Etiopathogenesis of Canine Hypothyroidism
ACVIM 2008
Peter A. Graham, BVMS, PhD, CertVR, DECVCP, MRCVS
Poulton-Le-Fylde, UK

Introduction

Hypothyroidism continues to be the most common endocrine disorder of the dog and remains a priority disease among dog breeders and exhibitors.

Hypothyroidism is manifested systemically by its association with an overall decreased metabolic rate. Clinical signs reflect lower metabolic rate and decreased tissue turnover and include obesity, predisposition to infection, alopecia or delayed hair growth cycle, skin changes, anemia, altered lipid metabolism, and possibly reduced reproductive efficiency.

In the dog, at least 95% of hypothyroidism is primary in nature, that is, the functional failure is located in the thyroid glands (not pituitary or hypothalamus). This primary hypothyroidism has been associated with two forms of disease processes; 1) lymphocytic thyroiditis (chronic atrophic autoimmune thyroiditis, auto-immune thyroid disease (AITD)), and 2) idiopathic (non-inflammatory) thyroid follicular atrophy. Some evidence even links these, and suggests that idiopathic non-inflammatory atrophic thyroid disease may be a late consequence of lymphocytic thyroiditis in some cases. Lymphocytic thyroiditis can progress through stages identifiable by laboratory tests, including subclinical thyroiditis, subclinical or partial hypothyroidism, hypothyroidism with circulating thyroid antibodies, and possibly hypothyroidism with no circulating thyroid antibodies.

Lymphocytic thyroiditis is characterized by focal and/or diffuse lymphoplasmacytic infiltration with macrophages. During this process, antibodies directed against thyroid antigens are released into the circulation. The most notable of these is thyroglobulin autoantibody (TgAA), and in humans, thyroperoxidase (TPO) antibody.

The availability of a commercial canine thyroglobulin antibody (TgAA) assay allows us to use serologic evidence of thyroiditis to perform studies on its prevalence, epidemiology and progression.

In addition to the progressive forms of AITD, there are transient/subacute forms of thyroiditis in humans associated with clinical signs including lethargy, malaise, and painful neck. Whether these forms of thyroid disease exist in the dog is difficult for us to determine because of the expected subtle and non-specific nature of their clinical presentation.

Studies at Michigan State University using thyroglobulin antibody as a marker for canine AITD have demonstrated:

 Strong breed dispositions

 A high prevalence in "healthy" populations

 Slow, or in some cases no, progression from subclinical pathology to loss of functional reserve and thyroid failure

 Possible transient forms--in some animals TgAA wanes with no negative thyroid functional sequelae

The slow progression rate of this disease hampers investigations into cause and effect relationships. Temporal associations with individual causal events are difficult when clinical disease may not occur for several years.

Etiology

Little is known about the initiators of canine thyroid disease although recent work has laid the ground work for further study and epidemiological investigations hope to give some direction for suitable areas of investigation. Most of what we understand about the initiation of canine thyroid disease comes from studies in other species including humans although the canine disease has recently been the subject of further investigation.

Experimental and human autoimmune thyroiditis appear to be disorders of immunoregulation. Therefore, in the search for the underlying molecular abnormality in this condition, research effort has been focused on mechanisms of immunoregulation and particularly the contribution made by the Human Leukocyte Antigen (HLA) complex. Some association has been documented between certain HLA subtypes and the presence of disease but so far these associations have generally been weak. Work on the contributions of Dog Leukocyte Antigen (DLA) subtypes to the disease in dogs is under investigation. The genetics of the Dog Leukocyte Antigen has been recently investigated and indeed predisposing alleles have been identified. The DLA-DQA1*00101 allele appears to be particularly influential and is associated with an increased risk of hypothyroidism (overall odds ratio 1.97, p<0.001). Although especially prevalent in Dobermans, English Setters and Rhodesian Ridgeback breeds (including in unaffected individuals) this was not the case in other breeds such as the Boxer. This is consistent with the predisposition associated with Human Leukocyte Antigen (HLA) subtypes.

