals. In: ABVP 2009 proceedings. Available at: http://www.vin.com/members/ proceedings/proceedings.plx?CID5ABVP2009&PID526736&O5VIN&id5 3944802. Accessed July 7, 2013. 49. Shumaker RC, Paik SK, Houser WD. Tumors in gerbillinae: a literature review and report of a case. Lab Anim Sci 1974;24:688–90. 50. Martin LB, Chidambaram RM, Schroeder KE, et al. Thyroparathyroidectomy procedures and thyroxine levels in the chinchilla. Contemp Top Lab Anim Sci 2005; 44:9–14. 51. Fritsche R, Simova-Curd S, Clauss M, et al. Hyperthyroidism in connection with suspected diabetes mellitus in a chinchilla (chinchilla laniger). Vet Rec 2008; 163:454–6. 52. Vankonack WJ, Johnson HD. Relationship of thyroid and adrenal function to “furchewing” in the chinchilla”. Comp Biochem Physiol A Comp Physiol 1973;45A: 115–20. 53. Norton JN, Reynolds RP. Diseases and veterinary care. In: Suckow MA, Stevens KA, Wilson RP, editors. The laboratory rabbit, guinea pig, hamster, and other rodents. Amsterdam (United Kingdom): Elsevier Academic Press; 2012. p. 993–1008.
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KEYWORDS Thyroid disease Hyperthyroidism Hypothyroidism Thyroid neoplasia KEY POINTS There are abundant studies of thyroid disease in rodents in a laboratory setting; however, research is limited in pet rodent populations. Validated reference intervals for thyroid testing are scarce, making interpretation of blood work difficult. Hyperthyroidism and hypothyroidism has been reported in multiple rodent species, with the most data available for guinea pigs. Thyroid neoplasia has been reported in the most common rodent species although often as an incidental finding at necropsy. Further research is needed to determine frequencies of disease, methods of diagnosing, and treatment options with the best efficacy.
INTRODUCTION
Information available on naturally occurring thyroid disease in small mammals is extremely limited. Although there is an abundance of research with experimentally induced thyroid disease in laboratory rodents, this does not follow the pattern of naturally occurring diseases in these species and often has limited value when evaluating pet rodents. Overall, naturally occurring thyroid gland dysfunction is poorly documented in rodents, and more research is needed to explore these diseases. The expense associated with diagnostics is a limiting factor for many exotic pet owners, often preventing clinicians from being able to diagnose thyroid diseases definitively. Furthermore, due to the small size of most rodents, it may difficult to obtain sufficient blood volume to run multiple diagnostics. Even if enough blood is collected, it is also quite challenging to interpret the results because the assays have not been validated in most rodent species.
Central Animal Hospital, 317 Ardsley Road, Scarsdale, NY 10583, USA * 77 Lake Avenue, Tuckahoe, NY 10707. E-mail address: [email protected] Vet Clin Exot Anim 17 (2014) 51–67 http://dx.doi.org/10.1016/j.cvex.2013.09.002 vetexotic.theclinics.com 1094-9194/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
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ANATOMY
The thyroid gland, located at the cranial-ventral aspect of the trachea, is bilobed and connected by an isthmus.1 It is closely associated with the parathyroid glands, which are responsible for secretion of parathyroid hormone. Based on embryologic development, it is possible to have ectopic thyroid tissue in other locations, ranging from the larynx to the diaphragm2; this becomes important if the ectopic tissue begins secreting excess thyroid hormones. Histologically, the thyroid gland is composed of 2 cell types: follicular cells, which predominate, and C cells, which are also known as parafollicular cells.2 The main functional units of the thyroid gland are the numerous follicles, which are lined by low cuboidal epithelium (follicular cells).1,2 C cells are found in small groups of 10 cells or fewer scattered throughout the gland, either in connective tissue between follicles or at the base of the follicular cells. These cells account for 0.1% of thyroid epithelial cells.1 PHYSIOLOGY
Thyroid hormones are essential for normal body function including growth and the development of neurologic and skeletal systems.2 They increase normal metabolism in most tissues and have catabolic effects on muscle and fat. They also increase the number and affinity of b-adrenergic receptors, which have inotropic and chronotropic effects on the heart. The hormones are also responsible for erythropoiesis and cholesterol synthesis and breakdown.3 In rodents, thyroid hormones, along with catecholamines, play an important role in thermogenesis of brown fat, allowing them to adapt to cold temperatures.4 As stated previously, the thyroid gland consists of 2 primary cell types. Follicular cells produce thyroglobulin and are responsible for the uptake and oxidation of iodine. Once oxidized, the iodine is released into the follicular lumen and interacts with thyroglobulin, producing mostly thyroxine (T4) and a small amount of triiodothyronine (T3). T4 is the main product of the thyroid gland and is solely produced there. In contrast, only a small portion of T3 is made in the thyroid gland; the remainder is produced from deiodination of T4 to T3 within target cells.3 When signaled to be released, the iodinated thyroglobulin undergoes hydrolysis, releasing T3 and T4 into the bloodstream.2 The vast majority (>99%) of serum thyroid hormones are stored in the biologically inactive, protein-bound state.3 It is the unbound, free T4 (fT4) and T3 (fT3) that are biologically active and able to enter cells and stimulate negative feedback on the