THYROID HORMONE SYNTHESIS.

The basic functional unit of the thyroid gland is the follicle, a hollow sphere of cells surrounded by a basement membrane (Fig. 3-1). The wall of the follicle is a single layer of thyroid cells, which are cuboidal when quiescent and columnar when active. The follicular lumen contains colloid, a viscous gel that is primarily a store of thyroglobulin secreted by the thyroid cells. Thyroglobulin is a large glycoprotein dimer containing iodotyrosines that serve as precursors for thyroid hormone synthesis.

FIGURE 3-1 A and B, Histologic section of a thyroid gland from a healthy dog, illustrating variable-sized follicles, each lined by follicular epithelial cells and filled with an amorphous material, colloid. (A, H&E ×40; B, H&E ×160)

Adequate ingestion of iodide is a prerequisite for the normal synthesis of thyroid hormones by the thyroid. Iodide is actively transported from the extracellular fluid into the thyroid follicular cell, where it is rapidly oxidized by thyroid peroxidase into a reactive intermediate that is then incorporated into the tyrosine residues of acceptor proteins, primarily thyroglobulin (Greenspan, 2001). Iodinated tyrosine residues (monoiodotyrosine [MIT], diiodotyrosine [DIT]) in thyroglobulin combine to form iodothyronines—thyroxine and triiodothyronine (Fig. 3-2).

FIGURE 3-2 Structure of the thyroid hormones and their precursors.

Thyroglobulin is stored extracellularly in the follicular lumen. As a prerequisite for thyroid hormone secretion into the blood, thyroglobulin must first reenter the thyroid cell and undergo proteolysis. Pseudopods from the apical cell surface extend into the colloid in the follicular lumen, and large colloid droplets enter the cytoplasm by endocytosis (Greenspan, 2001). Each colloid droplet is enclosed in a membrane derived from the apical cell border. Electron-dense lysosomes then fuse with the colloid droplets to produce phagolysosomes. These phagolysosomes migrate toward the basal aspect of the cell, during which time lysosomal proteases hydrolyze thyroglobulin. Thyroxine and, to a much lesser degree, triiodothyronine liberated from thyroglobulin by the proteolytic process pass from the phagolysosome into the blood, possibly by diffusion. Most of the liberated iodotyrosines (MIT, DIT) are deiodinated, thus releasing iodide, which can be reused for thyroglobulin iodination or can diffuse out into the circulation. A small quantity of intact thyroglobulin also enters the circulation. This leakage can be increased when the thyroid cells are damaged, such as occurs with lymphocytic thyroiditis.

REGULATION OF THYROID FUNCTION.

Thyroid hormone synthesis and secretion are regulated by extrathyroidal (thyrotropin) and intrathyroidal (autoregulatory) mechanisms. Thyrotropin (TSH) is the major modulator of thyroid activity, the net result of which is increased thyroid hormone secretion (Fig. 3-3). TSH secretion by the pituitary is modulated by thyroid hormone in a negative feedback regulatory mechanism. At the pituitary, it is primarily 3,5,3’-triiodothyronine (T₃), produced locally by the monodeiodination of thyroxine (T₄), that inhibits TSH secretion (Greenspan, 2001). The “thermostat” setting of the thyroid hormone–TSH feedback loop is modulated by thyrotropin-releasing hormone (TRH) from the hypothalamus. Hypothalamic production and release of TRH are controlled by poorly understood neural pathways from higher brain centers.

FIGURE 3-3 Schematic of the hypothalamic-pituitary-thyroid axis. TRH, Thyrotropin-releasing hormone; TSH, thyrotropin; T₄, thyroxine; T₃, 3,5,3’-triiodothyronine; rT₃, reverse 3,3’,5’-triiodothyronine; +, stimulation; –, inhibition.

