Rance K. Sellon, DVM, PhD
Small animal clinicians see many endocrine diseases, primarily in dogs. Several endocrinopathies, particular those resulting in hormonal deficiencies, have an immune-mediated basis to their development. Endocrinopathies that can, in some patients, be attributed to immune-mediated glandular injury include hypothyroidism, hypoadrenocorticism, diabetes mellitus in some patients, and hypoparathyroidism.
Hypothyroidism in dogs is generally categorized as primary hypothyroidism, which reflects thyroid gland pathology, secondary hypothyroidism, from disorders in the pituitary thyrotropic cells, and tertiary hypothyroidism, which is a deficiency of TRH production and has not been reported in small animal patients.
In dogs, primary hypothyroidism is most common, accounting for more than 95% of hypothyroid cases, and lymphocytic thyroiditis accounts for approximately half of the cases of primary hypothyroidism. Lymphocytic thyroiditis is considered an immune-mediated disease, and is recognized histologically by infiltration of the thyroid gland with lymphocytes, plasma cells and macrophages. Idiopathic follicular atrophy is the other common cause of primary hypothyroidism in dogs and may reflect an end-stage of glandular injury.
The pathophysiologic mechanisms driving the development thyroiditis are poorly understood and characterized. Genetics are likely to play a large role given the central role that immune genes play in the development of any immune response. The role of genetics is supported by several observations. Thyroiditis has been shown in some colony raised Beagles to be an inherited disorder. Thyroiditis has breed and line predispositions, including, Golden retriever, Labrador retriever, Doberman pinscher, Dachshund, Irish setter, Great Dane, Poodle, and Boxer. Recent work has established an association of thyroiditis with the presence of a specific DLA gene, although it is not present in all dogs with thyroiditis. To date, there is no conclusive evidence linking the development of thyroiditis to environmental risk factors.
There is evidence that humoral immune responses play a role in the development of thyroiditis. There is an increased incidence of circulating autoantibodies to thyroglobulin, thyroid antigens, and T3 in affected dogs. Intrathyroidal injection of anti-thyroglobulin antibodies induces the development of lesions in the basement membrane of follicular cells, believed to be deposition of immune complexes, similar to those observed in dogs with spontaneous disease. The presence of antibodies to specific portions of the thyroglobulin molecule has been demonstrated in sera of dogs with thyroiditis. Cell-mediated immune responses may also play a role in the development of thyroiditis, though the author is unaware of any experiments that have documented the presence in dogs of cytotoxic T cells with activity against thyroid antigens. Other components of the immune response believed to be important in the destruction of the thyroid gland are complement and antigen-dependent cellular cytotoxicities against follicular cell or follicular antigens. Regardless of the driving mechanisms, the development of thyroiditis leads to progressive destruction of the follicular cells and follicles with secondary fibrosis. Clinical signs of hypothyroidism are believed to occur when greater than 75% of the thyroid gland has been destroyed, which may take several years to occur.
Circulating antibodies to thyroglobulin can be found in hypothyroid dogs with thyroiditis, and can be detected by a wide variety of assays, with ELISA based assays the most commonly used. In general, detection of these antibodies would suggest the presence of underlying thyroiditis, and may portend the development of hypothyroidism. Antibodies to thyroglobulin can be detected in the absence of antibodies to either T4 or T3. In addition to being detected in dogs with thyroiditis, thyroglobulin antibodies can occasionally be detected in dogs with non-thyroidal illness. The use of thyroglobulin antibodies as a definitive diagnostic test for hypothyroidism is likely not a practical application of this technology, especially in light of the fact that a large proportion of dogs will be hypothyroid because of thyroid atrophy, and not thyroiditis. Given the familial/genetic links to thyroiditis, the one application of thyroglobulin antibody testing is its use as a screening tool for the presence of lymphocytic thyroiditis in breeding animals and programs.
With currently available assays, a logical approach to the diagnosis of hypothyroidism in dogs would be to assess the history and physical examination for compatible findings. Suspect dogs should be screened with blood counts, biochemical profiles and urinalyses to evaluate the potential for existence of non-thyroidal illness. Since the probability of a correct diagnosis increases when the results of two or more tests agree, measurement of either a free T4 by dialysis or total T4, in conjunction with TSH concentrations, should provide a diagnosis, or effectively exclude a diagnosis, in the majority of cases. When results of such tests are not conclusive in the face of strong clinical suspicion, evaluation of response to replacement therapy is still an accepted means of diagnosis.
Where hypothyroidism is a common endocrine disorder in dogs, hypoadrenocorticism is seen far less often, and compared to hypothyroidism, there is less known about the pathogenesis of the disease. Hypoadrenocorticism in people can be a consequence of immune-mediated destruction of the adrenal cortex, and a similar pathogenesis is suspected in dogs. Discovery of the mechanisms behind loss of adrenal function in dogs has been hampered in some respects by the fact that affected dogs can be successfully treated, and so histopathologic and immunologic information about these dogs is sparse.
There is some circumstantial evidence compatible with hypoadrenocorticism as an immune-mediated disease. Histopathologic assessment of adrenal glands in a number of dogs with hypoadrenocorticism has found lymphocytic, plasmacytic infiltrates in the cortex. That more dogs with long-standing hypoadrenocorticism don't have evidence of infiltrates may reflect the chronicity of the disease and the development of atrophic or fibrotic glands, perhaps as a consequence of chronic inflammation. Additional evidence of the immune mediated nature of this disease awaits the consistent use of assays that can detect circulating anti-adrenal antibodies in suspect animals, or induction of the disease as has been done with canine hypothyroidism.