pituitary gland and hypothalamus. Circulating fT3 enters cells more rapidly and has a faster onset of action than T4.3 Once in cells, T3 is able to act directly, and T4 is deiodinated to the more bioactive T3, which acts on the cell to exert its effects. Thyroid hormone production and release are controlled by the hypothalamicpituitary-thyroid axis. The hypothalamus detects decreased circulating levels of thyroid hormones and releases thyrotropin-releasing hormone (TRH). TRH acts on the anterior pituitary gland to release thyrotropin-stimulating hormone (TSH), which stimulates T3 and T4 release from the thyroid gland. Rising levels of thyroid hormones in the blood initiates a negative feedback loop, which inhibits additional release of TSH.3 The thyroid also contains C cells, which are responsible for the production of calcitonin. Calcitonin is responsible for controlling calcium deposition in bone by inhibiting bone resorption by osteoclasts, leading to decreased serum calcium levels. Calcitonin acts in opposition to parathyroid hormone.2
Thyroid Diseases in Rodent Species
LABORATORY TESTS
Thyroid function can be assessed by measuring blood levels of total T4 (TT4), fT4, total T3 (TT4), fT3, and TSH. In addition, T3 suppression and TSH stimulation tests can be performed.5,6 Due to the small size of most rodents, it can be difficult to obtain adequate blood samples to perform these tests. In addition, validated reference ranges are limited in exotic species; therefore, the results can be difficult to interpret. As with dogs and cats, TT4 is generally the initial screening test. Determining fT4 values is beneficial because it is less likely to be affected by medications or euthyroid sick syndrome.2,7 Total T3 and fT3 values are not used as frequently because they are generally considered less reliable in veterinary medicine.3 TSH assays are used in thyroid testing of humans and dogs; however, this method has yet to be validated in rodents. T3 suppression tests have recently been increasing in use for diagnosing feline hyperthyroidism. Last, a TSH response test can be performed, although the adequate dose and response need further validation.6 It is also worth noting that several medications are known to decrease serum thyroxine levels including glucocorticoids, sulfonamides, phenobarbital, and nonsteroidal anti-inflammatory drugs.2,8 For this reason, evaluating thyroid levels in patients on these medications can be difficult. GUINEA PIGS (CAVIA PORCELLUS) Thyroid Testing
There have been several reports of reference intervals in both laboratory and pet guinea pigs.5–12 Although there are multiple reference ranges reported, interpretation is somewhat difficult based on differences in testing modalities used (chemiluminescent competitive assays, Radioimmunoassay [RIA], Enzyme Immunoassay [EIA]), sample sizes, age ranges, and sources of animals (some pet, other laboratory).10 Further evaluation of these testing methods is needed to determine the validity of these tests. Table 1 shows the various reference ranges that have been reported.
Table 1 Thyroid hormone levels that have been reported for groups of guinea pigs Thyroid Hormone
Reference Ranges
TT4 (mg/dL)
1.1–5.2 (2.1) 2.26–5.82 (4.04) 2.3–3.5 2.9 0.6 (male) 3.2 0.7 (female) 0.56–1.33 (0.7)
fT4 (ng/dL)
1.26 1.33 0.67 1.17
TT3 (ng/dL)
22–56 39 17 (male) 44 10 (female
fT3 (pg/dL)
257 35 (male) 260 59 (female)
Data from Refs.5–12
0.41 (male) 0.25 (female) 0.57 0.09
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Age and sex both affect thyroid levels in several other species,11,13 raising the question of whether this also holds true for guinea pigs. One study11 found a statistically significant difference in thyroid levels between females and neutered males, while others have not seen a significant difference.10 Although age has yet to be reported as a significant factor in the guinea pig, this observation is limited in its implications because many studies used juvenile to mid adult animals. Further research is needed to determine if age and sex play a role in thyroid levels. Hyperthyroidism
Hyperthyroidism is not well-documented in guinea pigs in the United States, although reports recently have been increasing.7,10 Interestingly, it is a fairly common syndrome in German literature7 and may be due to genetic differences between German and American guinea pigs or could be an indication that hyperthyroidism is underdiagnosed in the United States. The neoplasia section reports on the incidence of thyroid pathologic abnormality. The percentage of thyroid neoplasms that secrete excess hormones is unknown. Cause/physiology
Excess thyroid hormone leads to increased metabolic rate and calorie utilization and can affect the sympathetic nervous system, leading to clinical signs of hyperthyroidism.14,15 Hyperthyroidism is thought to be secondary to functional thyroid tumors, including thyroid hyperplasia, adenoma, and adenocarcinoma. The tumors may be unilateral or bilateral and in some cases can also be the result of excess secretion by ectopic thyroid tissue.2,6 Further research is needed to determine what type of tumor most commonly leads to hyperthyroidism. Signalment
Hyperthyroidism can affect guinea pigs of any age; however, most reported cases occur in pigs older than 3 years of age. There is no known sex predilection, although there is speculation that females may be more prone to thyroid hypertrophy, and therefore, hyperthyroidism.12 More research is needed to determine if this is the case. Clinical signs
