1. Subclinical thyroid disorders: still a matter of controversy Simon HS Pearce

2. • Background • Subclinical hypothyroidism -Vascular risk • Subclinical hyperthyroidism -Understand the pathophysiology -Approach to Management Plan

3. What is normal? • 16 healthy individuals, having monthly TFTs for 1 year • People stick to their own “reference” interval • Extrapolating to Free T4 values -setpoint +/- ~2.5 pmol/l • “My normal range is different from yours” Andersen et al. JCEM 2002

4. TSH in centenarians and offspring Δ 232 Ashkenazim, age 97 o 366 of offspring, age 69  177 age-matched controls Atzmon et al. JCEM 2009

5. Lancet 1971; I: 203

6. Possible mechanisms • Dyslipidaemia • Cardiac systolic & diastolic dysfunction • Hypertension • Endothelial dysfunction • Hypercoagulability

7. Hard outcomes • Rotterdam Heart Study • Community-based cross sectional survey • 1149 women (mean age 69 +/-7 yrs) • 10.8% had “subclinical hypothyroidism” (TSH>4.0, N FT4) • Odds ratio for MI= 2.3 (CI; 1.3-4.0) • OR for aortic atherosclerosis 1.7 (1.1-2.6) • Population attributable risk of TSH to MI estimated to be 14% • N.B. Diabetes 14%, Smoking 15% Hak et al. Ann Intern Med 2000;132: 270

8. Meta-summary of meta-analyses • Relative risks (5-95% confidence intervals)

9. Meta-summary of meta-analyses • Relative risks (5-95% confidence intervals)

10. All cause mortality in SCH M Thvilum, F Brandt, TH Brix & L Hegedüs. Nat Rev Endocrinol 2012

11. Janus response: Age •Thanks to Stefano Mariotti & David Cooper

12. Meta-analysis • Performed by Salman Razvi/ Abdul Shakoor • Longitudinal or cross sectional studies of independent community-based subjects • 14 studies fitted stringent criteria • 2,531 SCH participants • 26,491 euthyroid individuals • Divided studies according to age of inclusion • <65 yr vs 65 and above: median 60 & 74 yr

13. IHD prevalence in cross-sectional studies of SCH & euthyroid controls Younger Older

14. IHD incidence in longitudinal studies of SCH & euthyroid controls Younger Older

15. Cardiovascular mortality in longitudinal studies of SCH & euthyroid controls Younger Older

16. Summary • Prevalent and incident IHD, and IHD mortality is increased in SCH compared to euthyroid population • Evidence of increased IHD confined to studies that have included people aged less than 65 years Razvi et al. JCEM 2008

17. Patient-level analysis • 55,287 participants; 3,450 with SCH (6.2%) • Information derived from 11 studies • 9664 deaths; 2168 from CHD • SCH defined as TSH 4.5-19.99 mU/l (N FT4) Rodondi et al. JAMA 2010

18. Patient-level analysis: TSH

19. Patient-level analysis: TSH

20. Patient-level analysis: Age

21. Interim Summary • Meta-analysis with many thousands of patient events shows vascular death is associated with SCH • Effect is greater at higher TSH levels, reaching significance at TSH of 7.0 mU and above • Effect is attenuated at older ages

22. UK General Practice Research Database • Primary care resource linking ~10 million patient records, labs, prescriptions & death certificates • During 2001 there were 322,291 TSH measurements • Identified 4,735 people >40 yrs with TSH 5.0- 10.0 mU/l, normal FT4 • Excluded individuals on L-T4, ATDs, previous thyroid disease, previous IHD, stroke, other vascular disease Razvi S et al. Arch Intern Med 2012

23. UK General Practice Research Database • Participants followed until March 2008 (median 7.6 yrs) • People aged 40- 70 yrs (n=3093) and >70 yrs (n=1642) • 52.9% and 49.9% were treated with L-thyroxine during follow up (Primary Care decision) • Analysed outcomes for incident IHD, vascular and all cause mortality over follow up period (Cox regression MVA)

24. L-Thyroxine treated group • 94% of people continued to take L-T4 • Median dose 75μg (12.5-175 μg) daily

25. Untreated group • 1.3% developed overt hypothyroidism -(TSH >10, or  FT4) • 58% remained with elevated TSH • 38% reverted to euthyroidism • 2.5% developed low TSH

26. Baseline characteristics

27. Fatal & non-fatal vascular events 40-70 yrs HR 0.61 (0.39- 0.95); p=0.02

28. All cause mortality40-70 yrs HR= 0.36 (0.19 – 0.66) ; p<0.001

29. Fatal & non-fatal IHD events >70 yrs HR 0.99 (0.59- 1.33); p=0.56

30. All cause mortality>70 yrs HR= 0.71 (0.56 – 1.08) ; p=0.11

31. Event rate stratified by age • LT4 vs untreated; Fatal + non fatal CV events

32. Degree of serum TSH elevation • Median serum TSH 6.6 mU/l • Reference group (HR=1) is untreated patients Razvi et al. Arch Intern Med; 2012

33. Atrialfibrillation

34. Summary • L-T4 treatment of SCH was associated with a lower CV mortality and CV event rate in patients <70 yrs • Importantly, L-T4 treatment was not associated with AF • Not an RCT study, but represents outcome of real-life practice Razvi et al. Arch Intern Med 2012

35. Who should we treat? • Pregnant patients, or planning pregnancy • Patients with serum TSH > 10.0 mU/l

36. Who should we consider treating? • Symptoms or signs of hypothyroidism • Age less than 70 yrs • TSH >7.0 mU/l • Goitre • High vascular risk including • Ischaemic heart disease • Diabetes • Dyslipidaemia

37. • 380 attendees at ITC 2010 • Electronic voting system • Female, serum TSH 6.8 Pearce, Wemeau, Vaisman. Eur Thyroid J 2012

38. Subclinical hyperthyroidism

39. What is normal in extreme old age? • Age-related decline in median TSH levels (ill people excluded) Mariotti et al. JCEM 1993

40. What is normal in extreme old age? • Age related decline in T3 levels (ill people excluded) • FT4 (and TT4) levels remain constant Mariotti et al. JCEM 1993

41. Magri et al. 2002

42. Change to function of HPT axis • Reduced hepatic thyroid hormone clearance -glucuronidation, sulfation • Reduced T4 to T3 conversion • Reduced type 1 deiodinase activity • Blunted diurnal TSH secretion • Flattened TSH response to TRH

43. Subclinical Hyperthyroidism

44. Degrees of hyperthyroidism

45. Degrees of hyperthyroidism 12 months follow up 76% returned to normal 87% remained <0.1 Parle JV et al. 1991 Clin Endo

46. Prevalence Both grades • 1-3% of elderly subjects in NHANESIII • 2.1 % in Colorado Health Fair study Suppressed TSH • ~0.7% of TFTs from people not on T4 at RVI NHANES III

47. Evidence Should we be concerned about subclinical hyperthyroidism?

48. Small risk of progressionto overt disease • Parle et al. 1991 TSH <0.1 2%/ year • Wiersinga et al. 1995 5%/ year • Pirich et al. 2000 TSH <0.1 7%/ year • Schouten et al. 2011 5-8%/ year • Rosario et al. 2010 TSH 0.1-0.4 1% /year

49. AF in Framingham survey TSH (mU/l) <0.1 0.1- 0.4 >5.0 0.4- 5.0 Sawin et al. NEJM; 1994

50. Cardiovascular Health Study • 3233 US community dwelling individuals over 65, mean age 73 • AF rate 2.0 (CI 1.3-3.0) in Sub Hyper Cappola et al. JAMA 2006