Diseases of the Thyroid Gland

Anatomy

The thyroid glands are paired lobular glands lying adjacent to the tracheal rings, connected by an isthmus in the dog but independent in the cat. The normal size of each thyroid gland in the dog is approximately 2 cm x 1 cm x 0.5 cm and approximately 2 cm x 0.5 cm x 0.3 cm in the cat [1,2]. The blood supply varies slightly between the two species. The blood supply in the dog is derived from the cranial and caudal thyroid artery; the cat thyroid lobes are supplied solely from the cranial thyroid artery. Venous drainage is via the cranial and caudal thyroid veins. Efferent lymphatic drainage in the dog is into the cervical lymphatic trunk or internal jugular vein [2]. Ectopic thyroid tissue can be present anywhere along the cervical region to the base of the heart [1].

Thyroid Hormone Metabolism

The thyroid gland regulates basal metabolism. Two molecules, tyrosine and iodine, are important for thyroid hormone synthesis. Tyrosine is a part of a large molecule (MW 660,000) called thyroglobulin, which is formed within the follicle cell and secreted into the lumen of the follicle. Iodine is converted to iodide in the intestinal tract and transported to the thyroid where the follicle cells trap the iodide through an active transport process. The tyrosyl ring can accommodate two iodide molecules: if one iodide attaches, it is called monoiodotyrosine (MIT), if two iodide molecules attach to the tyrosyl ring, it is called diiodotyrosine (DIT). The coupling of two iodinated tyrosines results in the formation of the main thyroid hormones. Two DIT molecules form tetraiodothyronine (T4), whereas one MIT coupled with one DIT molecule forms triiodothyronine (T3). Thyrotropin, or thyroid stimulating hormone (TSH), is the most important regulator of thyroid activity. TSH secretion is regulated by thyroid hormones by way of negative feedback inhibition of the synthesis of thyrotropin releasing hormone (TRH) at the level of the hypothalamus and by inhibition of the activity of TSH at the level of the pituitary.

Thyroxine (T4) is the major storage form of thyroid hormone, whereas T3 is the active form of the hormone. The majority of T3 formation occurs outside of the thyroid gland by the deiodination of T4. Another type of T3 is formed when an iodide molecule is removed from the inner phenolic ring of T4. This compound is called reverse T3 and has few of the biologic effects of thyroid hormones. Reverse T3 increases in non-thyroidal illness and is responsible for the decrease in total serum T4 (T T4) seen in "euthyroid sick" syndrome. As for all lipid soluble hormones that are transported in plasma, T3 and T4 are bound to plasma proteins. The amount of thyroid hormone that is free in plasma is remarkably low, e.g., in dogs, the amount of free hormone is a little less than 1.0% for T4 and slightly greater than 1.0% for T3 [2-4].

Canine and Feline Hypothyroidism

Primary canine hypothyroidism is the most common cause of naturally occurring hypothyroidism, accounting for more than 95% of all cases [3]. The two histologic forms are lymphocytic thyroiditis or idiopathic thyroid atrophy. Congenital hypothyroidism may be caused by thyroid dysgenesis, dyshormonogenesis, T4 transport defects, and goitrogens, or rarely, by iodine deficiency. Secondary hypothyroidism may be acquired, as in German shepherd dogs with cystic Rathke’s pouch, or secondary to pituitary tumors, radiation therapy, or endogenous or exogenous glucocorticoids [2,5]. Congenital causes of secondary hypothyroidism include hereditary TSH deficiency as observed in the giant schnauzer breed. Tertiary hypothyroidism can be acquired, for example, with hypothalamic tumors, or can be congenital as a result of defective TRH or TRH receptor defects [5].

Feline hypothyroidism is generally iatrogenic, occurring after surgical or radioactive iodine treatment. This condition is usually transient, resolving when ectopic thyroid tissue resumes production of normal thyroid hormone concentrations [6].

The signalment of hypothyroid dogs carries a distinct breed predisposition, with high-risk breeds presenting as early as 2 to 3 years of age and low-risk breeds presenting at a slightly older age (4 to 6 years). Breeds predisposed to hypothyroidism include golden retrievers, Doberman pinschers, and dachshunds [7].