The thyroid is able to regulate its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms independent of TSH. Examples of autoregulatory mechanisms include the Wolff-Chaikoff block (decrease in thyroglobulin iodination and thyroid hormone synthesis with increasing iodide intake), intrathyroidal alterations in thyroid sensitivity to TSH stimulation, and increased ratio of T₃ to T₄ secretion by the thyroid during periods of iodide insufficiency.

THYROID HORMONES IN PLASMA.

Thyroid hormones in plasma are largely bound to protein, most notably thyroid hormone–binding globulin (TBG), thyroxine-binding prealbumin (TBPA), albumin, and certain plasma lipoproteins. Less than 1% of T₄ and T₃ circulate “free” in the unbound state. Free or unbound thyroid hormones enter cells, produce their biologic effects, and are in turn metabolized. Only the free hormone regulates the pituitary feedback mechanism. Protein-bound thyroid hormones serve as a large reservoir that is slowly drawn upon as the free hormone dissociates from the binding proteins and enters the cells. Thyroid hormone secretion is precisely regulated to replenish the metabolized thyroid hormones.

THYROID HORMONE METABOLISM.

Thyroxine is the major secretory product of the normal thyroid. The major pathway of T₄ metabolism is the progressive deiodination of the molecule. The initial deiodination of T₄ may occur in the outer ring, producing T₃, or in the inner ring, producing reverse T₃ (rT₃; Fig. 3-2). Because conversion of T₄ to T₃ represents a “step up” in biologic activity, whereas conversion of T₄ to rT₃ has the opposite effect, the conversion of T₄ to T₃ or rT₃ by outer or inner ring iodothyronine deiodinase is a pivotal regulatory step in determining thyroid hormone biologic activity. Less than 20% of total T₃ is produced in the thyroid, and the remaining 80% to 90% is derived from outer ring monodeiodination of T₄ in peripheral tissues. The tissues that concentrate the most thyroid hormone are liver, kidney, and muscle (Greenspan, 2001). Conjugation of thyroid hormone to soluble glucuronides and sulfates with subsequent excretion in the bile and urine represents another major metabolic pathway for thyroid hormone.

THYROID HORMONE ACTIONS.

The thyroid hormones affect many metabolic processes, influencing the concentration and activity of numerous enzymes; the metabolism of substrates, vitamins, and minerals; the secretion and degradation rates of virtually all other hormones; and the response of their target tissues to them. Thyroid hormones are critically important in fetal development, particularly of the neural and skeletal systems. Thyroid hormones stimulate calorigenesis, protein and enzyme synthesis, and virtually all aspects of carbohydrate and lipid metabolism, including synthesis, mobilization, and degradation (Larsen et al, 1998). Furthermore, thyroid hormones have marked chronotropic and inotropic effects on the heart; are necessary for normal hypoxic and hypercapnic drive to the respiratory centers; stimulate erythropoiesis; and stimulate bone turnover, increasing both formation and resorption of bone (Greenspan, 2001). In essence, no tissue or organ system escapes the adverse effects of thyroid hormone excess or insufficiency.

LYMPHOCYTIC THYROIDITIS.

Lymphocytic thyroiditis is characterized histologically by a diffuse infiltration of lymphocytes, plasma cells, and macrophages within the thyroid gland, resulting in progressive destruction of follicles and secondary fibrosis (Gosselin et al, 1981a; Fig. 3-4). Neutrophils are usually not abundant and, when present, are associated with necrotic areas of the thyroid gland. Destruction of the thyroid gland is progressive, and clinical signs may not become evident until more than 75% of the gland is destroyed. Based on experiences following dogs with positive thyroglobulin autoantibody test results (see page 124), the onset of clinical signs and development of decreased serum thyroid hormone and increased serum TSH concentrations is usually a gradual process, often requiring 1 to 3 years to develop, suggesting that the destructive process is slow (Nachreiner et al, 2002). Graham et al (2001a) have proposed several stages in the development of lymphocytic thyroiditis in dogs, beginning with a subclinical stage characterized by positive thyroglobulin and thyroid hormone autoantibody tests and minimal inflammation in the thyroid gland through progressively worsening inflammation and destruction of the thyroid gland and the eventual development of increased serum TSH and decreased serum thyroid hormone concentrations (Table 3-2). The terminal stages of destruction are characterized by few follicles and extensive adipose connective tissue replacement of atrophied parenchymal structures, with residual infiltrates of lymphocytes and plasma cells interspersed with nests of parafollicular cells and a few small follicles containing degenerating follicular cells and poorly staining colloid (Conaway et al, 1985b). Analysis of age distributions of dogs with laboratory test results (i.e., thyroglobulin antibody, T₄, and TSH) consistent with the different stages or classifications of lymphocytic thyroiditis suggest that the age of peak prevalence progresses by 1 to 2 years through each of the classifications (Graham et al, 2001a). Studies also suggest that differences in progression rate or likelihood of progression may exist for different breeds of dogs.