Clinical signs of hyperthyroidism vary considerably. The most consistent signs include weight loss despite an increased appetite, hyperactivity, nervousness, and hyperesthesia.10–12 Clinical signs that occur more sporadically include polyuria, polydipsia, soft stools, and progressive alopecia. In addition to a decreased body condition, physical examination may reveal a palpable thyroid nodule, tachycardia, arrhythmia, or heart murmur. Anorexia can also occur at later stages of hyperthyroidism.10–12 Differential diagnoses
Table 2 describes the differentials of hyperthyroidism. The various clinical signs of hyperthyroidism include a cervical neck mass, weight loss, alopecia, PU/PD, soft stool, and cardiac abnormalities. As a result, the differential diagnoses are quite varied based on the clinical signs seen in an individual patient. Diagnostic testing
Table 3 provides an overview of treatment options to diagnose hyperthyroidism, as well as the advantages and disadvantages of each. Diagnostics include bloodwork, which can include a CBC, serum chemistry, TT4, fT4, and TSH test. Additional diagnostics include thoracic radiographs, ultrasound, FNA and cytology of the mass, and biopsy. Advanced diagnostics include CT, MRI, and nuclear scintigraphy. In
Thyroid Diseases in Rodent Species
Table 2 Differentials of hyperthyroidism Clinical Sign/ Finding Cervical neck mass
Weight loss
Possible Differential Diagnosis Thyroid hyperplasia/neoplasia Cervical lymphadenitis or other abscess Lymphadenopathy Mandibular salivary gland neoplasia Granuloma
T4, cytology, biopsy FNA
Dental disease Endoparasites Renal disease Ovarian cysts
Skull rads/oral examination Fecal CBC/Chem/UA History, abdominal palpation, ultrasound T4 History
Late-stage hypothyroidism Food competition/deprivation/poor nutrition Alopecia
Diagnostics that May Aid in Differentiation
Ovarian cysts Barbarism (self/cagemate) Late-stage hypothyroidism Ectoparasites/Dermatophytosis Adrenal tumor
FNA/biopsy FNA/biopsy FNA/biopsy
History, palpation abdomen, ultrasound Evaluate for broken hair shafts, history T4 Skin scrape, determine if pruritic Ultrasound
PU/PD
Renal disease Diabetes
CBC/chem/UA Blood and urine glucose, fructosamine
Soft stool/diarrhea
Endoparasites Recent antibiotic use Bacterial infection
Fecal Owner history History/physical examination
Cardiac abnormalities
Primary cardiac disease
Echocardiogram, ECG, thoracic radiographs
Data from Refs.5,10,12,15,16
cases where diagnostics cannot be performed, a methimazole trial can be initiated. Further information about each diagnostic is described below. Blood work Initial blood work should consist of a complete blood count (CBC) and
serum chemistry to determine the overall health status of the patient. A TT4 is the initial thyroid screening test; it is important to keep in mind that hyperthyroid animals can have thyroxine levels within the normal reference interval.14 Additional thyroid testing may be necessary because diagnosing hyperthyroidism based on one elevated T4 is not ideal.5 Euthyroid sick syndrome, which is well documented in dogs and cats, may also occur in guinea pigs and could result in a hyperthyroid animal having a TT4 level within the normal range.7 Obtaining a fT4 may be helpful because it is less likely to be affected by concurrent illnesses, although reference intervals are not complete. As with hyperthyroid cats, it is possible to encounter hyperthyroid guinea pigs that do not have significant elevations of T3 and T4, making diagnosis more challenging. A T3 suppression test may also be helpful.6 Ultrasound/Fine-Needle Aspiration/Cytology A palpable thyroid nodule supports the
diagnosis of hyperthyroidism but is not diagnostic. If present, an ultrasound of the mass using a high-frequency probe of 10 mHz or higher will give information about
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Table 3 Diagnostics available to diagnose hyperthyroidism Diagnostic
Advantages
Disadvantages
CBC/chem
Can help rule out other diseases for clinical signs, tell about overall status of the animal
Does not evaluate thyroid function directly
T4 fT4 TSH test
Will give information on thyroid
Fully validated reference intervals not established Euthyroid sick syndrome possible
Ultrasound
Will detect anatomic changes of gland Will give information of vascular supply Can use ultrasound to assist FNA
Will not reveal if tumor is functional Gas in trachea can interfere with evaluation
FNA, cytology, T4
If mass is exfoliative, cytology may yield diagnosis Thyroxine level of aspirated fluid may reveal increased T4
May be nondiagnostic
Radiographs
Can rule out some other causes of clinical signs, such as dental disease Can evaluate for pulmonary metastases Will be able to detect osseous metaplasia of the mass, making thyroid neoplasia higher on the differential list
Will not give information if tumor is functional
CT
Will give information of the structure of the mass Will be able to evaluate for pulmonary metastases, more sensitive than thoracic radiographs
Will not give information if tumor is functional
Magnetic resonance imaging
Can help define local tissue invasion, as has a higher contrast resolution than ultrasound Will be able to evaluate tissue dorsal to the trachea as is not affected by gas
Will not give information if the tumor is functional
Nuclear scintigraphy
Appears to be one of the most precise methods of diagnosis in guinea pigs Will detect local and distant metastases, ectopic thyroid tissue Can have false negatives if not hypersecreting
Limited availability of facilities
Data from Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509–23; and Reese S. Cervical soft tissues. In: Krautwald-Junghanns ME, Pees M, Reese S, editors. Diagnostic imaging of exotic pets: birds, small mammals, reptiles. Germany: Schluetersche; p. 247, 255.