Clinical Signs

Clinical signs of hypothyroidism are gradual and subtle in onset, with lethargy and obesity being most common. Owners are often not aware of the onset of signs and think that their dog is just becoming "older". Dermatologic evidence of hypothyroidism is the most common clinical finding after lethargy and obesity. Symmetric truncal or tail head alopecia is a classic finding in hypothyroid dogs. The skin is often thickened because of myxedematous accumulations in the dermis [5,7].

Cardiovascular signs of hypothyroidism, including bradycardia, decreased cardiac contractility, and electrocardiographic abnormalities, are rare presenting complaints [3]. Neuromuscular signs such as myopathies and megaesophagus are also uncommon manifestations of canine hypothyroidism. Neuropathies including bilateral or unilateral facial nerve paralysis, vestibular disease, and lower motor neuron disorders are occasionally seen in hypothyroid dogs. Myxedema coma is an unusual finding in hypothyroid dogs and manifests as stupor and coma secondary to myxedematous fluid accumulations in the brain and severe hyponatremia [4,5,7].

Diagnosis

The clinicopathologic finding of a normocytic normochromic anemia resulting from erythropoietin deficiency, decreased bone marrow activity, and decreased serum iron and iron binding capacity may be seen in many hypothyroid dogs. Even more commonly seen is hypercholesterolemia, seen in approximately 75% of hypothyroid dogs, owing to altered lipid metabolism, decreased fecal excretion of cholesterol and decreased conversion of lipids to bile acids [3]. Other findings include hyperlipidemia, presence of target cells, and rare mild hypercalcemia in cases of congenital hypothyroidism [3].

Diagnosis is based on measurement of serum basal total thyroxine (T4) and triiodothyronine (T3) concentrations, serum free T4 and T3 concentrations, endogenous canine serum TSH levels, and/or dynamic thyroid function tests including the TRH and TSH stimulation tests. Variables that affect T4 are many and include age, breed, environmental and body temperature, diurnal rhythm, obesity, and malnutrition. Euthyroid-sick syndrome is characterized by a decrease in serum T T4 and increase in reverse T3 (see above). Concurrent illnesses such as diabetes mellitus, chronic renal failure (CRF), hepatic insufficiency, and infections can cause euthyroid-sick syndrome, resulting in decreases in serum T T4 concentrations. Drugs such as anesthetics, phenobarbital, primidone, diazepam, trimethoprim-sulfas, quinidine, phenylbutazone, salicylates, and glucocorticoids can also decrease serum basal T T4 concentrations [3,5,7].

Free thyroid (FT) hormone concentrations, or unbound thyroxine and triiodothyronine, are used in human medicine to differentiate between euthyroid sick syndrome and true hypothyroidism. In humans, the diagnostic accuracy of a single FT4 measurement is approximately 90% [8]. Measurement of FT4 concentrations is achieved by equilibrium dialysis (gold standard) or analogue immunoassays. Theoretically, FT4 is not subject to spontaneous or drug-induced changes that occur with T T4. Early studies, classifying dogs as hypothyroid based on TSH-stimulation tests, indicated that FT4 by equilibrium dialysis was 90% accurate whereas other FT4assays (analogue assays) were no better than T T4 [8].

With the advent of the endogenous canine TSH assay, veterinarians now have a method of assessing the thyroid-pituitary axis in dogs without dynamic testing. With thyroid gland failure, decreases in serum FT4 and T T4 are sensed by the pituitary gland, resulting in an increase in serum endogenous TSH concentration. As FT4 concentration falls, a logarithmic increase occurs in serum endogenous TSH concentration making it the most sensitive test for the detection of early hypothyroidism. However, nonthyroidal disease can affect endogenous TSH concentrations as well as FT4 and T T4 concentrations; therefore, the use of endogenous TSH alone is not recommended as a method of assessing thyroid function [8,9].

Feline Hyperthyroidism

Hyperthyroidism is the most common endocrinopathy of cats. Middle-aged to older cats are typically affected, and no breed or sex predilection exists. Hyperthyroidism is characterized by hypermetabolism; therefore, polyphagia, weight loss, polydipsia, and polyuria are the most prominent features of the disease [6]. Activation of the sympathetic nervous system is also seen with hyperactivity, tachycardia, pupillary dilatation, and behavioral changes. Long-standing hyperthyroidism leads to hypertrophic cardiomyopathy, high-output heart failure, and cachexia, which may lead to death [2,6].