FIGURE 3-4 A and B, Histologic section of a thyroid gland from a dog with lymphocytic thyroiditis and hypothyroidism. Note the mononuclear cell infiltration, disruption of the normal architecture, and loss of colloid-containing follicles. (A, H&E ×63; B, H&E ×250)

TABLE 3-2 PROPOSED FUNCTIONAL STAGES OF LYMPHOCYTIC THYROIDITIS IN DOGS

Lymphocytic thyroiditis is an immune-mediated disorder. Involvement of humoral immune mechanisms is supported by these findings: increased incidence of circulating autoantibodies to thyroid antigens, including thyroglobulin, T₄, and T₃; identification by electron microscopy of thickened basement membranes containing electron-dense deposits, which are believed to be antigen-antibody complexes, in thyroid follicles; and the induction of lesions similar to lymphocytic thyroiditis in dogs following the intrathyroidal injection of thyroglobulin antibodies (Gosselin et al, 1980; 1981a; 1981b; 1981c; Gaschen et al, 1993). Antibody binding to the follicular cell, colloid, or thyroglobulin antigens is believed to activate the complement cascade, antibody-dependent cell-mediated cytotoxicity, or both, causing follicular cell destruction. Identifiable thyroid antigens include the following: thyroglobulin, which is the main antigen in colloid and has the strongest correlation with the presence of lymphocytic thyroiditis; colloidal antigen (CA-2), a nonthyroglobulin, noniodine component of colloid; microsomal antigen and antinuclear substance antigen, located within the follicular cells; and cell-surface antigen (Gosselin et al, 1980; Vajner, 1997).

The cell-mediated immune system may also play an important, possibly primary, role in the development and perpetuation of lymphocytic thyroiditis. A defect in suppressor T cell function is suspected in this disorder. This would allow effector T lymphocytes to attack follicular cells and allow helper T cells to induce plasma cell differentiation, with subsequent production of thyroid antibodies (Strakosch et al, 1982).

The initiating factors involved in the development of lymphocytic thyroiditis are poorly understood. Genetics undoubtedly plays a major role, especially given the increased incidence of this disorder in certain breeds and in certain lines within a breed (see page 96). Lymphocytic thyroiditis is an inherited disorder in colony-raised Beagles, with a polygenic mode of inheritance, and was identified as an autosomal-recessive trait in a family of Borzoi dogs (Conaway et al, 1985a). An increased frequency of circulating thyroid hormone autoantibodies has also been found in certain breeds (Table 3-3; Nachreiner et al, 2002). Environmental risk factors have not been well defined in the dog. A link between infection and development of lymphocytic thyroiditis has been speculated but not proved (Penhale and Young, 1988). Infection-induced damage to the thyroid gland, causing release of antigens into the circulation and their subsequent exposure to the host’s immune system, or antigenic mimicry of thyroid antigens by viral or bacterial agents could initiate the immune-mediated inflammatory process. Vaccine administration has also been hypothesized to be a contributing factor for development of lymphocytic thyroiditis (Smith, 1995; Allbritton, 1996). A recent study documented a significant increase in antibovine and anticanine thyroglobulin antibodies in research Beagles after repeated vaccinations beginning at 8 weeks of age (Scott-Moncrieff et al, 2002). A significant increase in anticanine thyroglobulin antibodies was also documented in adult pet dogs 2 weeks after vaccination. The clinical importance of this finding as it relates to development of lymphocytic thyroiditis is unknown. The study did not determine how long the thyroglobulin antibodies persisted, although antibody levels had decreased to prevaccination values by the time of the next vaccination in most research dogs. None of the dogs in the study, with the exception of three dogs believed to have developed spontaneous thyroiditis, developed evidence of thyroid dysfunction by 4.5 years of age. The authors speculated that the antithyroglobulin antibodies detected in their study was the result of contamination of the vaccine by bovine thyroglobulin. There is considerable sequence homology for thyroglobulin between species, and antibodies to thyroglobulin have some species cross-reactivity (Tomer, 1997).

