Thyroid disease - hyper- and hypothyroidism, together with goitre and thyroid cancer - is extremely common. The familial clustering of autoimmune diseases such as Graves' hyperthyroidism illustrates the genetic contribution to susceptibility; we have described advances in understanding of the role of the CTLA4, HLA and other immune response genes in this susceptibility. We have shown that hyperthyroidism results in increased mortality, especially from vascular disease. Development of AF as a complication of hyperthyroidism is an independent risk factor for that mortality. Increasing evidence suggests that even subclinical hyperthyroidism is a risk factor for development of AF and vascular mortality. Development of hypothyroidism also reflects genetic susceptibility. While hypothyroidism is postulated to exert an adverse effect on cardiovascular risk, our own data argue against this, both in groups of patients with subclinical hypothyroidism and those developing overt hypothyroidism after treatment for thyrotoxicosis. Hypothyroidism is, however, highly relevant to the developing fetus. Maternal thyroid status in early pregnancy predicts birth head size and body length. Intrauterine growth restriction (IUGR) is characterised by maternal hypothyroxinaemia which may itself contribute to neurodevelopmental delay. We have shown that IUGR modulates expression and function of deiodinases, thyroid receptors, and the novel T3 transporter MCT8, mutations in MCT8 being associated with a profound neurological phenotype. Differentiated thyroid cancer, which represents a diagnostic challenge given the population prevalence of thyroid enlargement, is associated with over-expression of the oncogene PTTG. We have shown that PTTG expression is a predictor of tumour behaviour, as is expression of its transforming binding factor PBF. PTTG promotes expression of a variety of angiogenic genes in the thyroid, inhibits NIS expression and iodide uptake, and results in genetic instability through its role as a securin. Critical to its function is its SH3-interacting domain and the phosphorylation of this domain. Advances in genetics and thyroid cell biology are beginning to shed light on thyroid disease pathogenesis and will ultimately impact on prevention.
04 - 06 Apr 2005
British Endocrine Societies