Diagnosis

Clinicopathologic features of hyperthyroidism include erythrocytosis and an excitement leukogram (neutrophilia, lymphocytosis) caused by increased circulating catecholamine concentrations. Increased catabolism of muscle tissue in hyperthyroid cats may result in increased BUN, but not creatinine [10]. Increased metabolic rate results in liver hypermetabolism; therefore, serum activities of liver enzymes increase (ALT, AST) in 80% to 90% of hyperthyroid cats. Serum cholesterol decreases, not as a result of decreased synthesis, but rather as a result of increased hepatic clearance mediated by thyroid hormone excess [6,10,11].

Diagnosis of feline hyperthyroidism is achieved by measurement of total serum concentrations of thyroxine (T T4); total serum triiodothyronine (T T3) is generally non contributory to a diagnosis [10,11]. Because the disease has become more common and recognized in its early stages, serum free-thyroxine concentrations (FT4) have recently been shown to be more diagnostic of early or "occult" hyperthyroidism [8]. Diagnosis may be challenging in cats with occult hyperthyroidism that demonstrate clinical signs suggestive of hyperthyroidism (polyphagia, polyuria, polydipsia, weight loss, goiter) but who have normal (usually high-normal) T T4 concentrations. In cases of suspected occult hyperthyroidism, dynamic endocrine testing using the T3-suppression test or the TRH-stimulation test may be beneficial [10,12,13,14].

Treatment Options

Options for treatment of feline hyperthyroidism include oral supplementation, radioactive iodine treatment, or surgical thyroidectomy. Radioactive iodine (131I) is the optimal therapy for feline hyperthyroidism. It is safe and effective with minimal side effects or complications. Approximately 80% of cats become euthyroid within 3 months after a single treatment. Radiation safety procedures must be strictly followed [15-17]. Oral methimazole is given by supplementation daily and may be associated with side effects including anorexia, vomiting, pruritus, and uncommonly, more serious effects such as thrombocytopenia and agranulocytosis [18]. Surgical excision is a potentially definitive treatment. Patients may be high-risk candidates for anesthesia; when possible, euthyroid status is achieved prior to treatment with oral methimazole.

Surgical Techniques

Surgery is performed via a ventral midline cervical approach, and the thyroid glands are excised via an intracapsular, modified intracapsular, extracapsular, or modified extracapsular technique. A modified extracapsular approach has been associated with the lowest number of hypocalcemia-related complications. The patient should be monitored carefully after surgery for complications including hypocalcemia, hypothyroidism, and laryngeal paralysis [2,19]. Hyperthyroidism can reoccur if inadequate excision was performed or if hypertrophy of ectopic thyroid tissue exists. Recurrent disease may be treated with re-exploratory surgery, medication, or ideally, 131I therapy [15].

Thyroid Neoplasia

Whereas benign adenomatous changes of the thyroid gland are most common in cats, a larger percentage of dogs have malignant disease. Although carcinoma in cats is often associated with clinical signs of hyperthyroidism, dogs have typically nonfunctional tumors [2,4]. In feline patients, treatment of thyroid carcinoma involves a combination of surgical and radioiodine therapy. Although complete excision may be curative for nonmetastatic disease, the rate of metastasis may be as high as 71% [20].

Canine thyroid carcinoma is typically more aggressive than feline thyroid carcinoma. Of canine tumors, 90% are malignant; they are only rarely functional and associated with clinical signs associated with hyperthyroidism [4,21]. Dogs may present asymptomatically or with a palpable mass in the cervical region. Definitive diagnosis is based on histologic evaluation. Owing to the highly vascular nature of the tumor, coagulation parameters should be assessed prior to biopsy and open, rather than needle, biopsy is recommended. Ultrasound, nuclear scintigraphy, and CT scan have all been evaluated to better delineate the extent of tumor invasion [22-24]. Surgical resection of the tumors has been associated with the best response if the mass is freely moveable, small in size, nonmetastatic, and completely resected [25]. Radiation or chemotherapy may be elected to treat masses that are incompletely resected or not amenable to resection [26]. Surgical complications include hemorrhage, damage to regional structures including the recurrent laryngeal nerve, as well as postoperative hypocalcemia or, rarely, hypothyroidism [2,4,21,25]. Long-term survival may be achieved in dogs depending on the histologic features of the tumor and whether early diagnosis is made before local invasion or metastatic spread of the disease [21].