1. END2.10 - Thyroid miscellany Dr SS Nussey © S Nussey and  ios

2. Thyroid hormone transport

3. Thyroid hormone metabolism Box 3.29

4. Thyroid hormone assay

5. TSH Assay

6. Implications

7. Thyroid hormone assay - potential problems Protein-tracer interactions e.g. immunoglobulins (IgG) Dilution effects and protein dependence Substances competing with T4 for binding to binding proteins or IgGs e.g. fatty acids As a result the TSH assay is more robust in many clinical situations (though more expensive) Population screening?

8. Non-thyroid illness aka ‘Sick euthyroid syndrome’

9. Drugs and the thyroid gland

10. Clinical implications of non- thyroid illness

11. Amiodarone and the thyroid Effects: –Source of iodine –Thyroid cytotoxic –Inhibitor of type 1 and 2 deiodinases –Antagonise thyroid hormone action Clinically, may cause hypo- or hyper- thyroidism

12. (‘Non-autoimmune’) Thyroiditis Includes - sporadic (silent); subacute (DeQuervain’s); post-partum; fibrous (Riedel’s) Genetic, clinical, histopathological differences Clinical course of transient thyrotoxicosis, hypothyroidism and then recovery Investigations show - elevated serum thyroid hormones, suppressed TSH, reduced 99m Tc uptake and elevated Tg + elevated ESR Treatment

13. Subclinical hyperthyroidism

14. TSH assays Limits of detection –First generation -1.0mU/l –Second generation -0.1mU/l –Third generation - 0.01mU/l –Fourth generation -0.001mU/l Normal range - 0.4-4mU/l

15. Definition ‘Sustained thyrotrophin concentration <0.01mU/l with normal concentrations of free thyroxine and tri-iodothyronine in the absence of hypothalamo- pituitary dysfunction or non-thyroidal illness’

16. Prevalence Large scale community studies - 2-16% Increases with: age, being female and nodular thyroid disease Most common cause - thyroid hormone replacement (~20-40%) In those not due to thyroid hormone treatment, progression to clinical hyperthyroidism is infrequent

17. Effects Lancet 2001, 358:861

18. Circulatory disease

19. Atrial fibrillation Original Framingham cohort of 2007. Age >60 Excluded those taking thyroxine or treated thyroid disease TSH assay - Low (<0.1mU/l), ‘Slightly low’ (0.1-0.4mU/l), Normal (0.4-5mU/l), High (>5mU/l)

20. Atrial fibrillation

21. Implications Assuming that treatment prevents AF, 4.2 cases would need to be treated to prevent 1 case of AF. Note: –there is only limited evidence that AF reverts spontaneously or after DCC once the TSH has been normalised –ranges of embolism in thyrotoxic AF - ‘negligible’ to 40% (mean 10-15%) - is the risk the same? –no (clinical trial) evidence for efficacy of warfarin

22. Bone density Clinical hyperthyroidism is known factor in osteoporosis Effects of subclinical hyperthyroidism are uncertain Needs longitudinal study J Clin Endocrinol Metab 1996, 81:4278

23. Subclinical hypothyroidism

24. Definition ‘Sustained thyrotrophin concentration >4 mU/l with normal concentrations of free thyroxine and tri-iodothyronine in the absence of symptoms and signs of hypothyroidism’

25. Prevalence Large scale community studies - 5-10% Increases with: age, being female and in areas of higher iodine intake Causes as for clinical hypothyroidism Progression to clinical hyperthyroidism is high (~5% per annum)

26. Causes of hypothyroidism

27. Implications NB - Cross-sectional study - Previous smaller studies had failed to show an effect

28. Treatment BMJ 2001,323: 891 Treatment in subclinical hypothyroidism: –reduces goitre by ~80% –improves memory and wellbeing –reduces total and HDL cholesterol slightly

29. ‘Hot topic’ Lancet 2001, 2034

30. Background Thyroid diseases are more common in females and may be exacerbated by pregnancy Are these auto-immune or allo-immune i.e. graft-versus-host? In women with scleroderma there is an increase in male cells in the skin (presumably from fetal transfer) Is there a similar increase in male cells in the thyroid glands of women with thyroid disease?

31. Methods Archival thyroid gland pathological paraffin sections 29 patients; controls from 8 necropsies FISH - X - red signal; Y - green signal

33. Results Cells with both X and Y seen in 16 of 29 thyroid patients but none of controls 12 of 20 (63%) patients with at least one male child had male cells in the thyroid

34. Origin of male cells in female thyroid Male stem cells from fetal-maternal transfusion during pregnancy, labour, delivery. Male stem cells from a twin gestation, organ transplant or blood transfusion Artefact