TABLE 3-3 DOG BREEDS REPORTED TO HAVE AN INCREASED PREVALENCE OF THYROID HORMONE AUTOANTIBODIES

* Odds of having serum thyroid hormone autoantibodies (THAA) among breeds with an increased risk of having THAA, compared with dogs of all other breeds.

LYMPHOCYTIC THYROIDITIS AND IMMUNOENDOCRINOPATHY SYNDROMES (POLYGLANDULAR AUTOIMMUNE SYNDROMES).

Because autoimmune mechanisms play an important role in the pathogenesis of lymphocytic thyroiditis, it is not surprising that lymphocytic thyroiditis may occur with other immune-mediated endocrine deficiency syndromes. In humans, two polyglandular autoimmune syndromes, type I and type II, predominate (Table 3-4). Polyglandular autoimmune syndrome type II (Schmidt’s syndrome) is the most common of the immunoendocrinopathy syndromes in humans and is usually defined by the occurrence of primary adrenal insufficiency in combination with autoimmune thyroid disease, insulin-dependent diabetes mellitus, or both (Neufeld et al, 1981). Combinations of endocrine deficiency disorders (e.g., hypothyroidism and diabetes mellitus; Addison’s disease and hypothyroidism) have been documented in dogs (Hargis et al, 1981; Haines and Penhale, 1985; Bowen et al, 1986; Ford et al, 1993; Kooistra et al, 1995; Greco, 2000), although occurrence is uncommon (Table 3-5). In a retrospective study of 225 dogs with hypoadrenocorticism, 4% of the dogs also had hypothyroidism, 0.5% had concurrent diabetes mellitus, and one dog had concurrent hypothyroidism, diabetes mellitus, and hypoparathyroidism (Peterson et al, 1996).

TABLE 3-4 COMPONENT DISORDERS OF TYPE I AND TYPE II POLYENDOCRINE AUTOIMMUNE SYNDROMES

TABLE 3-5 NUMBER OF DOGS WITH VARIOUS ENDOCRINE DEFICIENCY SYNDROMES, SINGLY AND IN COMBINATIONS, SEEN AT OUR HOSPITAL BETWEEN 1990 AND 1994

The initial lesion and precipitating events that result in these syndromes are unknown in dogs. Genetic predisposition to polyglandular autoimmune syndromes has been confirmed in humans (Eisenbarth and Jackson, 1992) and may play a role in the dog as well. Type II polyglandular autoimmune syndrome is the most common form in humans and is inherited as an autosomal dominant trait associated with human leukocyte antigens (HLA; Verge, 1998). Lymphocytic and plasmacytic destruction of affected endocrine glands is identified histologically, and circulating organ-specific autoantibodies are commonly present. Environmental factors combined with an HLA-associated genetic predisposition are thought to trigger the destructive process. Both cell-mediated and humoral immunity appear to be involved in the destruction of target tissues. The most consistent abnormality is a functional defect leading to decreased suppressor T cell immunity. Lymphocytic and plasmacytic destruction of endocrine glands (e.g., lymphocytic thyroiditis, lymphocytic insulitis, lymphocytic adrenalitis) and circulating organ-specific autoantibodies (e.g., thyroglobulin autoantibodies, anti-islet cell antibodies, antiadrenal gland antibodies) have been identified in affected dogs (Haines and Penhale, 1985; Kooistra et al, 1995), findings that suggest etiopathogenic mechanisms in dogs similar to those that have been identified in human beings.