In the investigation of potential non-immunogenetic etiologies such as mutations in the canine thyroglobulin gene or its promoter, no variations which correlate with the presence of thyroiditis have been revealed although canine thyroglobulin has now been cloned and sequenced opening the possibility for further research in this area. The possibility that thyroiditis is induced in predisposed individuals by antigenic mimicry of thyroid antigens by viral or bacterial agents has been suggested. This possibility is supported by the protective effects of intestinal sterilization in experimental thyroiditis and serological evidence of recent infections in affected human. Yersinia enterocolitica antibodies have been identified in humans with Grave's disease (a form of autoimmune thyroid disease in which anti-TSH receptor antibodies result in hyperthyroidism) and an increased frequency of anti-retroviral antibodies has been found in humans with autoimmune thyroiditis. An alternative viral mechanism could be through the local induction of IFN-{gamma} triggering H(D)LA expression by thyrocytes initiating an autoimmune process. The contribution of immunoregulation in this disease is also inferred by the possible modulation of immunotolerance by oral feeding of thyroglobulin following which some measures of thyroid autoimmunity can be ameliorated.

The diversity of prevalence among breeds and several specific heritability studies indicate the highly heritable nature of this condition and further studies indicate that there is a breed influence on age and progression of the disease.

There has been controversy in recent years concerning the possible contribution that routine vaccination might make to the origin of thyroiditis in dogs. In one study, it seemed that there might be support for vaccination as an initiator of thyroid pathology. Scott-Moncrief and others reported an increase in circulating antibodies that reacted with thyroglobulin following repeated vaccination however, further research by the same group failed to demonstrate an increased prevalence of thyroiditis in vaccinated beagles at post-mortem after a 5.5 year follow-up study.

Epidemiology Studies at Michigan State University

Descriptive Studies

The research experience in other species and in related immune mediated disease has shown that the origins of thyroiditis in an individual animal are likely to be multifactorial. Using a large research database of containing the results of 143,000 serum thyroid investigations and questionnaire studies, researchers at Michigan State University have explored candidate predisposing factors including breed, seasonality, and geography contribute to the initiation of thyroid pathology.

In addition to identifying the prevalence of thyroglobulin antibody (as a marker for the prevalence of thyroiditis) across a range of breeds, we have also noted a wide variation in the relative proportions of antibody-positive (thyroiditis) and antibody negative (idiopathic atrophy) hypothyroidism across breeds. The widely reported overall average of 50:50 holds true but in some breeds, the contribution of thyroiditis is much greater or much less. In English Setters for example more than 80% of cases diagnosed with hypothyroidism were TgAA positive, whereas less than 30% of hypothyroid Dobermans were antibody-positive. These findings suggest different rate or type of progression of thyroiditis or breed differences in predisposition to non-inflammatory forms of thyroid disease.

Using age-distribution profiles on a breed specific basis, there is indeed some evidence to suggest that there may be different progression rates among breeds. There may be a small contribution of season of the year to the occurrence of earliest evidence of thyroiditis. Of dogs with no laboratory evidence of thyroid dysfunction, the proportion with evidence of thyroiditis (positive TgAA) was highest in the summer (July, August and September) and lowest in the fall (October, November, December).

In a preliminary investigation of the influence on geography on the prevalence of thyroiditis in samples submitted to Michigan State University some significant differences were observed. The prevalence of TgAA was significantly higher in samples submitted from North Dakota, Vermont, Wyoming, Minnesota and Colorado compared to Michigan (Odds ratios 1.19 to 1.41, p<0.05). The prevalence was significantly lower in samples from Massachusetts, Maryland, Virginia, North Carolina, Florida, South Carolina, Kentucky, Texas, West Virginia Tennessee and Alabama (Odds ratios 0.39 to 0.79, p<0.05). There was no interaction with breed prevalence but the underlying reasons (if any) for these observations have yet to be discovered.

