Pathogenesis of hyperthyroidism

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Feline hyperthyroidism, thyroid nodule

The pathogenesis of hyperthyroidism in cats is still unclear, but much work is being done in this complex field of endocrinology.

The normal thyroid gland contains subpopulations of follicular cells with a constitutively high growth potential. In a thyroid gland destined to become goitrous, a fraction of these cells may replicate autonomously[1]/. Once these rapidly dividing cells are present in sufficient numbers, they may grow in the absence of any further extra-thyroidal stimulation. The development of follicular cell adenomas may be the result of the preferential growth of cell clones with reduced sensitivity to a factor(s) that inhibits growth.

A striking feature of feline hyperthyroidism is that enlargement of both lobes occurs in approximately 70% of cases. Because no physical connection exists between feline thyroid lobes, researchers have postulated that circulating factors (e.g. immunoglobulins), nutritional factors (e.g. isoflavones, or iodine), or environmental factors (e.g. toxins such as PCBs) may interact to cause thyroid pathology in cats (August, 2006).

In all studies of cells from cats with functional hyperthyroidism, responses of individual cells are heterogeneous within both lobes of the thyroid gland. This stepwise activation of all adenomatous cells enables the thyroid to adapt its activity in an economical way to changing demands[2].

Normally in thyroid cells, the TSH receptor (TSHR) interacts with a heterotrimeric G protein, which has three subunits, α, β and γ. When TSH is bound to its receptor, the TSHR is activated and will bind to the G protein, in turn activating it. G proteins can be either stimulatory (Gs) or inhibitory (Gi) with respect to activity of the enzyme adenylate cyclase. On other words, if an activated receptor binds Gs, adenylate cyclase increases, whereas if the receptor binds Gi, enzymatic activity decreases. Augmented adenylate cyclase activity leads to mitogenesis and hormone production.

Studies in hyperthyroid cats has shown that a mutation in the gene for the α-subunit of the Gs protein, which suggests that mutations in this gene might play a role in the etiopathogenesis of this disease[3]. Two recent reports have demonstrated that tissue from hyperthyroid cats had reduced quantity of Gi proteins. These results may indicate that Gi normally may play a role in the inhibition of growth and differentiation of feline thyroid glands, and decreased amounts of Gi could lead to cell growth and hyperthyroidism. A subsequent study demonstrated the Giα2 subtype was suppressed in feline adenomas[4].

It seems likely that, regardless of the goitrogenic trigger, hyperthyroidism in cats is a result of some abnormality in the regulation of TSH hormone production, with resultant overstimulation of systemic adenylate cyclase enzyme activity. Hypersecretion of TSH is a direct consequence of increased activity of stimulatory proteins (Gs) that lead to chronic hyperstimulation of TSH-receptors and resultant long-term hypersecretion of thyroidal hormones into the blood stream.

References

  1. August, JR (2006) Consultations in feline internal medicine. Vol 5. Elsevier Saunders, USA pp:213-214
  2. Ferguson, DC (1994) Pathogenesis of hyperthyroidism. In August, JR, editor: Consultations in feline internal medicine. Vol 2. Elsevier Saunders, Philadelphia. pp:133-142
  3. Peeters, ME et al (2002) Feline thyroid adenomas are in part associated with mutations in the Gs alpha gene and not with polymorphisms found in the thyrotropin receptor. Thyroid 12(7):571-575
  4. Hammer, B, Holt, DE & Ward, CE (2000) Altered expression of G proteins in thyroid gland adenomas obtained from hyperthyroid cats. Am J Vet Res 61:874-879
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