Immunoendocrinopathy syndromes should be suspected when multiple endocrine gland failure is identified in a dog. Hypoadrenocorticism, hypothyroidism, and to a lesser extent, diabetes mellitus, hypoparathyroidism, and primary gonadal failure are recognized combined endocrine deficiency syndromes. In most affected dogs, each endocrinopathy is manifested separately, with additional disorders following one by one after variable time periods (usually 3 to 18 months). Diagnosis and treatment are directed at each disorder as it becomes recognized, because it is not possible to reliably predict or prevent any of these problems. Furthermore, the clinician must consider the effects that one endocrine disorder may have on the tests used to diagnose another disorder (e.g., untreated diabetes mellitus suppresses circulating thyroid hormone concentrations) and the effects that treating one endocrine disorder may have on the treatment of concurrent endocrine disorders (e.g., initiation of thyroid supplementation may dramatically improve insulin sensitivity in a diabetic animal). Immunosuppressive drug therapy is not indicated in these syndromes and may actually create problems (e.g., insulin resistance or thyroid suppression with high-dose glucocorticoid therapy).

IDIOPATHIC ATROPHY.

Idiopathic atrophy of the thyroid gland is characterized microscopically by loss of the thyroid parenchyma, which is replaced by adipose tissue (Fig. 3-5). An inflammatory infiltrate is lacking, even in areas in which small follicles or follicular remnants are present (Gosselin et al, 1981b) and tests for lymphocytic thyroiditis are negative. The parathyroid glands are rarely affected, and variable numbers of parafollicular cells remain.

FIGURE 3-5 A and B, Histologic section of a thyroid gland from a dog with idiopathic atrophy of the thyroid gland and hypothyroidism. Note the small size of the gland (compare with C), decrease in follicular size and colloid content, and lack of a cellular infiltration (A, H&E ×40; B, H&E ×250). C, Histologic section of a normal thyroid gland at the same magnification as A. Note the increased size of the gland, the follicles, and the colloid content compared with the gland in A. (H&E ×40)

The cause of idiopathic thyroid atrophy is not known. It has been suggested that idiopathic atrophy is a primary degenerative disorder involving individual follicular cells (Gosselin et al, 1981b). Degeneration of follicular cells is seen histologically early in the lesion, with their subsequent exfoliation into the colloid or the interfollicular spaces. Progressive reduction in the size of the follicles and replacement of the degenerating follicles with adipose tissue occur. This atrophy can be distinguished from the atrophy associated with decreased TSH secretion (i.e., secondary hypothyroidism), in which the follicles are lined by low cuboidal epithelial cells with no indication of degeneration.