Follow-up Studies

By following a group of dogs with positive serum TgAA results but no evidence of thyroid dysfunction, we were able to estimate progression rates, identify factors associated with progression to thyroid dysfunction and compare against dogs with no evidence of thyroid pathology (serum TgAA negative).

In summary, the first group of 171 dogs had no laboratory evidence of thyroid dysfunction but had positive serum TgAA (TgAA+ve). The second, age and breed matched, control group of 134 dogs had no evidence of thyroid dysfunction and were TgAA negative (TgAA-ve). Repeat serum samples were obtained every three months from the TgAA+ve group and at the end of 1-year from the TgAA-ve group. Laboratory evidence of thyroid dysfunction was defined as TSH > 0.68ng/mL and/or FreeT4 by equilibrium dialysis (FT4d) <6 pmol/L.

Thirty-three TgAA+ve dogs (19.3%) developed laboratory evidence of thyroid dysfunction indicated by either both high TSH and low FT4d (7; 4.1%), high TSH (23; 13.4%), or low FT4d (3; 1.8%). None of the TgAA-ve group developed laboratory evidence of hypothyroidism (both low FT4 and high TSH) but 4 had laboratory evidence of thyroid dysfunction indicated by either high TSH (3; 2.3%), or low FT4d (1; 0.8%). The presence of a positive serum TgAA result in a dog with normal thyroid function was, therefore, associated with a significantly increased risk of deterioration in thyroid function over the course of 1-year (Odds ratio 7.77; 95%CI 2.64-30.87, p < 0.0001).

The following table summarises the factors that were associated with progression to thyroid dysfunction within the serum TgAA positive group.

Factor

OR

95% CI

p

4 years and younger

3.63

1.16-14.95

0.016

Exposure to Bordetella vaccine

2.55

1.02-6.98

0.030

Glucocorticoid use during the follow-up period

0.29

0.05-1.04

0.044

Concurrent T3/T4AA

2.32

1.01-5.38

0.029

Initial TgAA >1200

9.84

3.76-25.66

0.000

Initial TT4 <26 nmol/L

2.30

0.99-5.36

0.032

Initial TSH >0.30 ng/mL

3.13

1.29-7.46

0.004

Both TT4 <26nmol/L and TSH >0.30 ng/mL

5.99

1.70-21.05

0.002

Financial support provided by Companion Animal Fund and Animal Health Diagnostic Laboratory of the College of Veterinary Medicine, Michigan State University. Contributing colleagues to the work presented include KR Refsal, RF Nachreiner and Ryan Lundquist.

References

1.  Graham PA, Refsal KR, Nachreiner RF. Etiopathologic findings of canine hypothyroidism. Veterinary Clinics of North America, 2007. 37(4): p. 617-631.

2.  Graham PA. Lymphocytic thyroiditis. Veterinary Clinics of North America, 2001. 31(5): p. 915-933.

3.  Graham PA, Lundquist RB, Refsal KR, Nachreiner RF, Provencher AL. 12-month prospective study of 234 thyroglobulin antibody positive dogs which had no laboratory evidence of thyroid dysfunction (Abstr). J Vet Intern Med. 2001;14:298.

4.  Hogenesch H, Azcona-Olivera J, Scott-Moncrieff C, Snyder PW, Glickman LT. Vaccine-induced autoimmunity in the dog. Adv Vet Med. 1999;41:733-747.

5.  Scott-Moncrieff JC, Azcona-Olivera J, Glickman NW, Glickman LT, HogenEsch H. Evaluation of antithyroglobulin antibodies after routine vaccination in pet and research dogs. J Am Vet Med Assoc. Aug 15 2002;221(4):515-521.

6.  Scott-Moncrieff JC, Glickman NW, Glickman LT, HogenEsch H. Lack of association between repeated vaccination and thyroiditis in laboratory Beagles. J Vet Intern Med. Jul-Aug 2006;20(4):818-821.

Speaker Information
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Peter Graham, BVMS, PhD, CertVR, DECVCP, MRCVS
NationWide Laboratories
Poulton-leFylde, Lancashire, United Kingdom


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