morphology and blood supply to the mass. A fine-needle aspirate (FNA) and cytology may diagnose the type of tumor but would not reveal if the mass is functional.16 Performing a T4 on any fluid aspirated from the thyroid mass may reveal elevated thyroxine, which correlates with elevated serum levels.12 If the cytology is not diagnostic or is unable to be performed, a biopsy with histopathology is needed for definitive diagnosis of the type of tumor present.5 Advanced Diagnostics Computed tomography (CT) and magnetic resonance imaging will also give information about the architecture of the mass. CT and thoracic
Thyroid Diseases in Rodent Species
radiographs may be beneficial to reveal pulmonary metastases. Radiographs of the mass may reveal osseous metaplasia, which is present in some benign and malignant thyroid neoplasias.17 Nuclear scintigraphy is currently considered the gold standard for diagnosing hyperthyroidism in guinea pigs. One benefit of this test in neoplasia is that it may be able to detect metastases, both local and distant, as well as ectopic thyroid tissue.7 Methimazole Trial Although it is ideal to have full diagnostics to support hyperthyroidism, as an alternative, a methimazole trial can be performed. Hyperthyroid guinea pigs should show a rapid improvement in weight gain and behavioral changes when placed on methimazole. Clinical signs will quickly return when taken off of the medication.12 Other If any cardiac abnormalities are detected on physical examination, cardiac
diagnostics, such as an echocardiogram, should be performed. Treatment
Treatment of hyperthyroidism is aimed at reducing the levels of circulating thyroid hormones. Options are extrapolated from treating feline hyperthyroidism and include daily oral medication, radioactive iodine (131I), and surgery.12 Table 4 overviews the treatment options. Oral Medications The goal of medication is to suppress production of thyroid hormones directly. The most common options include methimazole and carbimazole.5 The advantages of this approach include the relatively low cost, noninvasive nature
Table 4 Treatment options for guinea pig hyperthyroidism Treatment
Advantage
Disadvantage
Oral medication
Inexpensive Rapid response Can be used before 131I or surgery to stabilize Can be used as a therapeutic trial when diagnostics not possible No reported side effects in the literature currently
Not addressing underlying cause Therapy will be lifelong Stopping medication will result in rapid return of clinical signs
131
May be curative Able to target ectopic thyroid tissue Less invasive than surgery No risk of affecting parathyroid glands
Expense Limited availability Treatment doses not fully determined Recurrence is possible
Thyroidectomy
May be curative If tumors is malignant, may prevent metastasis
I
Technically difficult surgery Can potentially recur May miss ectopic thyroid tissue Risk of complications: recurrent laryngeal nerve damage, parathyroid gland removal, hemorrhage
Data from Brandao K, Vergneau-Grosset C, Mayer J. Hyperthyroidism and hyperparathyroidism in guinea pigs (cavia porcellus). Vet Clin North Am Exot Anim Pract 2013;16:407–20; and Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509–23.