Atrophy of the thyroid gland may also represent an end stage of lymphocytic thyroiditis. Evaluation of the morphologic changes involved in lymphocytic thyroiditis in a colony of related Borzoi dogs revealed initial degenerative thyroidal parenchymal changes, which progressed to progressively worsening inflammation, subsequent fibrosis, and an end stage of thyroid gland destruction, which manifested itself as an entity histologically similar to idiopathic follicular atrophy (Conaway et al, 1985b). However, residual inflammation was still evident histologically at the end stage of lymphocytic thyroiditis. In a recent study, the mean age at the time of diagnosis of hypothyroidism was older in dogs with suspected idiopathic atrophy, compared with dogs diagnosed with lymphocytic thyroiditis; a finding that supports the theory that idiopathic atrophy may be an end stage of lymphocytic thyroiditis (Graham et al, 2001a). Results for serum thyroglobulin and thyroid hormone autoantibody tests also progress from positive to negative with time in dogs with lymphocytic thyroiditis, suggesting that the inciting antigens for lymphocytic thyroiditis disappear with time. Although idiopathic atrophy may represent an end-stage form of autoimmune lymphocytic thyroiditis, the inability to demonstrate an inflammatory cell infiltrate, even when follicles are still present, on histopathologic examination of the thyroid gland in dogs diagnosed with idiopathic atrophy suggests that there may be more than one etiology for thyroid atrophy in the dog. Unlike for lymphocytic thyroiditis, there are no blood tests currently available that establish the diagnosis of idiopathic atrophy. Hence the diagnosis tends to be one of exclusion; that is, if the tests for lymphocytic thyroiditis are negative, the dog must have idiopathic atrophy. Until histologic evaluation of several thyroid gland biopsies obtained from the same dog over time has been done in a group of dogs in the early stages of naturally acquired lymphocytic thyroiditis, the relationship between lymphocytic thyroiditis and idiopathic atrophy of the thyroid gland will remain conjectural.

FOLLICULAR CELL HYPERPLASIA.

Histologic evaluation of the thyroid gland in some dogs with hypothyroidism reveals small thyroid follicles that contain minimal amounts of colloid. Follicular cell hyperplasia is present, however. No appreciable inflammation is seen within the gland, and circulating antithyroglobulin antibody has been undetectable in a few dogs studied. The cause of these pathologic changes is not known, although the histologic changes resemble those found with iodine deficiency or in juvenile dogs and cats with defects in thyroid hormone biosynthesis (Chastain et al, 1983; Arnold et al, 1984). Iodine deficiency is extremely unlikely because these dogs have been fed nutritionally balanced, commercial dog foods. One possible explanation is impaired function of the follicular cells (e.g., dyshormonogenesis), resulting in a thyroid-deficient state. Follicular cell hyperplasia may develop secondary to the stimulatory effects of increased TSH secretion in response to thyroid hormone deficiency, assuming appropriate binding of TSH to its receptor occurs. It is interesting to note that ingestion of diets containing an excessive amount of iodine can cause significant impairment of thyroid function and hypothyroidism (Castillo et al, 2001). Excessive iodine intake inhibits iodide uptake and organification and thyroid hormone secretion by thyroid follicular cells, resulting in a compensatory increase in circulating TSH concentrations (Pisarev and Gartner, 2000).

NEOPLASTIC DESTRUCTION.

Clinical signs of hypothyroidism may develop following destruction of more than 75% of the normal thyroid gland by an infiltrative tumor. Tumors may arise from the thyroid gland or from adjacent tissues, which then infiltrate the thyroid gland. Thyroid carcinoma and squamous cell carcinoma are the most common tumors causing extensive destruction of the thyroid gland.

In most dogs, thyroid tumors are hormonally inactive and do not secrete excessive amounts of thyroid hormone. As a result, clinical signs of hyperthyroidism are uncommon. In our hospital, 55% to 60% of dogs with thyroid neoplasia have normal serum thyroid hormone concentrations, 30% to 35% have low serum thyroid hormone concentrations and clinical signs supportive of hypothyroidism, and approximately 10% have increased serum thyroid hormone concentrations and signs supportive of hyperthyroidism (see Chapter 5).

Although most canine thyroid tumors have been considered “nonfunctioning,” they may secrete inactive or altered forms of thyroid hormone. The altered hormone may not cause thyrotoxicosis and may not be detected by standard radioimmunoassay techniques. These products, however, may be capable of suppressing TSH secretion, in which case atrophy of the remaining normal thyroid tissue would result. This process was thought to have occurred in one dog described as having hypothyroidism and a follicular thyroid carcinoma involving only one lobe of the thyroid gland (Branam et al, 1982).

MISCELLANEOUS CAUSES.

