1. Thyroid hormones in health and disease Dr S Razvi Endocrinologist and Senior Lecturer 1 st October 2013

2. Agenda Physiology Clinical data and evidence Some real life cases – interactive Summary

3. TRH Hypothalamus Pituitary TSH Thyroid Gland T4T4 T3T3 Hypothalamic-Pituitary-Thyroid Axis Clinical Utility TSH reflects tissue thyroid hormone actions TSH for diagnosis of hypothyroidism and thyrotoxicosis TSH as an index of therapeutic success and potential toxicity Adapted from Merck Manual of Medical Information. ed. R Berkow. 704:1997. T 4  T 3 Liver, Muscle T4T4 T3T3

4. Reference ranges

5. 2.5 th 0.4 mU/L 97.5 th 4.0 mU/L Individual vs population reference range (e.g., serum TSH) AB

7. Factors affecting thyroid function (TSH) Age Gender Smoking Iodine status Illness Pregnancy

8. Surks & Hollowell, 2007 Age group (yrs)Median97.5 th centile 20 – 301.263.56 > 801.907.49 Effect of age

9. Clinical consequences of raised or low TSH

11. Raised TSH Cholesterol increases with TSH Associated with heart disease in younger (<65/70 yr olds) Higher risk of progression to overt hypothyroidism (particularly if TPO +ve) Associated with heart failure

12. Leiden 85+ study Gussekloo et al, JAMA 2004

13. Clinical consequences of raised or low TSH

15. Low TSH Associated with atrial fibrillation Osteoporosis Higher cardiovascular mortality (only if TSH undetectable <0.1 mU/L) Dementia

16. Pregnancy

17. Every thing changes......

18. 5% 19% 0510152025 Consequences of Mild Hypothyroidism Fetal Brain Development Children of women with untreated hypothyroidism during pregnancy: –Averaged 7 points lower on IQ testing* –Had a significant percentage (19%) of IQ  85 IQ Scores of  85 Control Children Children of Mothers with Untreated Hypothyroidism (P<0.005) *Full-scale Wechsler Intelligence Scale for Children. Haddow JE, et al. N Engl J Med. 1999;341:549-555.

19. Guidelines for raised TSH If TSH > 10 consistently then treat. For consistently raised TSH in younger people (70 – 75 yrs) with symptoms – a trial of treatment is recommended for 3 – 6 months. For consistently raised TSH in older people (> 75 yrs) – wait and watch policy. Pregnancy: should be treated with aim for low normal TSH

20. Guidelines for low TSH If TSH consistently < 0.1 (suppressed) AND if other risk factors (AF, osteoporosis) or symptoms – treat. If TSH mildly low and asymptomatic - wait and watch policy. In pregancy, low TSH is of no consequece (normal in 1 st trimester).

21. Case 1 45 year old woman Seen by GP for tiredness Examination and all other Ix normal TSH 6.6 mIU/L (0.4 – 4.0) FT4 15.6 pmol/L (9 – 22) TPO positive What is the diagnosis? Is treatment beneficial?

22. Case 2 86 yr old man with forgetfulness TSH 7.4 mU/L FT4 15.4 pmol/L Treat?

23. Case 3 34 yr old lady trying to conceive TSH 5.4 mU/L FT4 12 pmol/L Treat?

24. Case 4 32 yr old lady with weight loss, palpitations and tremor. TSH<0.01 mU/L, FT4 42 pmol/L Next step?

25. Case 4 cont Tc uptake thyroid scan – 0% uptake TSH receptor and TPO antibody – negative Diagnosis? Thyroiditis TSH 3.5 mU/L four months later.

26. Case 5 20 yr old lady 8/40 pregnant. On LT4 100 mcg/day What would you do next? Check TFTs Possibly increase LT4 to 125 mcg/day Refer her to antenatal endocrine clinic

27. Case 6 68 yr old woman presents with Next step? TFT, TPO Refer to endocrinology / ENT USS +/- FNA (3-5% cancer)

28. Case 7 34 yr old man on LT4 (150 mcg/day) after thyroidectomy for Graves’ disease TSH 13.5 mU/L FT4 12.6 pmol/L Next step? Intermittent compliance (mainly)

29. Excessive Thyroxine Therapy Inadequate Thyroxine Therapy 30% 20% 10% Ross, 1990 Parle, 1993 Canaris, 2000 Hollowell, 2002 27% 21% 14% 18% 22% 15% 18% 10% 20% 30% Ross DS, et al. JCEM. 1990;71:764-769. Parle JV, et al. Br J Gen Pract. 1993;43:107-109. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Hollowell J, et al. JCEM. 2002;87:489-499. How Common Is Suboptimal Thyroxine Therapy? 32% 48% 40% 33%

30. Conditions and medications affecting thyroid function (including those on LT4) Iron Calcium PPI Coeliac disease Pernicious anaemia Amiodarone Lithium Consider taking LT4 at a different time prior to increasing the dose Different formulations may have varying strengths

31. Take home messages Thyroid function is affected by multiple processes. Slightly high TSH in elderly may not have an adverse impact. In pregnancy, high TSH should always be treated. Overt hyperthyroidism should always be referred to endocrinologists for further assessment. Thyroid nodules need specialist assessment with USS and ?FNA

32. Thank you!