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 (G_i) and G stimulatory protein (G_s). In the hyperthyroid cats, the expression of G_i was significantly reduced when compared with the euthyroid cats. Expression of G_s for both groups was similar. Reduced G_i 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 G_i 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.

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 G_s-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, G_s-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