Primary hypothyroidism may result from the ingestion of toxic agents or antithyroid medications (e.g., propylthiouracil, methimazole) or following surgical removal of a thyroid tumor. Accessory thyroid tissue is common in dogs and may be found from the base of the tongue to the base of the heart. Therefore surgical removal of the thyroid gland rarely results in permanent hypothyroidism. Use of radioactive iodine (iodine-131) to treat hyperthyroidism may result in total ablation of the thyroid, especially if both thyroid lobes are affected and excessive doses are used (Meric et al, 1986).

SUMMARY.

Although there are several potential causes (see Table 3-1), lymphocytic thyroiditis and idiopathic atrophy account for most of the clinical cases of primary hypothyroidism diagnosed in dogs. Both cause progressive loss of thyroid function as a result of either immune-mediated destruction (lymphocytic thyroiditis) or degeneration (idiopathic atrophy) of the thyroid. The result is a deficiency in thyroid hormone synthesis and secretion and development of clinical signs of hypothyroidism.

PITUITARY MALFORMATION.

Congenital abnormalities involving the pituitary gland have been recognized in many breeds but are reported most commonly in German Shepherd dogs. Cystic Rathke’s pouch or hypoplasia of the anterior pituitary affecting the thyrotropic cells results in impaired secretion of TSH (Eigenmann, 1981; Hamann et al, 1999; Kooistra et al, 2000a). Because of the involvement of other anterior pituitary hormones, most notably growth hormone (GH), congenital defects affecting the anterior pituitary usually result in the development of dwarfism (see Chapter 2). If TSH but not GH secretion were affected, cretinism would develop (see page 104).

PITUITARY DESTRUCTION.

Although uncommon, pituitary tumors may cause secondary hypothyroidism following destruction of thyrotrophs by an expanding, space-occupying mass. Neoplasia-induced pituitary destruction may create additional endocrinopathies, including hypocortisolism (secondary adrenal insufficiency), diabetes insipidus, reproductive dysfunction (i.e., irregular estrous cycles, failure to cycle, loss of libido, testicular atrophy, azoospermia), and pituitary dwarfism in immature animals. The owner’s primary concern may depend, in part, on which endocrine system is most severely affected. The most common pituitary tumor affecting thyroid gland function in the dog is a functional corticotropic tumor causing pituitary-dependent hyperadrenocorticism. In these dogs, secondary hypothyroidism results from suppression of thyrotroph function (i.e., suppressed TSH secretion) rather than from destruction of thyrotrophs by the tumor.

PITUITARY THYROTROPH SUPPRESSION.

Secondary hypothyroidism may develop following suppression of thyrotroph function by concurrent illness, drugs, hormones, or malnutrition (see Factors Affecting Thyroid Gland Function Tests, page 126). These are the most common causes of secondary hypothyroidism in the dog. From a clinical standpoint, perhaps the most important is the suppressive effect of glucocorticoids, either from exogenous administration or from naturally acquired hyperadrenocorticism. In a study of 102 dogs with naturally acquired hyperadrenocorticism, randomly obtained basal serum T₄ and/or serum T₃ levels were decreased in 68% of the dogs (Ferguson and Peterson, 1986). The thyroid is usually subnormally responsive to TSH administration (see Chapter 6). Unlike the other causes, secondary hypothyroidism induced by suppression of thyrotroph function is potentially and usually reversible. Thyroid hormone supplementation is not required if the cause for the suppression can be identified and treated.

MISCELLANEOUS CAUSES.

In humans, secondary hypothyroidism may also develop following production of a defective TSH molecule or impaired interaction between TSH and its receptor on follicular epithelial cells. These causes have not yet been reported in the dog. Secondary hypothyroidism can follow radiation therapy for expansile adrenocorticotrophic hormone (ACTH)–secreting pituitary tumors. Secondary hypothyroidism can also be caused by hypophysectomy (Lantz et al, 1988; Meij et al, 1998).