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of treatment, and rapid improvement once medications are started. Most guinea pigs only need once-a-day dosing so owner compliance is fairly high. Because the medication is generally well tolerated, it can be used as a trial therapy when diagnostics are not possible. The main disadvantage of these medications is that the guinea pig will require lifelong therapy because the underlying cause of overproduction is not being addressed. In addition, when medications are stopped, clinical signs return very quickly, typically within a couple days.12 Methimazole is generally started at 0.5 mg/kg orally every 12 to 24 hours and anecdotally can be increased to 2.0 mg/kg every 12 to 24 hours if needed. Many cases respond to once-a-day dosing.12 Compounding is often required because of the large tablet size relative to the dose needed. One author12 found some success with transdermal methimazole, although noted that the treatment depigmented brown guinea pig skin. Possible side effects are extrapolated from felines and include anorexia and depression. There are currently no confirmed side effects in guinea pigs. Carbimazole is another option and is used at a dose of 1 to 2 mg/kg orally every 24 hours. Side effects are similar to methimazole.12 Although a link between hyperthyroidism and renal disease has not been firmly established in guinea pigs, as it has in cats, it is certainly possible. Therefore monitoring renal values before and during treatment is recommended. Response to therapy is based largely on clinical signs. It is recommended to recheck the physical examination, including weight and T4 levels, every 2 weeks until clinical signs have improved and levels are within normal range. Subsequently, the examination and thyroid levels should be rechecked every 3 to 6 months based on how the patient is doing at home.12 131
I Radioactive iodine is possibly curative and helps with longterm control of hyperthyroidism. It is less invasive than surgery and is able to target ectopic thyroid tissue.5 Disadvantages include a high expense, limited number of facilities, and a possibility of recurrence. Although there are currently no studies regarding the best dose to use, 2 guinea pigs in the literature were successfully treated with radioactive iodine.12 Placing the patient on methimazole for several weeks before 131 I is recommended to stabilize the patient and to observe for possible unmasking of renal disease. Radioactive iodine:
Thyroidectomy Thyroidectomy may be an option to remove either a portion of or the entire gland, depending on the extent of involvement of the tumor.18 This procedure is performed in laboratory settings but is relatively uncommon in clinical practice. Surgery is potentially curative if the tumor is not invading surrounding tissue and has not metastasized.5 The procedure is technically difficult, and there is a risk of missing ectopic thyroid tissue. For this reason, before surgery it is recommended to perform an ultrasound to determine morphology and blood supply to the mass and a nuclear scintigraphy to determine if there is ectopic thyroid tissue present. In addition, as with any potential neoplasia, preoperative thoracic radiographs (or CT) can be helpful to rule out pulmonary metastases. If the tumor is functional, it is recommended to have the patient on methimazole before surgery for stabilization.5 Caution must be used to avoid contact with the recurrent laryngeal nerves and to prevent removing the parathyroid glands. If the entire gland must be removed, the patient will need thyroxine and oral calcium supplementation. Ionized calcium should be checked immediately after surgery and the animal should be supplemented with oral calcium daily for at least 7 to 10 days before attempting to wean off of the calcium. Ionized calcium should be rechecked 2 weeks after surgery.12 In one study, 42% of guinea pigs had regrowth of thyroid tissue, indicating a high risk of recurrence.18
Thyroid Diseases in Rodent Species
Additional therapies Radiation Radiation therapy has not been reported in guinea pigs but has been used
in both humans and dogs with thyroid gland tumors.5 Radiation may prove useful for incompletely excised tumors or in cases in which surgery is not in the best interest of the patient. Percutaneous ethanol ablation Percutaneous ethanol ablation has been described in
the literature but is currently not recommended.12 Hypothyroidism Cause
Hypothyroidism is an uncommon condition in guinea pigs. As with other animals, the disease can be congenital, acquired, or iatrogenic. Although neoplastic lesions in the thyroid gland can be functional and result in hyperthyroidism, they can also destroy the normal architecture of the gland, leading to reduced synthesis of thyroid hormones.3,14 In dogs, most cases of hypothyroidism are due to lymphocytic thyroiditis.3 Other mechanisms include primary or metastatic neoplasia, and in rare cases, a deficiency of TSH or congenital causes. It is unknown if these same mechanisms occur in guinea pigs. Iatrogenic causes include 131I iodine treatment, oversupplementation of antithyroid medications, and thyroidectomy.3 Clinical signs
Clinical signs are variable and often include decreased activity and weight gain. As seen with canine hypothyroidism, the onset of clinical signs is often subtle and gradual, which may make it difficult for owners to recognize. Clinical signs of chronic cases can coincide with signs of hyperthyroidism including weight loss and bilateral alopecia, often on the dorsum and thighs. Bradycardia may also occur.12 Differential diagnosis