Hypoadrenocorticism is even less common in cats than it is in dogs, so the pathogenesis in this species is even more elusive than in dogs. Cats with spontaneous hypoadrenocorticism exhibit an atrophy of the adrenal gland comparable to that seen in dogs, but there has not been any evidence of immunocyte infiltration as has been described in the few canine cases. Nevertheless, the end stage appearance of the glands could still be the result of immune-mediated inflammation of the adrenal glands.
Another infrequently encountered endocrinopathy of dogs and cats is primary hypoparathyroidism. Like hypothyroidism and hypoadrenocorticism, there is evidence that immune-mediated destruction of the parathyroid gland may be the primary aspect underlying the development of the disease. Primary hypoparathyroidism may exist independently of primary hypothyroidism, likely reflecting the specificity of the immune response for parathyroid-specific or thyroid-specific antigens.
Lymphocytic parathyroiditis has been described in a series of dogs all with hypocalcemia and clinical signs referable to hypocalcemia. In the reported cases, there did not appear to be a sex predisposition as is seen with hypoadrenocorticism. Although any breed of dog can develop primary hypoparathyroidism, most reported cases have been seen in the following breeds: Toy poodle, Miniature schnauzer, Labrador retriever, German shepherd, and Terrier breeds.
Naturally occurring primary hypoparathyroidism has also been described in a very small numbers of cats with parathyroid atrophy. The pathogenesis of the disease in cats remains unknown, but as has been speculated for hypoadrenocorticism in dogs, the atrophy observed in reported cases may reflect end-stage immune-mediated inflammation.
Diabetes mellitus in dogs may have an immune-mediated basis. Islet cell antibodies and antibodies to beta cells have been found in dogs with insulin dependent diabetes mellitus. In addition, immune-mediated insulitis has been observed in dogs. Transient diabetes mellitus was described in a dog with concurrent immune-mediated hemolytic anemia. Beta cell specific antibodies were found in this dog, and the antibodies persisted after resolution of the anemia with immunosuppressive therapy and resolution of the diabetes mellitus. The role of autoimmunity in the pathogenesis of diabetes mellitus has been questioned by some, arguing that the immune responses to beta cells could be non-specific responses that develop secondary to some other cause of islet cell injury. Such arguments could be made for most other of the "autoimmune" diseases observed in small animal practice, with the distinction being a semantic one. It is widely acknowledged that immune-mediated diseases in both people and animals may be a process that develops secondary to some other inciting event. It is fair to say that the role of immune-mediated injury to islets cells in dogs awaits additional clarification.
There is no real evidence at this time that the development of diabetes mellitus in cats is the result of immune mediated disease. Cats, unlike dogs, are predisposed to the formation and deposition of amyloid in their pancreatic islets. The amyloid deposited in cats is not the inflammatory amyloid that mediates renal and hepatic amyloidosis, but rather seems to be a protein made in islet cells that is co-secreted with insulin. There have been isolated instances of lymphocytic infiltration of islets in cats, but this appears to be uncommon.
Autoimmune Polyglandular Syndromes
In people, a group of apparently immune-mediated endocrinopathies involving multiple endocrine organs has been described and are referred to as autoimmune polyglandular syndromes. Two categories of autoimmune polyglandular syndrome are recognized in people and are referred to as type I and type II. Each has characteristic patterns of endocrine abnormalities as follows:
Type I autoimmune polyglandular syndrome: hypoparathyroidism, hypoadrenocorticism, cutaneous candidiasis
Type II autoimmune polyglandular syndrome (two or more of the following): hypoadrenocorticism, primary hypothyroidism, insulin-dependent diabetes mellitus, hyperthyroidism, myasthenia gravis, hypogonadism, celiac disease
Each has some distinguishing clinical features. Type I occurs more commonly in children while type II occurs more commonly in young adults. Type I has no HLA association while type II does (HLA are a group of human major histocompatibility antigens--some HLA haplotypes have known associations with predispositions to immune-mediated disease). Type II is the more common of the two syndromes.
Syndromes similar to the type II autoimmune polyglandular syndrome have been described in dogs with both hypoadrenocorticism and hypothyroidism. In the largest assembly of cases, 7/10 affected dogs were neutered females. Affected dogs presented for evaluation of signs referable primarily to hypoadrenocorticism (lethargy, collapse, vomiting, weight loss, weakness), and hypothyroidism was discovered when clinical signs of lethargy, and laboratory abnormalities such as hyponatremia, persisted after appropriate therapy for hypoadrenocorticism. Affected dogs also exhibited more classic findings of hypothyroidism including dermatologic disease, hypercholesterolemia, obesity and heat seeking behavior. In the dog of the isolated case report, a middle-aged female dog presented in an acute hypothyroid crisis, and clinical signs of hypoadrenocorticism were precipitated by treatment of hypothyroidism. Bases on these cases, it has been recommended that thyroid function be evaluated in hypoadrenocorticoid dogs that respond poorly to therapy with mineralocorticoids, and have persistent hyponatremia, hypercholesterolemia, dermatologic disease, heat seeking behavior, obesity, or bradycardia.
A dog has been described that had concurrent diabetes mellitus, hypothyroidism and pituitary dependent hyperadrenocorticism. Poor glycemic control after initiation of insulin therapy prompted evaluation for hyperadrenocorticism, which was documented by low dose dexamethasone suppression testing. The diagnosis of hypothyroidism was made when diabetes mellitus and hyperadrenocorticism were controlled, but fasting hypercholesterolemia persisted. Antibodies to thyroglobulin or pancreatic beta cells were not measured in the dog of this report, but it was speculated that hypothyroidism and diabetes mellitus may have had an immune-mediated basis.
An immune-mediated basis underlies several endocrine diseases of primarily dogs. The unraveling of the canine genome will likely be a boon to researchers looking for the genetic and immunological basis to these immune-mediated endocrinopathies.
References are available upon request.