Examining the pathogenesis of feline hyperthyroidism

Since it was first documented in 1979, hyperthyroidism has become increasingly more common in cats. It is now the most commonly diagnosed endocrinopathy in cats. This may be a true increase in disease incidence, or it may be attributable to other factors, such as the longer life spans of cats or better detection by veterinarians.

Hyperthyroidism is characterized by increased serum concentrations of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). The increases in serum thyroid hormone concentrations are usually the result of benign adenomatous hyperplasia of the thyroid glands. In less than 2% of the cases, the hyperthyroidism is caused by thyroid adenocarcinoma. Ectopic thyroid tissue may be present as well, which may have implications for the type of treatment chosen. No specific etiologies have been identified, but environmental and genetic factors have been studied to help explain the increase in the incidence of hyperthyroidism over the past few decades.

ENVIRONMENTAL AND DIETARY FACTORS

In recent years, three large studies have examined possible environmental or dietary factors in the pathogenesis of hyperthyroidism. One of the studies included 100 cats with hyperthyroidism and 163 control cats.1 The cats' medical records were reviewed, and the owners completed questionnaires. Data collected included demographic variables, environmental exposures, and diet (including the preferred flavors of canned cat food). In this study, housing (indoor vs. outdoor), exposure to fertilizers and herbicides, regular use of flea products, and having a smoker in the house were not associated with an increased risk of hyperthyroidism. The results suggested that cats that preferred fish or liver and giblets flavors of canned cat food may have a significantly increased risk of hyperthyroidism.

In a second study, owners of 379 hyperthyroid and 351 control cats were asked about their cats' potential risk factors, including breed, demographic factors, medical history, indoor environment, exposure to topical and en vi ron mental chemicals, and diet.2 The researchers then evaluated the association between these potential risk factors and the outcome of disease. The cats of Siamese and Himalayan breeds (which are genetically related) had a reduced risk of developing hyperthyroidism. Cats that used cat litter were at greater risk of developing hyperthyroidism than cats that did not. Topical ectoparasiticides increased the cats' risk of developing hyperthyroidism. Cats that ate commercial canned food had about a twofold increase in the risk of disease, compared with cats that did not eat canned food. When these four variables (breed, cat litter use, canned cat food consumption, and topical ectoparasiticide use) were further analyzed, the researchers found a persistent protective effect of breed (Siamese or Himalayan). In addition, they found a twofold to threefold increase in the risk of developing hyperthyroidism among cats that ate mostly canned cat food and a threefold increase in risk among cats using cat litter. Use of commercial flea products did not retain a strong association when analyzed further. This study suggests that more research into dietary and other environmental factors (such as cat litter) is warranted.

In a recent retrospective study, the medical records of 169,576 cats seen at nine veterinary teaching hospitals from 1978 to 1997 revealed 3,570 diagnoses of feline hyperthyroidism.3 This information was compared to a case-controlled study population of 109 cats with hyperthyroidism and 173 normal cats assessed at one of the nine veterinary teaching hospitals between 1998 and 2000. The researchers found that there was a significant increase in the age-specific hospital prevalence of cats with hyperthyroidism over the 20-year period. Overall, two factors were associated with a greater risk of developing hyperthyroidism: each additional year of age and the consumption of pop-top canned food at various points in a cat's life. Female cats had a greater risk if they ate food from pop-top cans or from a combination of pop-top and regular cans. Male cats had a greater risk if they ate food from pop-top cans and as they aged. This research suggests that the increasing prevalence of feline hyperthyroidism is not due to the aging of the cat population alone, but that canned foods may be an important factor as well.3 However, further research into this area is warranted because up to 25% of cats that develop hyperthyroidism have never eaten canned foods.4 Likely, the cause of hyperthyroidism is multifactorial, with genetic factors also playing an important role.

GENETIC FACTORS

G protein expression

In another study comparing hyperthyroid and normal cats, altered G protein expression was found in the thyroid gland tissue from hyperthyroid cats.5 Researchers obtained adenomatous thyroid glands from eight hyperthyroid cats and thyroid glands from four age-matched euthyroid cats and examined them for expression of G inhibitory protein (Gi) and G stimulatory protein (Gs). In the hyperthyroid cats, the expression of Gi was significantly reduced when compared with the euthyroid cats. Expression of Gs for both groups was similar. Reduced Gi expression in adenomatous thyroid glands may reduce the negative inhibition of the cyclic adenosine monophosphate cascade in thyroid cells, leading to autonomous thyroid cell growth and hypersecretion of T4. Even if this is so, we do not know what causes the Gi reduction in hyperthyroid cats. The environmental and dietary risk factors studied in the research already mentioned may play a role in altering G protein expression.