Late-stage hypothyroidism can be confused with hyperthyroidism. A TT4 should help differentiate. Diagnostics
Appropriate clinical signs, paired with a TT4 less than 1 mg/dL, should make the clinician suspicious of hypothyroidism. A CBC and serum chemistry, as well as any other appropriate diagnostics based on history and physical examination, should be performed to rule out euthyroid sick syndrome. If no other illness can be found that would cause a decrease in T4, a TSH stimulation test is recommended if it is not cost prohibitive for the client.6 Although more research is needed to validate testing protocols and references, it is currently thought that the thyroxine level should at least double 3 to 4 hours after recombinant human thyroid-stimulating hormone (rhTSH) injection.6 Treatment
Therapy for hypothyroidism is thyroxine supplementation. L-thyroxine has been used at a dosage of 10 mg/kg orally every 24 hours.12 TT4 should be rechecked at 2 weeks and again at 2 months. Response is also based improvement of clinical signs. Neoplasia Cause
Although thyroid neoplasias are not well documented in guinea pigs, recent reports suggest that they are underdiagnosed. For example, a recent study found that 3.6% of guinea pigs at a pathology service had thyroid tumors. Adenomas comprised 63% of the tumors and adenocarcinomas comprised the remaining 37%.17 Many of
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these findings were incidental, with the guinea pigs not reported to show overt signs of hyperthyroidism. Another pathology facility found thyroid tumors in 4.6% of guinea pig submissions, second only to lymphoma.7,12 There have been various other reports in the literature of thyroid gland neoplasia.18,19–23 In some groups of guinea pigs, thyroid pathologic abnormality can reach up to 30% of the population.12 It is not known what percentage of thyroid tumors alter thyroid hormone synthesis. It is possible for the tumors to increase, decrease, or have no effect on hormone production.23 In one pathology laboratory, adenomas were thought to be nonfunctional and were often unilateral but adenocarcinomas/carcinomas were thought to have variable behavior with respect to their effect on hormone synthesis.23 Further research is needed to determine the percentage of tumors that lead to a hyperthyroid or hypothyroid state. Signalment
Neoplasia is uncommon in guinea pigs less than 1 year of age and increases in likelihood after 3 years of age.12 In one study, the average age of affected guinea pigs was 4.3 years, with the ages ranging from 2.5 to 6 years of age.17 In another study the age ranged from 3.5 to 7 years.23 A sex distribution has not been determined. In one report, 10 guinea pigs were female, 7 were male, and the sex of 2 were not reported.17 In another study, there was an even representation of sexes between adenomas and adenocarcinomas.23 Clinical signs
Often a palpable thyroid mass is detectable on physical examination, although this is not always the case. The guinea pig may be completely asymptomatic or signs may be nonspecific, such as weight loss or decreased appetite. The animal may show signs of hyperthyroidism if the tumor is functional, or hypothyroidism if the tumor inhibits normal thyroid hormone production.3,14 If metastases occur, clinical signs may develop based on the location that the tumor spreads. Differential diagnoses
Table 2 provides differentials of cervical neck masses. Diagnostics
Diagnostics are aimed at determining the identity of the tumor, its structure, and invasiveness, if there is any evidence of metastasis, and if the tumor is functional. The guinea pig hyperthyroidism section and Table 3 can be referred to for more information. Treatment
The need for treatment is determined by the type of tumor and clinical signs present. If the tumor has resulted in alterations of thyroid hormone production, then the animal will need to be treated accordingly. The tumors can be removed via thyroidectomy,18 although this is a difficult procedure. The treatment section of guinea pig hyperthyroidism can be referred to for more information. Concurrent disease
In one study, the most common concurrent findings included lesions consistent with congestive heart disease, myocardial degeneration, atrophy of fat, and nephrosclerosis. Many other concurrent findings were found in lesser proportions.17 In cats, hyperthyroidism is linked to cardiac disease and renal disease14; however, it is unknown if animals in this study had hyperthyroidism. Therefore, it is difficult to draw conclusions about whether there is a similar link in guinea pigs.
Thyroid Diseases in Rodent Species
RAT (RATTUS RATTUS)
A reported reference interval for TT4 in rats is 3 - 7 mg/dL and TT3 is 25 - 100 ng/dL.7,8 Although there is abundant research on experimentally induced thyroid disease in laboratory rats, there is very little published information on thyroid function and disease in pet rats. As a result, most of the information available is extrapolated from laboratory medicine. Different lines of rats have very different genetics and disease susceptibility; therefore, data can be difficult to interpret as the genetics of pet rats are usually unknown. Unique Features
The rat thyroid gland lies ventrolateral to the first 4 to 5 tracheal rings, just caudal to the larynx.24 In laboratory studies, male rats have higher circulating levels of throxine11 and TSH than female rats. Castration has been found to decrease TSH and response to TRH injection.2 T3 and T4 levels in rats decline with advancing age.13 Rats have been found to have euthyroid sick syndrome11; therefore, concurrent disease will affect thyroid hormone interpretation. Neoplasia
Spontaneously occurring thyroid gland tumors, usually benign, are commonly found during necropsies of large colonies of laboratory rats. Clinical signs from these tumors are uncommon.25–27 The incidence of these tumors varies greatly with genetics. One study found that most follicular adenomas were unilateral, with distinct foci of neoplastic tissue.28 Parafollicular C-cell adenomas and C-cell hyperplasia are also common in rats.26,27,29–31 Malignant tumors (follicular adenocarcinomas and C-cell carcinomas) have also been discussed in rats.25,26,31 Dietary goitrogens or prolonged iodine deficiency may promote thyroid tumors30; therefore, a diet history is important when a thyroid enlargement is suspected. Clinical signs
Thyroid tumors in rats are usually asymptomatic and not detectable on physical examination.30 Differential diagnoses
Other possible diagnoses for a palpable cervical swelling include insufficient iodine intake, enlarged lymph nodes, mandibular salivary gland neoplasia, abscess, and mammary gland neoplasia.16 Hypothyroidism
Naturally occurring hypothyroidism is uncommon in rats. Hypothyroidism has been found to cause polyuria as a result of impaired renal concentrating abilities, as well as decreased serum sodium concentrations.32 In addition, although nonregenerative anemia can be seen with hypothyroidism in other species, there is not a clear link seen in rats.33 In a study of experimentally induced hypothyroidism, rats were found to develop decreased appetite, weight loss, lethargy, and piloerection. Decreases in heart rate, blood pressure, and body temperature were also noted.34 On histopathology, myocardial segmental degeneration was found, showing a rapid alteration in cardiac function with hypothyroidism. Although hypothyroidism is traditionally thought to cause weight gain, the authors theorized that the weight loss may be related to the sudden decrease in thyroid hormones due to the hypothyroidism being experimentally induced. However, the authors did note that decreased appetite and failure to gain weight rapidly
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have been seen in other hypothyroid rats. Experimental hypothyroidism in rats is reversible with L-thyroxine supplementation.34,35 Although the clinical signs and changes in parameters were seen rapidly in this study (within 2 weeks), they are likely to have a slower onset in natural hypothyroidism as the decrease in thyroid hormones is likely slower. The information above may mimic the more acute drop in thyroid hormones that can occur with oversupplementation of methimazole, too high a dose of 131I, or if the entire thyroid gland needs to be removed due to neoplasia. Hyperthyroidism
Experimentally induced hyperthyroidism in rats has been found to cause weight loss, despite increased food intake,35 and to increase spontaneous physical activity.36 Euthyroid status has been successfully restored in laboratory rats using methimazole.37 MICE (MUS MUSCULUS)
A reported reference interval for TT4 in mice is 4 - 7 mg/dL and TT3 is 65 - 140 ng/dL.8 The thyroid gland in mice generally extends from the larynx along the first 3 to 4 tracheal rings. In adult mice, the gland is approximately 2 mm long, 1 mm wide, and 0.5 mm deep. Due to its small size, a significant enlargement would have to occur before it could be detected on palpation.1 Aging Changes
When evaluating aging changes in mice, it has been found that elderly mice are prone to immune dysfunction leading to amyloid deposition in multiple organs, including the thyroid gland. Long-term corticosteroid use can decrease this deposition.38 In addition, elderly mice have a decreased ability to bind iodine, causing the gland to increase in size and weight via hyperplasia. Decreased levels of circulating T3 and T4 and thyroid hyperplasia have also been reported in aging mice.38 Neoplasia
Spontaneously occurring follicular cell adenomas have been reported.25,29,30,39 HAMSTER (MESOCREICETIS AURATUS)
The thyroid gland in the hamster sits at the level of the first tracheal cartilage.40 A reported reference interval for TT4 in hamsters is 3 - 7 mg/dL and for TT3 is 30 - 80 ng/dL.8 Thyroid hormone production in hamsters is affected by age, pregnancy, as well as several external factors, including hibernation status and temperature.9 Chronic exposure to decreased photoperiods and temperatures, consistent with hibernation or the shortened length of days in winter, leads to a decrease in levels of TSH, T3, and T4. This change has been found when hamsters are exposed to less than 12.5 hours of daylight, as well as in blind animals. Aging leads to decreased levels of T3 and T4 and TSH response.41–44 Pregnancy may also alter thyroid metabolism due to decreased protein-bound iodine.9 These factors should be taken into account when interpreting thyroid hormone results. Neoplasia
Thyroid gland tumors in hamsters are one of the most commonly seen tumors in this species.45 Most of these tumors are benign and are usually not found on gross examination. One study of laboratory hamsters reported an incidence between 1.5% and
Thyroid Diseases in Rodent Species
2.6%.45 Another study of spontaneous endocrine tumors in 2 groups of laboratory hamsters found carcinomas in approximately 1% of each group, and adenomas in approximately 7% of one group and 5.5% of the other.46 Most of these neoplasms were not visible grossly. As with rats, iodine deficiency may contribute to the development of benign follicular thyroid adenomas.47 Thyroidectomy has been described but has a poor postsurgical survival rate.48 Hypothyroidism