Oncogenes

Researchers have also examined oncogenes and the tumor suppressor gene p53 in cats with hyperthyroidism.6 They performed immunohistochemical analysis of formalin-fixed, paraffin-embedded thyroid glands from 18 hyperthyroid cats, looking for overexpression of the products of certain oncogenes (c-Ras, a mitogenic oncogene; and Bc12, an apoptosis inhibitor) and the tumor suppressor gene p53. For controls, they also examined 14 thyroid glands from euthyroid cats without histologically detectable thyroid lesions. In all cases, nodular follicular hyperplasia and adenomas stained positively for overexpression of c-Ras protein. No staining for either Bc12 or p53 occurred in any of the cats. According to these results, mutations in the c-Ras oncogene may play a role in the etiopathogenesis of feline hyperthyroidism. As with the G protein abnormalities, c-Ras mutations could either be a cause of hyperthyroidism or simply mediate the effects of an as yet unidentified dietary or environmental initiator.

Thyrotropin receptor gene alterations

In another study, researchers examined alterations in the thyrotropin receptor gene in cats with hyperthyroidism.7 The researchers had previously determined the DNA sequence in the transmembrane domain region of the gene. They then analyzed single-stranded conformational polymorphisms in thyroid DNA from 11 sporadic cases of feline thyrotoxicosis and leukocyte DNA from two cases of familial feline thyrotoxicosis. They also determined the DNA sequence of this region of the thyrotropin receptor gene in five of the cases of sporadic feline thyrotoxicosis and the two cats with familial thyrotoxicosis. The normal feline thyrotropin receptor gene sequence in the transmembrane domain region is highly homologous to that of other mammalian (e.g. canine, human, and bovine) thyrotropin receptor genes. Thyroid gland DNA from the 11 cats with sporadic thyrotoxicosis did not have mutations in the transmembrane domain region of the thyrotropin receptor gene. Leukocyte DNA from the two littermates with familial feline thyrotoxicosis did not harbor mutations of this region of the gene.

A more recent study examined a different set of gene codons than those cited in the study above.8 These researchers examined the thyroid tissue from 10 cats with hyperthyroidism and one normal cat. They discovered a polymorphism in the thyroid-stimulating hormone receptor gene but did not find an association with tumor formation. Four of the 10 hyperthyroid cats had a Gs-alpha gene mutation. As was the case in the study above, these results make it unlikely that mutations in the extracellular or transmembrane part of the thyroid-stimulating hormone receptor gene cause hyperthyroidism in cats. However, Gs-alpha gene mutation may be a factor in the pathogenesis of feline hyperthyroidism.

CONCLUSION

Obviously much more research is needed to reveal the pathogenesis of hyperthyroidism. Better information about the causes is needed to start meaningful work on newer therapies and to take steps to prevent this common disorder.

David S. Bruyette, DVM, DACVIM

VCA West Los Angeles Animal Hospital

1818 S. Sepulveda Blvd.

West Los Angele, CA 90025

REFERENCES

1. Martin, K.M. et al.: Evaluation of dietary and environmental risk factors for hyperthyroidism in cats. JAVMA 217 (6):853-856; 2000.

2. Kass, P.H. et al.: Evaluation of environmental, nutritional, and host factors in cats with hyperthyroidism. J. Vet. Intern. Med. 13 (4):323-329; 1999.

3. Edinboro, C.H. et al.: Epidemiologic study of relationships between consumption of commercial canned food and risk of hyperthyroidism in cats. JAVMA 224 (6):879-886; 2004.

4. White, H.L. et al.: Effect of dietary soy on serum thyroid hormone concentrations in healthy adult cats. AJVR 65 (5):586-591; 2004.

5. Hammer, K.B. et al.: Altered expression of G proteins in thyroid gland adenomas obtained from hyperthyroid cats. AJVR 61 (8):874-879; 2000.

6. Merryman, J.I. et al.: Overexpression of c-Ras in hyperplasia and adenomas of the feline thyroid gland: An immunohistochemical analysis of 34 cases. Vet. Pathol. 36 (2):117-124; 1999.

7. Pearce, S.H. et al.: Mutational analysis of the thyrotropin receptor gene in sporadic and familial feline thyrotoxicosis. Thyroid 7 (6):923-927; 1997.

8. Peeters, M.E. et al.: Feline thyroid adenomas are in part associated with mutations in the G(s alpha) gene and not with polymorphisms found in the thyrotropin receptor. Thyroid 12 (7):571-575; 2002.