Hypothyroidism has been anecdotally reported in hamsters.27,30 Clinical signs include alopecia, hyperpigmentation of the skin, lethargy, cold intolerance, and skin thickening. Hamsters treated with thyroxine showed an improvement in clinical signs. A differential for the alopecia is Cushing disease, which occurs more frequently in hamsters than hypothyroidism.30 Perifollicular Amyloidosis
One report cited 64% of perifollicular amyloidosis in aging hamsters. Other changes include cysts and reduced colloid.41 GERBIL (MERIONES UNGUICULATUS)
Information on thyroid disease in gerbils is extremely limited. There is one case report of a thyroid follicular adenoma in a laboratory gerbil, although the animal was not noted to show clinical signs as a result of the tumor.49 CHINCHILLA (CHINCHILLA LANIGERA)
A reported reference interval for TT4 in chinchillas is 3.4–6.4 mg/dL.50 Hyperthyroidism
A single case of hyperthyroidism has been reported in the chinchilla.51 The chinchilla presented with a history of weight loss. On physical examination the patient was underweight and had focal, scaly alopecia on one forelimb. Elevated TT4 was repeatable. Other abnormalities found were hyperglycemia and glucosuria, despite a low fructosamine, and elevated aspartate aminotransferase. These abnormalities were ultimately attributed to the hyperthyroidism. The animal was treated with methimazole and showed improvement in clinical signs. A thyroid nodule was not able to be detected on physical examination or ultrasonic evaluation. As with guinea pigs, there are no studies on treatment of hyperthyroidism in chinchillas. Therefore, treatment is extrapolated from feline medicine. Treatment options are similar to guinea pigs and include oral medications, 131I, and thyroidectomy.50,51 A possible sequela to hyperthyroidism is cardiomyopathy.23 A study in 1973 comparing fur-chewing chinchillas to normal chinchillas revealed that the fur-chewing group had increased thyroid activity than the normal group.52 The animals did not show weight loss or any other clinical signs of hyperthyroidism. Further studies are needed to determine if elevated thyroid levels led to the furchewing, or if fur-chewing led to the elevated thyroid levels. One theory is that fur-chewing chinchillas have less insulation and need increased thermogenesis to maintain body temperature, leading to an increase in thyroid hormones.52,53 Thyroidectomy
Thyroidectomy is difficult in chinchillas due to the size and location of the gland. In addition, the parathyroid glands are challenging to separate from the thyroid gland.
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For these reasons, the patient may need lifelong calcium gluconate supplementation. Regrowth of the thyroid tissue has been reported in over half of one group of chinchillas, indicating that recurrence of the hyperthyroidism is highly possible.50 SUMMARY
Although there is limited information on spontaneous thyroid disease in rodent medicine, documented cases indicate that rodents do develop thyroid diseases similar to dogs and cats. Hyperthyroidism has been reported in guinea pigs, and one case of a chinchilla, and many of the same methods used for diagnosing and treating feline hyperthyroidism are also effective in these species. In addition, experimentally induced hyperthyroidism in rats has also proven to have similar clinical signs and successful responsiveness to methimazole. Hypothyroidism has been reported in guinea pigs and hamsters, and although uncommon, the diseases follow patterns similar to canine hypothyroidism. For guinea pigs, hamsters, and laboratory rats, treatment with levothyroxine has been successful at restoring euthyroid status. Although thyroid neoplasia has been reported in many rodent species, it is often an incidental finding. Further research is needed to determine the incidence of thyroid disease in rodents, establish reference intervals for thyroid testing, and determine the best dosing for treatment. REFERENCES
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46. Pour P, Mohr U, Althoff J, et al. Spontaneous tumors and common disease in two colonies of Syrian hamsters. III. Urogenital system and endocrine glands. J Natl Cancer Inst 1976;56:949–61. 47. Harkness JE, Turner PV, VandeWoude S, et al. Specific diseases and conditions. In: Harkness JE, Turner PV, VandeWoude S, et al, editors. Biology and medicine of rabbits and rodents. 5th edition. Ames (IA): Wiley-Blackwell; 2010. p. 249–396. 48. Johnson-Delaney CA. Endocrine system and diseases of exotic companion mammals. In: ABVP 2009 proceedings. Available at: http://www.vin.com/members/ proceedings/proceedings.plx?CID5ABVP2009&PID526736&O5VIN&id5 3944802. Accessed July 7, 2013. 49. Shumaker RC, Paik SK, Houser WD. Tumors in gerbillinae: a literature review and report of a case. Lab Anim Sci 1974;24:688–90. 50. Martin LB, Chidambaram RM, Schroeder KE, et al. Thyroparathyroidectomy procedures and thyroxine levels in the chinchilla. Contemp Top Lab Anim Sci 2005; 44:9–14. 51. Fritsche R, Simova-Curd S, Clauss M, et al. Hyperthyroidism in connection with suspected diabetes mellitus in a chinchilla (chinchilla laniger). Vet Rec 2008; 163:454–6. 52. Vankonack WJ, Johnson HD. Relationship of thyroid and adrenal function to “furchewing” in the chinchilla”. Comp Biochem Physiol A Comp Physiol 1973;45A: 115–20. 53. Norton JN, Reynolds RP. Diseases and veterinary care. In: Suckow MA, Stevens KA, Wilson RP, editors. The laboratory rabbit, guinea pig, hamster, and other rodents. Amsterdam (United Kingdom): Elsevier Academic Press; 2012. p. 993–1008.
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